pyrimidinones and dabrafenib

The 3rd class of BRAF (B-Raf Proto-Oncogene, Serine/Threonine Kinase) variants including G466, D594, and A581 mutations cause kinase death or impaired kinase activity. It is unlikely that RAF (Raf Proto-Oncogene, Serine/Threonine Kinase) inhibitors suppress ERK (Extracellular Signal-Regulated Kinase) signaling in class 3 mutant-driven tumors due to the fact that they preferentially inhibit activated BRAF V600 mutants. However, there are suggestions that class 3 mutations are still associated with enhanced RAS/MAPK (RAS Proto-Oncogene, GTPase/Mitogen-Activated Protein Kinase) activation, potentially due to other mechanisms such as the activation of growth factor signaling or concurrent MAPK pathway mutations, e.g., RAS or NF1 (Neurofibromin 1). A 75-year-old male patient with squamous-cell cancer (SqCC) of the lung and with metastases to the kidney and mediastinal lymph nodes received chemoimmunotherapy (expression of Programmed Cell Death 1 Ligand 1 (PD-L1) on 2% of tumor cells). The chemotherapy was limited due to the accompanying myelodysplastic syndrome (MDS), and pembrolizumab monotherapy was continued for up to seven cycles. At the time of progression, next-generation sequencing was performed and a c.1781A>G (p.Asp594Gly) mutation in the BRAF gene, a c.1381C>T (p.Arg461Ter) mutation in the NF1 gene, and a c.37C>T (p.Gln13Ter) mutation in the FANCC gene were identified. Combined therapy with BRAF (dabrafenib) and MEK (trametinib) inhibitors was used, which resulted in the achievement of partial remission of the primary lesion and lung nodules and the stabilization of metastatic lesions in the kidney and bones. The therapy was discontinued after five months due to myelosuppression associated with MDS. The molecular background was decisive for the patient’s fate. NSCLC patients with non-V600 mutations in the BRAF gene rarely respond to anti-BRAF and anti-MEK therapy. The achieved effectiveness of the treatment could be related to a mutation in the NF1 tumor suppressor gene. The loss of NF1 function causes the excessive activation of KRAS and overactivity of the signaling pathway containing BRAF and MEK, which were the targets of the therapy. Moreover, the mutation in the FANCC gene was probably related to MDS development. The NGS technique was crucial for the qualification to treatment and the prediction of the NSCLC course in our patient. The mutations in two genes—the BRAF oncogene and the NF1 tumor suppressor gene—were the reason for the use of dabra

Topics: Aged; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Extracellular Signal-Regulated MAP Kinases; Genes, Neurofibromatosis 1; Humans; Lung Neoplasms; Male; Mutation; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Serine

Thyroid cancer is the most common malignancy of the endocrine system, accounting for ~ 5% of all thyroid nodules and 1% of all systemic malignancies.. We treated a 73-year-old man with metastatic. The mechanisms of lung disease after the combined treatment with dabrafenib and trametinib are unclear. We hypothesized that dual-targeted therapy with a BRAF inhibitor, dabrafenib, and a MEK inhibitor, trametinib, might prevent the regeneration and proliferation of fibrotic epithelium in lung disease by blocking downstream proliferative signals.

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Humans; Imidazoles; Lung Diseases, Interstitial; Male; Mitogen-Activated Protein Kinase Kinases; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Thyroid Neoplasms

The present study clarified the sensitivity of the BRAF tyrosine kinase inhibitor mechanism in patients with BRAF compound mutation and predicted the sensitivity using molecular dynamics simulation.. We examined 16 BRAF tumors with p.V600E-positive non-small-cell lung cancer.. One patient (6.2%) had a BRAF p.V600E and p.K601_W604 compound mutation with a good clinical response to dabrafenib and trametinib. Molecular dynamics simulation also complemented the effect.. The combination of a genetic analysis and computational simulation model may help predict the sensitivity for dabrafenib in cases with a rare BRAF compound mutation. The construction of a genomic and simulation fused database is important for the development of personalized medicine in this field.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Humans; Imidazoles; Lung Neoplasms; Mutation; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

Anaplastic thyroid carcinoma (ATC) is a highly aggressive, undifferentiated rare tumor. Median overall survival is usually between 8 and10 months, with a 1-year survival rate of 20%. Conventional anthracycline based chemotherapy regimens demonstrate low response rates with short duration. Novel therapeutic agents including BRAF and MEK inhibitors based on the molecular landscape of ATC have been investigated.. We herein report the rechallenge of a 52-year-old ATC patient with BRAF V600E mutation with dabrafenib plus trametinib. She presented with recurrent and progressive disease despite surgery, radiation therapy, 3 different chemotherapy regimens, and combination of dabrafenib-trametinib in different settings. She was rechallenged with dabrafenib-trametinib, and had a good response.. To our knowledge, this is the first ATC case who responded to dabrafenib-trametinib rechallenge, reported in the literature. We want to emphasize that combination of dabrafenib and trametinib might be a good choice for resistant locoregional and metastatic ATC patients with BRAF V600E mutation, particularly in whom rapid clinical response is urgently needed. Moreover, rechallenge with this combination should be kept in mind in selected cases.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Imidazoles; Middle Aged; Neoplasm Recurrence, Local; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms; Treatment Outcome

Immune checkpoint inhibitors and targeted therapies are approved for adjuvant treatment of patients with resected melanoma; however, they have not been compared in randomized controlled trials (RCTs). We compared the efficacy and safety of adjuvant nivolumab with other approved treatments using available evidence from RCTs in a Bayesian network meta-analysis (NMA).. A systematic literature review was conducted through May 2019 to identify relevant RCTs evaluating approved adjuvant treatments. Outcomes of interest included recurrence-free survival (RFS)/disease-free survival (DFS), distant metastasis-free survival (DMFS), all-cause grade 3/4 adverse events (AEs), discontinuations, and discontinuations due to AEs. Time-to-event outcomes (RFS/DFS and DMFS) were analyzed both assuming that hazard ratios (HRs) are constant over time and that they vary.. Of 26 identified RCTs, 19 were included in the NMA following a feasibility assessment. Based on HRs for RFS/DFS, the risk of recurrence with nivolumab was similar to that of pembrolizumab and lower than that of ipilimumab 3 mg/kg, ipilimumab 10 mg/kg, or interferon. Risk of recurrence with nivolumab was similar to that of dabrafenib plus trametinib at 12 months, however, was lower beyond 12 months (HR [95% credible interval] at 24 months, 0.46 [0.27-0.78]; at 36 months, 0.28 [0.14-0.59]). Based on HRs for DMFS, the risk of developing distant metastases was lower with nivolumab than with ipilimumab 10 mg/kg or interferon and was similar to dabrafenib plus trametinib.. Adjuvant therapy with nivolumab provides an effective treatment option with a promising risk-benefit profile.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bayes Theorem; Disease-Free Survival; Humans; Imidazoles; Ipilimumab; Melanoma; Nivolumab; Oximes; Patient Safety; Pyridones; Pyrimidinones

Epithelioid glioblastoma multiforme (eGBM) is a rare and aggressive variant of glioblastoma multiforme (GBM) that predominantly affects younger patients and can be difficult to distinguish from other gliomas. Data on how patients with eGBM might be best treated are limited, although genomic analyses have shown that almost half of tumours harbour activating BRAF gene mutations. Here we present the case of a young female with BRAF V600E-mutant eGBM who had a prolonged response to targeted therapy with the BRAF and MEK1/2 inhibitors dabrafenib and trametinib. We review current knowledge about eGBM, including the emerging role for BRAF- ± MEK1/2- targeted therapy.

Topics: Antineoplastic Agents; Brain Neoplasms; Fatal Outcome; Female; Glioblastoma; Humans; Imidazoles; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Spinal Cord Neoplasms; Young Adult

as adjuvant therapy for high-risk melanoma was extensively studied in regimens that varied by dosage, route of administration, formulation, and therapy duration. The high-dose regimen (HDI) showed significant improvements in relapse-free survival (RFS) in 3 trials and overall survival (OS) in 2. Ipilimumab at 3 mg/kg demonstrated significant OS benefits compared with HDI and less toxicity compared with ipilimumab at 10 mg/kg. More recently, the standard of care has changed in favor of nivolumab and pembrolizumab and BRAF-MEK inhibitors dabrafenib plus trametinib (for BRAF mutated melanoma), based on significant RFS benefits and more favorable toxicity profiles.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Chemotherapy, Adjuvant; Clinical Trials as Topic; Combined Modality Therapy; Humans; Imidazoles; Immunotherapy; Interferon-alpha; Ipilimumab; Lymph Node Excision; Melanoma; Nivolumab; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Radiotherapy, Adjuvant; Skin Neoplasms

Major therapeutic advances have been made recently in the treatment of metastatic melanoma, due to the development of targeted therapies, namely BRAF and MEK inhibitors, in patients with BRAF V600 mutation. Combinations of vemurafenib+cobimetinib, dabrafenib+trametinib, et encorafenib+binimetinib, evaluated in coBRIM, COMBI-d/COMBI-v and COLUMBUS trials respectively have been approved in this indication. Toxicities induced by combination therapies are different from those reported with monotherapies, in terms of frequency and intensity. Physicians who treat melanoma patients thus face news issues relating to prevention, detection and treatment of these adverse events. This paper summarizes tolerance data from the three pivotal trials (coBRIM, COMBI-v and COLUMBUS) and issues recommendations for the specific management of main toxicities, based on experts' opinion. We discuss dermatological, ophthalmological, cardiovascular, digestive, musculoskeletal, renal and general toxicities and propose a timetable for examinations to be performed before and during treatment.

Topics: Antineoplastic Combined Chemotherapy Protocols; Azetidines; Benzimidazoles; Carbamates; Drug Combinations; Humans; Imidazoles; Melanoma; Mitogen-Activated Protein Kinase Kinases; Mutation; Oximes; Piperidines; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Sulfonamides; Vemurafenib

The current systematic review aimed to evaluate and compare the efficacy and safety of dabrafenib-trametinib with those of other therapeutic alternatives in the treatment of patients with unresectable advanced/metastatic melanoma with BRAF-V600 mutation. The search was carried out on four databases up to July 2018. Two separate network meta-analyses (NMA) were performed using the frequentist method (random effects): one with an exclusive population with BRAF-V600 mutation (NMA-pBRAFV600) and another with mixed population (with or without the mutation: NMA-pMixed). An evidence profile was included using the GRADE method for NMA. The validity of the final estimator in the NMA-pMixed was assessed via a sensitivity analysis. Nine clinical trials were included in the NMA-pBRAFV600. Dabrafenib-trametinib was found to have a favorable effect on overall survival (OS) and progression-free survival (PFS) compared with dabrafenib, vemurafenib, and dacarbazine and on partial response rate (PRR) and overall response rate compared with dacarbazine and vemurafenib. In the NMA-pMixed, dabrafenib-trametinib was found to have a positive effect on OS versus ipilimumab 3 mg/kg and on PFS and PRR versus ipilimumab, nivolumab, and pembrolizumab. However, dabrafenib-trametinib and vemurafenib-cobimetinib significantly differed in terms of efficacy. In addition, dabrafenib-trametinib has a favorable effect on Grades 3 and 4 adverse events.

Topics: Antineoplastic Combined Chemotherapy Protocols; Humans; Imidazoles; Melanoma; Mutation; Network Meta-Analysis; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms

Although a myriad of novel treatments entered the treatment paradigm for advanced melanoma, there is lack of head-to-head evidence. We conducted a network meta-analysis (NMA) to estimate each treatment's relative effectiveness and safety.. A systematic literature review (SLR) was conducted in Embase, MEDLINE and Cochrane to identify all phase III randomised controlled trials (RCTs) with a time frame from January 1, 2010 to March 11, 2019. We retrieved evidence on treatment-related grade III/IV adverse events, progression-free survival (PFS) and overall survival (OS). Evidence was synthesised using a Bayesian fixed-effect NMA. Reference treatment was dacarbazine. In accordance with RCTs, dacarbazine was pooled with temozolomide, paclitaxel and paclitaxel plus carboplatin. To increase homogeneity of the study populations, RCTs were only included if patients were not previously treated with novel treatments.. The SLR identified 28 phase III RCTs involving 14,376 patients. Nineteen and seventeen treatments were included in the effectiveness and safety NMA, respectively. For PFS, dabrafenib plus trametinib (hazard ratio [HR] PFS: 0.21) and vemurafenib plus cobimetinib (HR PFS: 0.22) were identified as most favourable treatments. Both had, however, less favourable safety profiles. Five other treatments closely followed (dabrafenib [HR PFS: 0.30], nivolumab plus ipilimumab [HR PFS: 0.34], vemurafenib [HR PFS: 0.38], nivolumab [HR PFS: 0.42] and pembrolizumab [HR PFS: 0.46]). In contrast, for OS, nivolumab plus ipilimumab (HR OS: 0.39), nivolumab (HR OS: 0.46) and pembrolizumab (HR OS: 0.50) were more favourable than dabrafenib plus trametinib (HR OS: 0.55) and vemurafenib plus cobimetinib (HR OS: 0.57).. Our NMA identified the most effective treatment options for advanced melanoma and provided valuable insights into each novel treatment's relative effectiveness and safety. This information may facilitate evidence-based decision-making and may support the optimisation of treatment and outcomes in everyday clinical practice.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Azetidines; Benzimidazoles; Cancer Vaccines; Carboplatin; Dacarbazine; gp100 Melanoma Antigen; Humans; Hydrazines; Imidazoles; Interleukin-2; Ipilimumab; Lenalidomide; Melanoma; Network Meta-Analysis; Nitrosourea Compounds; Nivolumab; Organophosphorus Compounds; Oximes; Paclitaxel; Piperidines; Progression-Free Survival; Proportional Hazards Models; Pyridones; Pyrimidinones; Skin Neoplasms; Sorafenib; Survival Rate; Temozolomide; Treatment Outcome; Vemurafenib

Topics: Adult; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Bayes Theorem; Combined Modality Therapy; Disease-Free Survival; Female; Humans; Imidazoles; Interferons; Ipilimumab; Male; Melanoma; Middle Aged; Neoplasm Recurrence, Local; Network Meta-Analysis; Nivolumab; Oximes; Pyridones; Pyrimidinones; Randomized Controlled Trials as Topic; Skin Neoplasms; Treatment Outcome; Vemurafenib

The spectrum of treatment options for patients with metastatic BRAF-mutated melanoma is broad, spanning multiple treatment classes. However, there is a lack of head-to-head evidence comparing targeted and immunotherapies. The purpose of this study is to conduct a network meta-analysis (NMA) in previously untreated, BRAF-mutated melanoma patients and estimate the relative efficacy of systemic therapies for this patient population at the treatment level.. The literature review included searches of MEDLINE, EMBASE, and the Cochrane Central Registry of Controlled Trials (CENTRAL) to November 2018. Randomized controlled trials of previously untreated patients with advanced melanoma were eligible if at least one intervention was either a targeted or immune therapy. Relative treatment effects were estimated by fixed effect Bayesian NMAs on progression-free survival (PFS) and overall survival (OS), based on the hazard ratio.. Combination dabrafenib with trametinib (HR 0.22 [95% CrI 0.17, 0.28] vs dacarbazine) and combination vemurafenib with cobimetinib (HR 0.22 [95% CrI 0.17, 0.29] vs dacarbazine) were likely to rank as the most favorable treatment options for PFS, while combination nivolumab with ipilimumab was likely to be the most efficacious in terms of OS (HR 0.33 [0.24, 0.47] vs dacarbazine).. The findings highlight the efficacy of combination PD-1 with CTLA-4 inhibitors and combination BRAF with MEK inhibitors in the treatment of advanced melanoma. However, as few trials informed each treatment comparison, research is needed to further refine our understanding of this complex and rapidly evolving treatment landscape.

Topics: Antineoplastic Combined Chemotherapy Protocols; Azetidines; Dacarbazine; Humans; Imidazoles; Melanoma; Molecular Targeted Therapy; Mutation; Oximes; Piperidines; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Randomized Controlled Trials as Topic; Vemurafenib

Since the first documented lymph node dissection in 1892, many trials have investigated the potential effect of this surgical procedure on survival in patients with melanoma. Two randomised controlled trials were unable to demonstrate improved survival with completion lymph node dissection versus nodal observation in patients with sentinel node-positive disease, although patients with larger sentinel node metastases (>1 mm) might benefit more from observation than from dissection, and could potentially be considered for adjuvant systemic therapy instead of complete dissection. Adjuvant immunotherapy with high-dose ipilimumab has led to improvements in overall survival, whereas therapy with nivolumab and pembrolizumab has improved relapse-free survival with greater safety. Furthermore, adjuvant-targeted therapy with dabrafenib and trametinib has improved survival outcomes in BRAF

Topics: Chemotherapy, Adjuvant; Disease-Free Survival; Humans; Imidazoles; Ipilimumab; Lymph Node Excision; Lymph Nodes; Melanoma; Neoplasm Staging; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

Disseminated intravascular coagulation is a complex and potentially lethal complication of malignancy, in which the fundamental abnormality is excessive activation of the coagulation system. It is a rare complication of melanoma which can be difficult to diagnose in some circumstances, leading to delay in treatment. Herein, we describe the first case of disseminated intravascular coagulation occurring in BRAF and NRAS-mutant metastatic melanoma, and systematically review the literature regarding disseminated intravascular coagulation in melanoma. This review summarizes the reported cases of disseminated intravascular coagulation in melanoma and those secondary to the novel treatment of melanoma, and explores the pathophysiology of disseminated intravascular coagulation in melanoma, highlighting the key role of expression of markers of coagulation and fibrinolysis in disseminated intravascular coagulation, as well as more widely in melanoma. Current limitations in the literature are also identified and discussed, particularly with respect to improving the management of this lethal complication. Disseminated intravascular coagulation is a rare complication of melanoma that typically portends poor prognosis.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Blood Coagulation; Disseminated Intravascular Coagulation; Female; Fibrinolysis; GTP Phosphohydrolases; Humans; Imidazoles; Melanoma; Membrane Proteins; Mutation; Neoplasm Metastasis; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Treatment Outcome

The introduction of BRAF and MEK inhibitors into clinical practice improved the prognosis of metastatic melanoma patients. The combination of BRAF inhibitor dabrafenib with MEK inhibitor trametinib has shown its superiority to single agent therapy and is characterized by a tolerable spectrum of adverse events which shows a decrease in incidence over time on treatment. Areas covered: The current scientific literature on safety and adverse events (AEs) related to BRAF and MEK-inhibition has been investigated with special focus on the large phase 3 studies (COMBI-v, COMBI-d and CoBRIM) as well as recent updates presented at oncology and melanoma meetings. Additionally, published case series/case reports were screened for information on AEs. Expert opinion: Even though almost every patient (98%) under combination therapy with dabrafenib and trametinib experiences at least one adverse event, these are generally mild to moderate, reversible and can be managed with dose reductions or interruptions. However, due to an increased life expectancy, there is a substantial need to prevent and treat also mild adverse events, as they play a central role for the quality of life of patients. Ongoing clinical trials will have to demonstrate the efficacy as well as safety of triple combination with anti-PD-1/anti-PD-L1 antibodies.

Topics: Antineoplastic Combined Chemotherapy Protocols; Dose-Response Relationship, Drug; Humans; Imidazoles; Melanoma; Oximes; Prognosis; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Quality of Life; Skin Neoplasms

Topics: Clinical Trials, Phase III as Topic; Humans; Imidazoles; Immunotherapy; Lymphatic Metastasis; Melanoma; Neoplasm Staging; Oximes; Progression-Free Survival; Pyridones; Pyrimidinones; Sentinel Lymph Node

The case is presented of a 39-year-old woman with metastatic melanoma treated with dabrafenib and trametinib. She presented with a severe acute panuveitis with granulomatous anterior uveitis, vitritis, and multiple serous retinal detachments. Dabrafenib and trametinib were suspended, and treatment with a systemic and topical corticosteroid was started. A good response was obtained, with a recovery of visual acuity of 1.0 in both eyes within two weeks.. Dabrafenib and trametinib can lead to severe uveitis. Treatment with corticosteroids and discontinuation of therapy with dabrafenib and trametinib led to an anatomical and functional improvement, and resolved the episode rapidly. Ophthalmologists must be aware of this toxicity, given the increasing use of those drugs.

Topics: Adrenal Cortex Hormones; Adult; Antineoplastic Combined Chemotherapy Protocols; Azetidines; Drug Synergism; Fatal Outcome; Female; Humans; Imidazoles; MAP Kinase Kinase Kinases; Melanoma; Neoplasm Proteins; Oximes; Panuveitis; Piperidines; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Retinal Detachment; Vemurafenib

Topics: Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Humans; Imidazoles; Lung Neoplasms; Mutation; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

Tremendous progress has been made in the clinical landscape of advanced-stage. Targeted therapy with BRAF plus MEK inhibitors has become the standard of care for patients with advanced-stage

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Azetidines; Benzimidazoles; Carbamates; Fever; Humans; Imidazoles; Indoles; Melanoma; Mitogen-Activated Protein Kinase Kinases; Oximes; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Diseases; Sulfonamides; Vemurafenib

Major advances have been made in melanoma treatment with the use of molecularly targeted therapies and immunotherapies, and numerous regimens are now approved by the US Food and Drug Administration for patients with stage IV disease. However, therapeutic resistance remains an issue to both classes of agents, and reliable biomarkers of therapeutic response and resistance are lacking. Mechanistic insights are being gained through preclinical studies and translational research, offering potential strategies to enhance responses and survival in treated patients. A comprehensive understanding of the immune effects of common mutations at play in melanoma is critical, as is an appreciation of the molecular mechanisms contributing to therapeutic resistance to immunotherapy. These mechanisms and the interplay between them are discussed herein. Cancer 2017;123:2130-42. © 2017 American Cancer Society.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; CTLA-4 Antigen; Drug Resistance, Neoplasm; GTP Phosphohydrolases; Humans; Imidazoles; Immunotherapy; Indoles; Ipilimumab; MAP Kinase Kinase 1; Melanoma; Membrane Proteins; Molecular Targeted Therapy; Mutation; Nivolumab; Oximes; Programmed Cell Death 1 Receptor; Proto-Oncogene Mas; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins p21(ras); PTEN Phosphohydrolase; Pyridones; Pyrimidinones; Skin Neoplasms; Sulfonamides; Tumor Escape; Vemurafenib; Wnt Signaling Pathway

New treatments for metastatic melanoma work through distinct mechanisms: enhancing the immune response and blocking cellular proliferation. Agents that enhance the immune response include ipilimumab, pembrolizumb, and nivolumab; agents that block cellular proliferation include vemurafenib, dabrafenib, trametinib, cobimetinib, binimetinib, and selumetinib. The translational impact of laboratory discoveries has revolutionized management of metastatic melanoma and enhanced the prognosis of affected patients.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Azetidines; Benzimidazoles; Humans; Imidazoles; Immunologic Factors; Indoles; Ipilimumab; Melanoma; Molecular Targeted Therapy; Nivolumab; Oximes; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Sulfonamides; Vemurafenib

With increases in our understanding of the human genome and immune system, the treatment armamentarium for melanoma has benefitted from the development and approval of BRAF inhibitors, MEK inhibitors, immune checkpoint modulators via cytotoxic T-lymphocyte antigen-4 blockade, and PD-1 and PD-L1 inhibitors. These advances, however, have raised questions about combination therapy, the optimal sequential use of these agents, the limited assessment of response using traditional metrics, and the optimal selection of the population to be treated. In this review we summarize recent breakthroughs and then itemize the development of newer agents, potential prognostic and predictive biomarkers, resistance mechanisms, and strategies of combination therapy. We also emphasize the multifaceted attributes of immunotherapy in terms of durable responses and longterm survival that paradoxically necessitate further research into the underlying mechanisms and longer patient follow-up.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; CTLA-4 Antigen; Drug Resistance, Neoplasm; Humans; Imidazoles; Immunotherapy; Indoles; Melanoma; Mutation; Oximes; Programmed Cell Death 1 Receptor; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Sulfonamides; Vemurafenib

About 50% of patients with meta- static or inoperable melanoma carry a tumour with BRAF V600 mutation.The drug of first choice for these patients is vemurafenib, a BRAF inhibitor, which appears to prolong survival by a few months. Dabrafenib is a vemurafenib me-too with a slightly different known profile of adverse effects. Trametinib, a MEK inhibitor, is now authorised in the European Union for use in this setting, either as monotherapy or in combination with dabrafenib (marketed by the same company). Trametinib monotherapy has not been compared to BRAF inhibitor monotherapy. In a randomised, unblinded trial versus cytotoxic drugs in 322 patients, the median survival time did not differ statistically between the groups (15.6 versus 11.3 months; p = 0.09), but 65% of patients in the chemotherapy group received trametinib after disease pro- gression, making it more difficult to detect a difference between the groups. In an unblinded randomised controlled trial in 704 patients who had never received treatment for metastatic or inoperable disease, the trametinib + dabrafenib combination prolonged median survival by about 8 months more than vemurafenib. In another double-blind randomised controlled trial in 423 patients, median survival was about 6 months longer with trametinib + dabrafenib than with placebo + dabrafenib. The trametinib+ dabrafenibcombination was poorly effective after BRAF inhibitor failure in non-comparative trials including a few dozen patients in which the only endpoint was tumour response. Trametinib has many adverse effects, some of which can be life-threatening, such as heart failure, deep vein thrombosis, bleeding (including intracranial haemorrhage), neutropenia, and gastrointestinal perforation. Trametinib also causes retinal disorders and pneumonitis. Combining trametinib with dabrafenib reduces the risk of hyperkeratosis and skin cancer associated with dabrafenib, but increases the frequency of fever (including very high fever). Trametinib interactions mainly involve additive effects or antagonism. In practice, when a patient with metastatic or inoperable BRAF V600-positive melanoma is willing to accept the significant toxicity of trametinib in the hope of gaining several extra months of life, the trametinib + dabrafenib combination is a first-line option.

Topics: Heart Failure; Hemorrhage; Humans; Imidazoles; Intestinal Perforation; Intracranial Hemorrhages; MAP Kinase Kinase 1; Melanoma; Neutropenia; Oximes; Pneumonia; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Retinal Diseases; Skin Neoplasms; Survival Rate; Venous Thrombosis

Melanoma is a malignancy of pigment-producing cells that is driven by a variety of genetic mutations and aberrations. In most cases, this leads to upregulation of the mitogen-activated protein kinase (MAPK) pathway through activating mutations of upstream mediators of the pathway including BRAF and NRAS. With the advent of effective MAPK pathway inhibitors, including the US FDA-approved BRAF inhibitors vemurafenib and dabrafenib and MEK inhibitor trametinib, molecular analysis has become an integral part of the care of patients with metastatic melanoma. In this article, the key molecular targets and strategies to inhibit these targets therapeutically are presented, and the techniques of identifying these targets, in both tissue and blood, are discussed.

Topics: DNA Mutational Analysis; GTP Phosphohydrolases; Humans; Imidazoles; Indoles; MAP Kinase Kinase 1; MAP Kinase Kinase 2; MAP Kinase Signaling System; Melanoma; Membrane Proteins; Molecular Diagnostic Techniques; Molecular Targeted Therapy; Mutation; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Sulfonamides; Vemurafenib

In the 40-50% of advanced melanoma patients with tumors harboring BRAF V600E and V600 K mutations, BRAF inhibitors such as dabrafenib are a highly effective treatment. However, most patients develop resistance after several months on treatment. The addition of a MEK inhibitor, such as trametinib, to BRAF inhibition mitigates one key pathway of resistance, further increasing response rates and improving survival.. This article summarizes the mechanism of action of the combination of dabrafenib and trametinib, its evolution through Phase I, II and III clinical trials and discusses its current use in the management of patients with advanced melanoma.. Combination therapy with dabrafenib and trametinib improves response rate, progression-free survival and overall survival when compared to dabrafenib or vemurafenib alone. The addition of trametinib to dabrafenib changes the adverse event profile, making hyperkeratosis and cutaneous squamous cell carcinomas less common but side effects such as fever and nausea more common. How dabrafenib/trametinib is best sequenced with other effective treatments such as immune checkpoint blockade remains uncertain.

Topics: Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Fever; Humans; Imidazoles; MAP Kinase Signaling System; Melanoma; Mutation; Nausea; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms

Melanoma causes the majority of skin cancer-related deaths. The outcome of melanoma depends on its stage at diagnosis. Currently, for patients with advanced melanoma, two MEK inhibitors (trametinib and cobimetinib) have been authorized by the European Medicines Agency. The main objective of this study was to compare the relative efficacy of trametinib-dabrafenib and cobimetinib-vemurafenib in patients with advanced melanoma through adjusted indirect treatment comparisons (ITCs).. A search was made up to the 3rd of November 2015. Databases consulted were MEDLINE, the Cochrane Library and the Centre for Reviews and Dissemination. Randomized controlled trials (RCTs) which compared the efficacy of trametinib-dabrafenib or cobimetinib-vemurafenib versus a common treatment comparator, in which outcomes of overall survival, progression-free survival (PFS) and overall response rate (ORR) were considered. ITCs were carried out using the method proposed by Bucher et al.. Two RCTs were included (one for each drugs combination). The results of the adjusted ITCs showed that there were no statistically significant differences between the two combinations in terms of PFS and ORR.. The ITCs indicate no difference in efficacy between both treatments. However, there should be an independent, head-to-head trial of both combinations to confirm the results.

Topics: Antineoplastic Combined Chemotherapy Protocols; Azetidines; Disease-Free Survival; Humans; Imidazoles; Indoles; Melanoma; Neoplasm Staging; Oximes; Piperidines; Pyridones; Pyrimidinones; Randomized Controlled Trials as Topic; Skin Neoplasms; Sulfonamides; Survival Rate; Treatment Outcome; Vemurafenib

The BRAF inhibitor dabrafenib (Tafinlar(®)) and the MEK inhibitor trametinib (Mekinist(®)) are indicated, as monotherapy or in combination with each other, for the treatment of patients with unresectable or metastatic melanoma with a BRAF (V600) mutation. This article reviews the therapeutic efficacy and tolerability of combination treatment with dabrafenib and trametinib in this indication and summarizes relevant pharmacological data. Dabrafenib plus trametinib significantly prolonged progression-free survival (PFS) and overall survival (OS), improved objective response rates (ORRs) and preserved health-related quality of life (HR-QOL) to a greater extent than dabrafenib (in the double-blind COMBI-d study) and vemurafenib (in the open-label COMBI-v study) in two large, randomized, phase III studies in treatment-naïve patients with unresectable or metastatic melanoma with BRAF (V600E/K) mutation. Limited treatment benefit with the combination was also seen in patients who had progressed on prior BRAF inhibitor therapy, as indicated by ORRs of ≤ 15 % and stable disease in ≤ 50 % of patients in small phase I and II studies. Combination therapy did not increase overall toxicity relative to dabrafenib or vemurafenib monotherapy, with most adverse events (AEs) mild or moderate in severity and generally manageable. Fewer skin-related AEs (e.g. cutaneous malignancies, hyperkeratinosis and hand-foot syndrome) were reported with combination therapy than with dabrafenib or vemurafenib, probably because of reduced paradoxical activation of the MAPK pathway. Thus, dabrafenib plus trametinib provides an important treatment option for patients with BRAF (V600) mutation-positive unresectable or metastatic melanoma.

Topics: Antineoplastic Agents; Humans; Imidazoles; Melanoma; Mutation; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

In the last few years, melanoma treatment has been revolutionized by the development of immune checkpoint-blocking antibodies or immune checkpoint inhibitors including ipilimumab, vemurafenib, dabrafenib, trametinib, nivolumab, and pembrolizumab. Although they have shown promising results, they also have caused multiple adverse events (AEs), particularly immune-related AEs (irAEs). Specialists should be familiar with these AEs.

Topics: Adrenal Cortex Hormones; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Chemical and Drug Induced Liver Injury; Drug Eruptions; Gastrointestinal Diseases; Humans; Hypophysitis; Hypothyroidism; Imidazoles; Immunosuppressive Agents; Indoles; Ipilimumab; Melanoma; Mycophenolic Acid; Nivolumab; Oximes; Pyridones; Pyrimidinones; Skin Neoplasms; Sulfonamides; Sweet Syndrome; Thyrotoxicosis; Tumor Necrosis Factor-alpha; Vemurafenib; Vitiligo

Melanoma is an aggressive form of skin cancer which is the cause of a great number of skin cancer-related deaths worldwide and about 300 deaths in Denmark. After several years of failure of treatment of metastatic melanoma, the development of BRAF- and later MEK inhibitors was considered revolutionary. Treatment with BRAF inhibitors alone and especially in combination with a MEK inhibitor improves outcome for patients with BRAF V600-mutated metastatic melanoma. However, even when treated with the combination of the inhibitors, many patients develop acquired resistance within a year.

Topics: Antineoplastic Agents; Drug Resistance, Neoplasm; Humans; Imidazoles; Melanoma; Mitogen-Activated Protein Kinase Kinases; Mutation; Oximes; Prognosis; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms

Rhabdoid meningioma is an aggressive phenotype of meningioma, associated with a poor prognosis. We present a very rare case of high-grade meningioma with rhabdoid features that eventually expressed in a coma state. Comprehensive genomic profiling using a Next Generation Sequencing (NGS) assay revealed three genomic alterations: activating BRAF mutation (V600E), loss of CDKN2A/2B, and APC I1307K. After treatment with BRAF inhibitor (dabrafenib), the child's clinical condition improved progressively. After seven months, an MEK inhibitor was added (trametinib).

Topics: Adenomatous Polyposis Coli Protein; Antineoplastic Agents; Child; Cyclin-Dependent Kinase Inhibitor p15; Cyclin-Dependent Kinase Inhibitor p16; Female; Gene Expression Profiling; High-Throughput Nucleotide Sequencing; Humans; Imidazoles; Magnetic Resonance Imaging; Meningeal Neoplasms; Meningioma; Mutation; Oximes; Precision Medicine; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Rhabdoid Tumor

Oncogenic BRAF mutations are present in approximately 40-50% of patients with metastatic melanoma. Targeting BRAF mutations with either small molecule inhibitors of BRAF or one of the downstream mediators of oncogenic BRAF - MEK - is associated with improved outcomes compared with chemotherapy and has led to the US FDA approval of two BRAF inhibitors - vemurafenib and dabrafenib - and the MEK inhibitor trametinib. Further, the combination of dabrafenib and trametinib is well tolerated and associated with higher responses and improved survival compared with single-agent BRAF inhibitors.

Topics: Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Humans; Imidazoles; Melanoma; Oximes; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Randomized Controlled Trials as Topic

Combined BRAF and MEK inhibition out-performed BRAF inhibitor monotherapy in 3 randomized Phase 3 studies for BRAF-mutated metastatic melanoma patients and the combination of BRAF inhibitor dabrafenib with MEK inhibitor trametinib is now an FDA-approved treatment in this setting. Nevertheless, the majority of patients face progressive disease even when treated with the combination. Mechanisms of resistance to BRAF inhibition have been extensively investigated, whilst less is known about the specific mechanisms of resistance to combined therapy. The aim of this paper is to review the efficacy and safety of the combination of BRAF plus MEK inhibitors compared with BRAF inhibitor monotherapy and immunotherapy, as well as to discuss the existing evidence for the mechanisms of resistance to combined therapy and assess future treatment strategies to improve outcome based on data provided by clinical and translational research studies.

Topics: Humans; Imidazoles; Melanoma; Mitogen-Activated Protein Kinase Kinases; Mutation; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

During the past several years, targeted therapies have significantly improved outcomes in advanced basal cell carcinoma, psoriasis, and metastatic melanoma. This article reviews how advances in our understanding of the molecular pathogenesis of these diseases led to the development of targeted therapies and how these therapies are improving outcomes. Research is ongoing to address continuing challenges of drug resistance, adverse effects, and how best to use the new medications.

Topics: Adult; Anilides; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Azetidines; Brain Neoplasms; Carcinoma, Basal Cell; Dermatologic Agents; Dermatology; Etanercept; Female; Humans; Imidazoles; Indoles; Interleukin-17; Male; Melanoma; Middle Aged; Molecular Targeted Therapy; Oximes; Piperidines; Proto-Oncogene Proteins B-raf; Psoriasis; Pyridines; Pyridones; Pyrimidinones; Skin Neoplasms; Sulfonamides; Tumor Necrosis Factor-alpha; Ustekinumab; Vemurafenib

Treatment of advanced melanoma with selective BRAF and MEK inhibitors is associated with a series of mucocutaneous side effects, among which morphological changes in preexisting nevi and the development of new melanocytic lesions, both benign and malignant. Objective was to describe the changes observed in melanocytic nevi under vemurafenib therapy, followed by combination therapy with dabrafenib and trametinib for metastatic melanoma. The melanocytic lesions of a 51-year-old Caucasian male patient diagnosed with stage IV melanoma were monitored both clinically and dermoscopically throughout vemurafenib, followed by combined treatment with dabrafenib and trametinib. The 65 monitored nevi presented different behaviors under vemurafenib treatment: 18 reticular nevi, 9 reticular-homogenous nevi, 3 reticular-globular nevi, and 2 globular nevi showed a diffuse decrease in pigmentation. Ten reticular nevi remained unchanged, while the rest of the nevi, independent of the dermoscopic pattern, presented a gradual increase in pigmentation. On the other hand, under dabrafenib and trametinib treatment 57 of these nevi showed gradual decrease in pigmentation and central involution, while 7 reticular nevi and 1 globular nevus remained unchanged; none of the monitored nevi increased in pigmentation nor presented new globules following this combination therapy. Systematic total body skin examination is mandatory in patients receiving BRAF inhibitors. The divergent course of melanocytic nevi during vemurafenib vs. dabrafenib and trametinib therapy remains to be elucidated by further research.

Topics: Antineoplastic Combined Chemotherapy Protocols; Biopsy, Needle; Dermoscopy; Disease Progression; Follow-Up Studies; Humans; Imidazoles; Indoles; Male; Melanoma; Middle Aged; Neoplasm Invasiveness; Nevus, Pigmented; Oximes; Pyridones; Pyrimidinones; Risk Assessment; Skin Neoplasms; Sulfonamides; Treatment Outcome; Vemurafenib

Combination therapy with BRAF and MEK inhibitors is a recommended treatment strategy for metastatic melanoma patients with BRAF(V600) mutations. This treatment provides significant response rates and little added toxicity, with relatively improved survival outcomes compared to RAF/MEK inhibitor monotherapy and chemotherapy.. This review covers the pharmacology, efficacy, and toxicity data derived from clinical studies of dabrafenib, trametinib , and the combination thereof. The major downfall of combiDT is the limited durability of response, which is largely due to acquired resistance in the MAPK pathway.. Future directions of combiDT concentrate on further combinations with immunotherapy or other targeted inhibitors, referred to triple-agent therapy, which may be essential to improving durability of responses and overcoming resistance.

Topics: Antineoplastic Combined Chemotherapy Protocols; Humans; Imidazoles; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Melanoma; Mutation; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms

Patients treated with ipilimumab or targeted inhibitors of the RAF-MEK-ERK pathway (vemurafenib, dabrafenib, and trametinib) for advanced cutaneous melanoma often experience drug-related skin toxicities denoted as dermatologic adverse events (DAEs). Although rarely life-threatening, DAEs may emerge dramatically and potentially compromise oncologic therapy if not managed in a timely and effective manner. Early recognition of DAEs is critical to providing optimal skin care and prompt consultation with a dermatologist should be obtained when a diagnosis is unclear. The expanding utilization of new melanoma drugs compels physicians to maintain a watchful eye for both known and novel DAEs and to adopt a low threshold to biopsy worrisome skin findings. Numerous therapeutic options are available to manage DAEs including topical and systemic agents as well as surgical and destructive modalities. Applying such methods improves overall patient care and optimizes the effectiveness of new therapies for advanced cutaneous melanoma.

Topics: Antibodies, Monoclonal; Antineoplastic Agents; Humans; Imidazoles; Indoles; Inflammation; Ipilimumab; Melanoma; Melanoma, Cutaneous Malignant; Oximes; Pyridones; Pyrimidinones; Skin; Skin Diseases; Skin Neoplasms; Sulfonamides; Treatment Outcome; Vemurafenib

V-raf murine sarcoma viral oncogene homolog B1 (BRAF) inhibitors are emerging as the standard of care for treating advanced melanomas harboring the BRAF V600 oncogenic mutation. Dabrafenib is the second approved selective BRAF inhibitor (after vemurafenib) for the treatment of unresectable or metastatic BRAF V600-positive melanoma.. This review covers the current data on the efficacy and safety of the selective BRAF inhibitor dabrafenib in patients with metastatic BRAF V600 positive melanoma. The pharmacological, safety and efficacy data are discussed from Phase I, II, and III studies of dabrafenib monotherapy as well as in combination with the MEK inhibitor trametinib.. Dabrafenib has demonstrated comparable efficacy to vemurafenib in BRAF V600E mutant melanoma patients. Dabrafenib is well tolerated in patients with metastatic melanoma, including patients with brain metastases. Nevertheless side effects are common, but usually manageable. In the Phase III study testing dabrafenib, 53% of patients reported grade 2 or higher adverse events (AEs). Toxicities were similar to those seen in the early-phase trials, with the most common being cutaneous manifestations (hyperkeratosis, papillomas, palmar-plantar erythrodysesthesia), pyrexia, fatigue, headache, and arthralgia. Combining a BRAF inhibitor with a MEK inhibitor, which may block paradoxical MAPK activation in BRAF wild type (skin) cells, may lower the incidence of squamoproliferative eruptions.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Humans; Imidazoles; Melanoma; Mutation; Neoplasm Metastasis; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms

To examine the current controversies and discuss consensus recommendations regarding treatment sequencing and the role of BRAF inhibitor at disease progression.. An English-language literature search of MEDLINE/PubMed (1966-May 2014), using the keywords advanced melanoma, ipilimumab, cytotoxic T-lymphocyte antigen 4, dabrafenib, vemurafenib, BRAF inhibitor, trametinib, MEK inhibitor, and treatment sequencing was conducted. Data were also obtained from package inserts, meeting abstracts, and clinical registries.. All relevant published articles and abstracts on ipilimumab, vemurafenib, dabrafenib, and trametinib were reviewed. Clinical trial registries and meeting abstracts were used for ongoing studies.. The availability of new agents has made therapy selection more complex. Immunotherapy supporters reason that immunotherapy offers the best chance for long-term benefit and does not compromise the antitumor activity of subsequent BRAF inhibitors. Targeted therapy advocates rely on the high probability and rapid onset of response to BRAF inhibitors. Currently, there is insufficient evidence regarding the role of BRAF inhibitor at disease progression.. Therapy should be individualized based on patient- and disease-specific factors. Immunotherapy represents the best option for durable remission; however, targeted therapy is more appropriate for patients who are symptomatic or have rapidly growing tumors. The novel therapies have also demonstrated meaningful intracranial activity; thus, the presence of brain metastases should be taken into consideration in selecting therapy. Limited data exist about the continuation of BRAF inhibitors after therapeutic failure. Active research is ongoing to define the best option for patients with BRAF inhibitor refractory disease.

Topics: Antibodies, Monoclonal; Antineoplastic Agents; CTLA-4 Antigen; Drug Resistance, Neoplasm; Humans; Imidazoles; Immunotherapy; Indoles; Ipilimumab; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Melanoma; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Sulfonamides; Vemurafenib

Systemic agents are used in melanoma for adjuvant therapy and to treat metastatic disease. Currently, interferon-α is the only agent approved for adjuvant therapy. Six drugs are FDA approved for metastatic disease: dacarbazine, interleukin-2 (IL-2), vemurafenib, ipilimumab, dabrafenib, and trametinib. Vemurafenib and ipilimumab were approved in 2011, whereas dabrafenib and trametinib were approved in 2013.. This review will update the practicing dermatologist on the differences in efficacy, adverse events, and cost of systemic therapies available for the treatment of melanoma.. This article is a review of the current literature on systemic therapies for advanced melanoma. Key search words included "advanced melanoma," "systemic therapy," and "adjuvant therapy" with particular focus on the past 20 years.. Before 2011, dacarbazine and IL-2 were the only FDA approved therapies for metastatic melanoma, and IFN-α is the only approved agent for adjuvant therapy. The new agents vemurafenib, ipilimumab, dabrafenib, and trametinib are the first to have improved overall survival in Phase III studies in comparison with other systemic therapies.. Despite new developments, there remains a significant need for better therapies with improved long-term efficacy and decreased toxicity.

Topics: Animals; Antibodies, Monoclonal; Antineoplastic Agents; Bridged-Ring Compounds; Dacarbazine; Humans; Imidazoles; Indoles; Interferon-alpha; Interleukin-2; Ipilimumab; Melanoma; Oximes; Platinum Compounds; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Skin Neoplasms; Sulfonamides; Taxoids; Temozolomide; Vemurafenib

Metastatic melanoma has been a very poor prognostic cancer with a median of survival between six to eight months. A lot of new therapies have been discovered these last years. Two types of treatment have emerged: immunotherapy and targeted therapy. Targeted therapies have been developed because of the discovery of new oncogenic mutations with a big impact of melanoma development. The efficacy is great with a high overall response and a good tolerance. However, most of patients escape in few months of targeted therapy. The sequence of drug using and their combination are the question for the next years.

Topics: Antineoplastic Agents; Humans; Imidazoles; Indoles; MAP Kinase Kinase Kinase 1; Melanoma; Molecular Targeted Therapy; Neoplasm Proteins; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Sulfonamides; Vemurafenib

There have been significant advances in the treatment of malignant melanoma with the U.S. Food and Drug Administration approval of two drugs in 2011, the first drugs approved in 13 years. The developments of immune checkpoint modulation via cytotoxic T-lymphocyte antigen-4 blockade, with ipilimumab, and targeting of BRAF(V600), with vemurafenib or dabrafenib, as well as MEK, with trametinib, have been paradigm changing both for melanoma clinical practice and for oncology therapeutic development. These advancements, however, reveal new clinical questions regarding combinations and optimal sequencing of these agents in patients with BRAF mutant disease. We review the development of these agents, putative biomarkers, and resistance mechanisms relevant to their use, and possibilities for sequencing and combining these agents.

Topics: Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Drug Resistance, Neoplasm; Drug Synergism; Humans; Imidazoles; Indoles; Ipilimumab; MAP Kinase Kinase Kinases; Melanoma; Mutation; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Sulfonamides; Vemurafenib

Prior to 2011, the only commercially available agents commonly used to treat metastatic melanoma-including dacarbazine, temozolomide (Temodar), fotemustine, carboplatin, paclitaxel, and interleukin-2-demonstrated limited efficacy, and no study involving these agents had shown an improvement in overall survival. The standard of care for the treatment of metastatic melanoma was radically changed by the subsequent approval of two agents, ipilimumab (Yervoy) and vemurafenib (Zelboraf), both of which improved survival in randomized phase III trials. Within the relatively short time that ipilimumab and vemurafenib have been commercially available, phase II data for the investigational agents nivolumab and MK-3475, for the combination of dabrafenib and trametinib, and for adoptive cell therapy strongly suggest even further improvements in treatment outcomes. Within this rich context of effective agents, the challenge for clinicians and investigators will be to develop predictive biomarkers of response, the optimal sequence of therapy for individual patients, and effective combinations. An additional challenge will be to find the appropriate venue and populations to test promising new agents arising from substantial advances in our understanding of molecular alterations in melanoma cells, of mechanisms of resistance to current agents, and of tumor-host immune interactions.

Topics: Antibodies, Monoclonal; Drug Therapy, Combination; Humans; Imidazoles; Immunologic Factors; Immunotherapy, Adoptive; Indoles; Ipilimumab; Melanoma; Mutation; Nivolumab; Oximes; Programmed Cell Death 1 Receptor; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Sulfonamides; Vemurafenib

BRAF mutations are identified in 40-50% of patients with melanoma. Treatment of these patients with either of two BRAF inhibitors (vemurafenib, dabrafenib) or the MEK inhibitor trametinib is associated with improved clinical benefit (response rate, progression free survival, and overall survival) compared with treatment with chemotherapy in three phase III trials. Unfortunately, most patients, including those who experience initial, profound tumour regression, have evidence of disease progression within 6-8 months after commencing therapy with one of these agents. The mechanisms of resistance are varied and include activation of alternative signalling pathways as well as reactivating the MAP kinase pathway through alternative means. This review describes relevant aspects of MAP kinase pathway signalling, summarises the clinical data with BRAF and MEK inhibitors, presents the known resistance mechanisms to BRAF inhibitor therapy, and provides some strategies for how resistance may be overcome.

Topics: Disease-Free Survival; Drug Resistance, Neoplasm; Humans; Imidazoles; Indoles; MAP Kinase Signaling System; Melanoma; Mutation; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Sulfonamides; Vemurafenib

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Drug Discovery; Humans; Imidazoles; Indoles; MAP Kinase Signaling System; Mitogen-Activated Protein Kinases; Molecular Targeted Therapy; Neoplasms; Oximes; Pyridones; Pyrimidinones; raf Kinases; Research; Sulfonamides; Vemurafenib

Patients with metastatic melanoma had few treatment options until 2011, when two drugs-ipilimumab and vemurafenib-were approved following advances in the understanding of melanoma biology and tumour immunology. Almost 50% of melanomas harbour mutations in BRAF, mainly at codon 600, which result in constitutive activation of the MAPK pathway. The selective inhibitors of mutant BRAF Val600, vemurafenib and dabrafenib, showed major tumour responses, resulting in improved progression-free and overall survival in patients with metastatic disease, compared with chemotherapy. Antitumour activity was also recorded in brain metastases. The growth of cutaneous squamous-cell carcinomas is a unique side-effect of BRAF inhibitor therapy that is induced by the paradoxical activation of the MAPK pathway in cells with RAS mutations. Trametinib, which targets MEK downstream of BRAF, also produced an overall survival benefit compared with chemotherapy, although tumour responses were less frequent than they were with BRAF inhibitors. Despite this robust antitumour activity, most responses to these drugs are partial and disease progression is typically seen at a median of 5-7 months. Multiple resistance mechanisms have been identified, including those that lead to reactivation of the MAPK pathway and other pathways, such as the PI3K-AKT-mTOR and VEGF pathways. Some patients with BRAF Val600 mutant melanoma seem to also benefit from immunotherapies such as high-dose interleukin 2 and ipilimumab, which, by contrast with BRAF inhibitors, can produce durable complete responses. We review the available data to best guide initial treatment choice and the sequence of treatments for patients with BRAF Val600 mutant melanoma.

Topics: Antibodies, Monoclonal; Drug Resistance, Neoplasm; Humans; Imidazoles; Indoles; Ipilimumab; Melanoma; Mutation; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Sulfonamides; Vemurafenib

BRAFV600E alterations are prevalent across multiple tumors. Here we present final efficacy and safety results of a phase 2 basket trial of dabrafenib (BRAF kinase inhibitor) plus trametinib (MEK inhibitor) in eight cohorts of patients with BRAFV600E-mutated advanced rare cancers: anaplastic thyroid carcinoma (n = 36), biliary tract cancer (n = 43), gastrointestinal stromal tumor (n = 1), adenocarcinoma of the small intestine (n = 3), low-grade glioma (n = 13), high-grade glioma (n = 45), hairy cell leukemia (n = 55) and multiple myeloma (n = 19). The primary endpoint of investigator-assessed overall response rate in these cohorts was 56%, 53%, 0%, 67%, 54%, 33%, 89% and 50%, respectively. Secondary endpoints were median duration of response (DoR), progression-free survival (PFS), overall survival (OS) and safety. Median DoR was 14.4 months, 8.9 months, not reached, 7.7 months, not reached, 31.2 months, not reached and 11.1 months, respectively. Median PFS was 6.7 months, 9.0 months, not reached, not evaluable, 9.5 months, 5.5 months, not evaluable and 6.3 months, respectively. Median OS was 14.5 months, 13.5 months, not reached, 21.8 months, not evaluable, 17.6 months, not evaluable and 33.9 months, respectively. The most frequent (≥20% of patients) treatment-related adverse events were pyrexia (40.8%), fatigue (25.7%), chills (25.7%), nausea (23.8%) and rash (20.4%). The encouraging tumor-agnostic activity of dabrafenib plus trametinib suggests that this could be a promising treatment approach for some patients with BRAFV600E-mutated advanced rare cancers. ClinicalTrials.gov registration: NCT02034110 .

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Glioma; Humans; Imidazoles; Mutation; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

To evaluate the efficacy and safety of dabrafenib-trametinib-131I for the treatment of radioactive iodine refractory metastatic differentiated thyroid cancer (DTC) with a BRAF p.V600E mutation.. A prospective phase II trial including patients with RECIST progression within 18 months and no lesion > 3 cm. Following a baseline recombinant human (rh)TSH-stimulated diagnostic whole-body scan (dc1-WBS), dabrafenib and trametinib were given for 42 days. A second rhTSH-stimulated dc WBS (dc2-WBS) was done at day 28 and 131I (5.5 GBq-150 mCi after rhTSH) was administered at day 35. Primary endpoint was the 6-month RECIST objective response rate. In case of partial response (PR) at 6 or 12 months, a second treatment course could be given. Among 24 enrolled patients, 21 were evaluable at 6 months.. Abnormal 131I uptake was present on 5%, 65%, and 95% of the dc1-WBS, dc2-WBS, and post-therapy scans, respectively. At 6 months, PR was achieved in 38%, stable disease in 52%, and progressive disease (PD) in 10%. Ten patients received a second treatment course: one complete response and 6 PRs were observed at 6 months. The median progression-free survival (PFS) was not reached. The 12- and 24-month PFS were 82% and 68%, respectively. One death due to PD occurred at 24 months. Adverse events (AE) occurred in 96% of the patients, with 10 grade 3-4 AEs in 7 patients.. Dabrafenib-trametinib is effective in BRAF p.V600E-mutated DTC patients for restoring 131I uptake with PR observed 6 months after 131I administration in 38% of the patients.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Humans; Iodine Radioisotopes; Mutation; Oximes; Prospective Studies; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Thyroid Neoplasms; Thyrotropin Alfa

Effective treatments are needed to improve outcomes for high-grade glioma and low-grade glioma. The activity and safety of dabrafenib plus trametinib were evaluated in adult patients with recurrent or progressive BRAF. This study is part of an ongoing open-label, single-arm, phase 2 Rare Oncology Agnostic Research (ROAR) basket trial at 27 community and academic cancer centres in 13 countries (Austria, Belgium, Canada, France, Germany, Italy, Japan, the Netherlands, Norway, South Korea, Spain, Sweden, and the USA). The study enrolled patients aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0, 1, or 2. Patients with BRAF. Between April 17, 2014, and July 25, 2018, 45 patients (31 with glioblastoma) were enrolled into the high-grade glioma cohort and 13 patients were enrolled into the low-grade glioma cohort. The results presented here are based on interim analysis 16 (data cutoff Sept 14, 2020). In the high-grade glioma cohort, median follow-up was 12·7 months (IQR 5·4-32·3) and 15 (33%; 95% CI 20-49) of 45 patients had an objective response by investigator assessment, including three complete responses and 12 partial responses. In the low-grade glioma cohort, median follow-up was 32·2 months (IQR 25·1-47·8). Nine (69%; 95% CI 39-91) of 13 patients had an objective response by investigator assessment, including one complete response, six partial responses, and two minor responses. Grade 3 or worse adverse events were reported in 31 (53%) patients, the most common being fatigue (five [9%]), decreased neutrophil count (five [9%]), headache (three [5%]), and neutropenia (three [5%]).. Dabrafenib plus trametinib showed clinically meaningful activity in patients with BRAF. Novartis.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Female; Glioma; Humans; Imidazoles; Isocitrate Dehydrogenase; Male; Middle Aged; Mutation; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Young Adult

Autophagy is a resistance mechanism to BRAF/MEK inhibition in BRAFV600-mutant melanoma. Here we used hydroxychloroquine (HCQ) to inhibit autophagy in combination with dabrafenib 150 mg twice daily and trametinib 2 mg every day (D+T).. We conducted a phase I/II clinical trial in four centers of HCQ + D+T in patients with advanced BRAFV600-mutant melanoma. The primary objectives were the recommended phase II dose (RP2D) and the one-year progression-free survival (PFS) rate of >53%.. Thirty-four patients were evaluable for one-year PFS rate. Patient demographics were as follows: elevated lactate dehydrogenase: 47%; stage IV M1c/M1d: 52%; prior immunotherapy: 50%. In phase I, there was no dose-limiting toxicity. HCQ 600 mg orally twice daily with D+T was the RP2D. The one-year PFS rate was 48.2% [95% confidence interval (CI), 31.0%-65.5%], median PFS was 11.2 months (95% CI, 5.4-16.9 months), and response rate (RR) was 85% (95% CI, 64%-95%). The complete RR was 41% and median overall survival (OS) was 26.5 months. In a patient with elevated LDH (n = 16), the RR was 88% and median PFS and OS were 7.3 and 22 months, respectively.. HCQ + D+T was well tolerated and produced a high RR but did not meet criteria for success for the one-year PFS rate. There was a high proportion of patients with pretreated and elevated LDH, an increasingly common demographic in patients receiving targeted therapy. In this difficult-to-treat population, the RR and PFS were encouraging. A randomized trial of D+T + HCQ or placebo in patients with BRAFV600-mutant melanoma with elevated LDH and previous immunotherapy is being conducted.

Topics: Antineoplastic Combined Chemotherapy Protocols; Autophagy; Humans; Hydroxychloroquine; Imidazoles; Melanoma; Mitogen-Activated Protein Kinase Kinases; Mutation; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

Combined therapy with dabrafenib plus trametinib was approved in several countries for treatment of BRAF V600E-mutant anaplastic thyroid cancer (ATC) based on an earlier interim analysis of 23 response-assessable patients in the ATC cohort of the phase II Rare Oncology Agnostic Research (ROAR) basket study. We report an updated analysis describing the efficacy and safety of dabrafenib plus trametinib in the full ROAR ATC cohort of 36 patients with ∼4 years of additional study follow-up.. ROAR (NCT02034110) is an open-label, nonrandomized, phase II basket study evaluating dabrafenib plus trametinib in BRAF V600E-mutant rare cancers. The ATC cohort comprised 36 patients with unresectable or metastatic ATC who received dabrafenib 150 mg twice daily plus trametinib 2 mg once daily orally until disease progression, unacceptable toxicity, or death. The primary endpoint was investigator-assessed overall response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1. Secondary endpoints were duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety.. At data cutoff (14 September 2020), median follow-up was 11.1 months (range, 0.9-76.6 months). The investigator-assessed ORR was 56% (95% confidence interval, 38.1% to 72.1%), including three complete responses; the 12-month DOR rate was 50%. Median PFS and OS were 6.7 and 14.5 months, respectively. The respective 12-month PFS and OS rates were 43.2% and 51.7%, and the 24-month OS rate was 31.5%. No new safety signals were identified with additional follow-up, and adverse events were consistent with the established tolerability of dabrafenib plus trametinib.. These updated results confirm the substantial clinical benefit and manageable toxicity of dabrafenib plus trametinib in BRAF V600E-mutant ATC. Dabrafenib plus trametinib notably improved long-term survival and represents a meaningful treatment option for this rare, aggressive cancer.

Topics: Antineoplastic Combined Chemotherapy Protocols; Humans; Imidazoles; Mutation; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms

Preclinical data suggest the combination of an anti-programmed death receptor 1 antibody plus dabrafenib and trametinib to have superior antitumor activity compared with dabrafenib plus trametinib alone. These observations are supported by translational evidence suggesting that immune checkpoint inhibitors plus targeted therapy may improve treatment outcomes in patients with. Patients received spartalizumab 400 mg intravenously every 4 weeks plus dabrafenib 150 mg orally twice daily and trametinib 2 mg orally once daily or placebo-DabTram. Participants were age ≥ 18 years with unresectable or metastatic. At data cutoff (July 1, 2020), the median progression-free survival was 16.2 months (95% CI, 12.7 to 23.9 months) in the sparta-DabTram arm versus 12.0 months (95% CI, 10.2 to 15.4 months) in the placebo-DabTram arm (hazard ratio, 0.82 [95% CI, 0.66 to 1.03];. The study did not meet its primary end point; broad first-line use of sparta-DabTram is not supported by these results. Further biomarker-driven investigation may identify patient subpopulations who could benefit from checkpoint inhibitor plus targeted therapy combinations.

Topics: Adolescent; Adult; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Humans; Imidazoles; Melanoma; Mutation; Neoplasms, Second Primary; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Receptors, Death Domain; Skin Neoplasms

COMBI-AD demonstrated long-term benefit of adjuvant dabrafenib plus trametinib in patients with resected stage III BRAF V600E/K-mutant melanoma; however, 9% of patients permanently discontinued therapy due to pyrexia. COMBI-APlus evaluated whether an adapted pyrexia management algorithm reduces high-grade pyrexia and pyrexia-related adverse outcomes.. COMBI-APlus is an open-label, phase IIIb trial evaluating an adapted pyrexia management algorithm in patients with high-risk resected stage III BRAF V600E/K-mutant melanoma treated with up to 12 months of adjuvant dabrafenib plus trametinib. Both drugs were interrupted for pyrexia (temperature ≥38°C) or the occurrence of pyrexia syndrome for suspected recurrent pyrexia. Treatment was restarted at the same dose once patients were symptom free for ≥24 h. The primary endpoint was the composite rate of grade 3/4 pyrexia, hospitalisation due to pyrexia, or permanent discontinuation due to pyrexia versus historical COMBI-AD control (20.0%; 95% confidence interval [CI], 16.3%-24.1%).. At data cutoff (5 October 2020), COMBI-APlus met its primary endpoint of significant improvement in the composite rate of pyrexia (8.0% [95% CI, 5.9%-10.6%]), with rates of 3.8% for grade 3/4 pyrexia, 4.3% for hospitalisation due to pyrexia, and 2.4% for discontinuation due to pyrexia. Estimated 12-month relapse-free survival was 91.8% (95% CI, 89.0%-93.9%). The most common adverse events were consistent with those in COMBI-AD, and 14.7% of patients permanently discontinued treatment due to adverse events.. The adapted pyrexia management algorithm appears to reduce the incidence of severe pyrexia outcomes, enables patients to manage pyrexia at home, and helps patients remain on treatment.. NCT03551626.

Topics: Adjuvants, Immunologic; Algorithms; Antineoplastic Combined Chemotherapy Protocols; Fever; Humans; Imidazoles; Melanoma; Melanoma, Cutaneous Malignant; Mutation; Neoplasm Recurrence, Local; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms

Patients with advanced BRAFV600 mutant melanoma who progressed on prior treatment with BRAF-/MEK-inhibitors and programmed cell death 1 or cytotoxic T-lymphocyte-associated antigen 4 immune checkpoint inhibitors can benefit from retreatment with the combination of a BRAF- and a MEK-inhibitor ('rechallenge'). Hydroxychloroquine can prevent autophagy-driven resistance and improve the efficacy of BRAF-/MEK-inhibitors in preclinical melanoma models. This clinical trial investigated the use of combined BRAF-/MEK-inhibition with dabrafenib and trametinib plus hydroxychloroquine in patients with advanced BRAFV600 mutant melanoma who previously progressed on prior treatment with BRAF-/MEK-inhibitors and immune checkpoint inhibitors. Following a safety lead-in phase, patients were randomized in the phase 2 part of the trial between upfront treatment with dabrafenib, trametinib and hydroxychloroquine (experimental arm), or dabrafenib and trametinib, with the possibility to add-on hydroxychloroquine at the time of documented tumor progression (contemporary control arm). Ten and four patients were recruited to the experimental and contemporary control arm, respectively. The objective response rate was 20.0% and the disease control rate was 50.0% in the experimental arm, whereas no responses were observed before or after adding hydroxychloroquine in the contemporary control arm. No new safety signals were observed for dabrafenib and trametinib. Hydroxychloroquine was suspected of causing an anxiety/psychotic disorder in one patient. Based on an early negative evaluation of the risk/benefit ratio for adding hydroxychloroquine to dabrafenib and trametinib when 'rechallenging' BRAFV600mutant melanoma patients, recruitment to the trial was closed prematurely.

Topics: Antineoplastic Combined Chemotherapy Protocols; Humans; Hydroxychloroquine; Imidazoles; Immune Checkpoint Inhibitors; Melanoma; Mitogen-Activated Protein Kinase Kinases; Mutation; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms

Despite the poor prognosis associated with melanoma brain metastases (BM), data concerning these patients and their inclusion in clinical trials remains scarce. We report here the efficacy results of a subgroup analysis in patients with BRAFV600-mutant melanoma and BM treated with BRAF and MEK inhibitors dabrafenib (D) and trametinib (T).. This phase IIIb single-arm, open-label, multicenter, French study included patients with unresectable stage IIIc or IV BRAFV600-mutant melanoma with or without BM. The present analysis focuses on patients with BM. Response rates were determined clinically and/or radiologically as per standard clinical practice. Progression-free survival (PFS) was estimated using the Kaplan Meier analysis and modelled with multivariate Cox regression model. Risk subgroups were identified using an exponential regression tree analysis. Significance was set at p < 0.05.. Between March 2015 and November 2016, 856 patients were included and 275 (32%) patients had BM. Median PFS was 5.68 months (95% confidence interval [CI], 5.29-6.87). Significant independent factors associated with shorter PFS were ECOG ≥1, elevated serum lactate dehydrogenase (LDH), ≥3 metastatic sites, and non-naïve status. The binary-split classification and regression tree modelling identified baseline LDH and ECOG status as major prognostic factors.. This is to date the largest, close to real-world, study in advanced BRAFV600-mutant melanoma patients with BM treated with D+T. ECOG >1, ≥3 metastatic sites and elevated LDH were associated with shorter PFS, a finding previously demonstrated only in patients without BM. Further studies are warranted to determine the optimal treatment sequence in this population.

Topics: Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Humans; Imidazoles; Lactate Dehydrogenases; Male; Melanoma; Mitogen-Activated Protein Kinase Kinases; Mutation; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

Dabrafenib plus trametinib was found to have robust antitumor activity in patients with BRAF V600E-mutant metastatic NSCLC (mNSCLC). We report updated survival analysis of a phase 2 study (NCT01336634) with a minimum of 5-year follow-up and updated genomic data.. Pretreated (cohort B) and treatment-naive (cohort C) patients with BRAF V600E-mutant mNSCLC received dabrafenib 150 mg twice daily and trametinib 2 mg once daily. The primary end point was investigator-assessed overall response rate per Response Evaluation Criteria in Solid Tumors version 1.1. Secondary end points were duration of response, progression-free survival, overall survival, and safety.. At data cutoff, for cohorts B (57 patients) and C (36 patients), the median follow-up was 16.6 (range: 0.5-78.5) and 16.3 (range: 0.4-80) months, overall response rate (95% confidence interval [CI]) was 68.4% (54.8-80.1) and 63.9% (46.2-79.2), median progression-free survival (95% CI) was 10.2 (6.9-16.7) and 10.8 (7.0-14.5) months, and median overall survival (95% CI) was 18.2 (14.3-28.6) and 17.3 (12.3-40.2) months, respectively. The 4- and 5-year survival rates were 26% and 19% in pretreated patients and 34% and 22% in treatment-naive patients, respectively. A total of 17 patients (18%) were still alive. The most frequent adverse event was pyrexia (56%). Exploratory genomic analysis indicated that the presence of coexisting genomic alterations might influence clinical outcomes in these patients; however, these results require further investigation.. Dabrafenib plus trametinib therapy was found to have substantial and durable clinical benefit, with a manageable safety profile, in patients with BRAF V600E-mutant mNSCLC, regardless of previous treatment.

Topics: Antineoplastic Combined Chemotherapy Protocols; Genomics; Humans; Imidazoles; Lung Neoplasms; Mutation; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Survival Rate

Lay abstract This study aims to report the long-term outcome of intra-ocular inflammation (uveitis) associated with cancer immunotherapy (CIT). Serial patients complaining of blurred vision and painful eyes showed intra-ocular inflammation that was related to CIT, after infectious, inflammatory and tumoral causes of uveitis have been ruled out. The length of follow-up was more than 12 months for most patients. Eight serial patients treated with rituximab (anti-CD20), nivolumab (anti-PD-1), ipilimumab (anti-CTLA-4), vemurafenib and dabrafenib (anti-BRAF), trametinib (anti-MEK) and ibritunib showed intra-ocular inflammation with hypopion (one patient), macular edema (five patients) and choroiditis (two patients). Various regimens of corticosteroid therapy showed a favorable ophthalmological outcome, whether the CIT was continuing or suspended. Local corticosteroid injections in combination with CIT could be suggested as a first-line treatment. This could help to preserve the quality of life without threatening the vital prognosis.

Topics: Adrenal Cortex Hormones; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Imidazoles; Immunotherapy; Ipilimumab; Male; Middle Aged; Neoplasms; Nivolumab; Oximes; Pyridones; Pyrimidinones; Retrospective Studies; Rituximab; Uveitis; Vemurafenib

Combination treatment with BRAF (BRAFi) plus MEK inhibitors (MEKi) has demonstrated survival benefit in patients with advanced melanoma harboring activating BRAF mutations. Previous preclinical studies suggested that an intermittent dosing of these drugs could delay the emergence of resistance. Contrary to expectations, the first published phase 2 randomized study comparing continuous versus intermittent schedule of dabrafenib (BRAFi) plus trametinib (MEKi) demonstrated a detrimental effect of the "on-off" schedule. Here we report confirmatory data from the Phase II randomized open-label clinical trial comparing the antitumoral activity of the standard schedule versus an intermittent combination of vemurafenib (BRAFi) plus cobimetinib (MEKi) in advanced BRAF mutant melanoma patients (NCT02583516). The trial did not meet its primary endpoint of progression free survival (PFS) improvement. Our results show that the antitumor activity of the experimental intermittent schedule of vemurafenib plus cobimetinib is not superior to the standard continuous schedule. Detection of BRAF mutation in cell free tumor DNA has prognostic value for survival and its dynamics has an excellent correlation with clinical response, but not with progression. NGS analysis demonstrated de novo mutations in resistant cases.

Topics: Aged; Antineoplastic Agents; Azetidines; Humans; Imidazoles; Melanoma; Mutation; Oximes; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Vemurafenib

Melanoma lacks validated blood-based biomarkers for monitoring and predicting treatment efficacy. Cell-free circulating tumour DNA (ctDNA) is a promising biomarker; however, various detection methods have been used, and, to date, no large studies have examined the association between serial changes in ctDNA and survival after BRAF, MEK, or BRAF plus MEK inhibitor therapy. We aimed to evaluate whether baseline ctDNA concentrations and kinetics could predict survival outcomes.. In this clinical validation study, we used analytically validated droplet digital PCR assays to measure BRAF. In COMBI-d, pretreatment plasma samples were available from 345 (82%) of 423 patients and on-treatment (week 4) plasma samples were available from 224 (53%) of 423 patients. In cohort A of COMBI-MB, pretreatment and on-treatment samples were available from 38 (50%) of 76 patients with intracranial and extracranial metastatic melanoma. ctDNA was detected in pretreatment samples from 320 (93%) of 345 patients (COMBI-d) and 34 (89%) of 38 patients (COMBI-MB). When assessed as a continuous variable, elevated baseline BRAF. Pretreatment and on-treatment BRAF. Novartis.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Circulating Tumor DNA; Double-Blind Method; Female; Follow-Up Studies; Humans; Imidazoles; Male; Melanoma; Middle Aged; Oximes; Prognosis; Pyridones; Pyrimidinones; Survival Rate

To evaluate the potency of short-term neoadjuvant cytoreductive therapy with dabrafenib plus trametinib (BRAF and MEK inhibitor) to allow for radical surgical resection in patients with unresectable locally advanced melanoma.. Approximately 5% of stage III melanoma patients presents with unresectable locally advanced disease, making standard of care with resection followed by adjuvant systemic therapy impossible. Although neoadjuvant targeted therapy has shown promising results in resectable stage III melanoma, its potency to enable surgical resection in patients with primarily unresectable locally advanced stage III melanoma is still unclear.. In this prospective, single-arm, phase II trial, patients with unresectable BRAF-mutated locally advanced stage IIIC or oligometastatic stage IV melanoma were included. After 8 weeks of treatment with dabrafenib and trametinib, evaluation by positron emission tomography/computed tomography and physical examination were used to assess sufficient downsizing of the tumor to enable resection. The primary objective was the percentage of patients who achieved a radical (R0) resection.. Between August 2014 and March 2019, 21 patients (20/21 stage IIIC American Joint Committee on Cancer staging manual 7th edition) were included. Planned inclusion of 25 patients was not reached due to slow accrual and changing treatment landscape. Despite this, the predefined endpoint was successfully met. In 18/21 (86%) patients a resection was performed, of which 17 were R0 resections. At a median follow-up of 50 months (interquartile range 37.7-57.1 months), median recurrence-free survival was 9.9 months (95% confidence interval 7.52-not reached) in patients undergoing surgery.. This prospective, single-arm, open-label phase II trial, shows neoadjuvant dabrafenib plus trametinib as a potent cytoreductive treatment, allowing radical resection of metastases in 17/21 (81%) patients with prior unresectable locally advanced melanoma.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cytoreduction Surgical Procedures; Female; Humans; Imidazoles; Magnetic Resonance Imaging; Male; Melanoma; Middle Aged; Neoadjuvant Therapy; Neoplasm Staging; Netherlands; Oximes; Positron Emission Tomography Computed Tomography; Prospective Studies; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

BRAF and MEK inhibitors combination, including dabrafenib (D) and trametinib (T) have transformed the treatment of BRAF V600-mutant advanced melanoma patients, including patients with brain metastasis (BM). In a large phase IIIb, single-arm, open-label, multicenter French study, we assessed safety, response to treatment, progression-free survival (PFS) and factors associated with progression, and stratified the population into risk groups.. Patients with unresectable, advanced, BRAF V600-mutant melanoma were included, including those with the presence of BM, Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≤2, elevated lactate dehydrogenase (LDH) or previous melanoma treatments. Responses were determined locally, without central review. PFS was estimated using the Kaplan-Meier analysis and modelled with multivariate Cox model. Risk subgroups were identified using a regression tree analysis.. Between March 2015 and November 2016, 856 patients received at least one D + T dose. Overall, 92% had stage IV melanoma, 38% ECOG PS ≥1, 32% BM and 37.5% elevated LDH. Median PFS was 8.02 months (95% confidence interval [CI] 7.33-8.77). Significant factors associated with lower PFS were ECOG PS ≥1, elevated LDH, ≥3 metastatic sites and presence of BM. Patients with <3 metastatic sites, ECOG = 0 and no BM had the highest probability of PFS at 6 months (83%, 95% CI 76-87) and 12 months (56%, 95% CI 47-64), respectively.. This is the largest prospective study in advanced BRAF V600-mutant melanoma patients treated with D + T, conducted in conditions close to 'real-world practice'. We confirm previous findings that LDH, ECOG PS and ≥3 metastatic sites are associated with shorter PFS, but the real-world setting introduces BM as a major prognostic factor.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Disease Progression; Female; Humans; Imidazoles; Male; Melanoma; Middle Aged; Mutation; Neoplasm Staging; Oximes; Prospective Studies; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

Prognostic groups defined by lactate dehydrogenase concentration and number of organ sites containing metastases have been reported for patients treated with dabrafenib and trametinib for advanced melanoma. We aimed to validate these prognostic groups for patients treated with vemurafenib and cobimetinib in the coBRIM and BRIM-3 clinical studies. Eight hundred nine patients were included, 240 treated with vemurafenib plus cobimetinib and 569 with vemurafenib. For patients treated with vemurafenib and cobimetinib, both overall survival (P < 0.001, c-statistic = 0.72) and progression-free survival (P < 0.001, c-statistic = 0.65) differed markedly between prognostic groups. Two-year progression-free survival ranged from 3 (lactate dehydrogenase ≥2 times the upper limit of normal) to 50% (normal lactate dehydrogenase and ≤3 sites), and two-year overall survival ranged from 7 to 71%. For patients treated with vemurafenib monotherapy, overall survival (P < 0.001, c-statistic = 0.66) and progression-free survival (P < 0.001, c-statistic = 0.62) also differed significantly between prognostic groups. In conclusion, prognostic groups identified for patients treated with dabrafenib and trametinib are also applicable to patients treated with vemurafenib and cobimentinib.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Azetidines; Biomarkers; Female; Humans; Imidazoles; L-Lactate Dehydrogenase; Male; Melanoma; Melanoma, Cutaneous Malignant; Middle Aged; Mutation; Oximes; Piperidines; Prognosis; Progression-Free Survival; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Treatment Outcome; Vemurafenib

Adjuvant dabrafenib plus trametinib reduced the risk of relapse versus placebo in patients with resected, BRAF. COMBI-AD is a randomised, double-blind, placebo-controlled, phase 3 trial comparing dabrafenib 150 mg orally twice daily plus trametinib 2 mg orally once daily versus two matched placebos. Study participants were at least 18 years of age and underwent complete resection of stage IIIA (lymph node metastases >1 mm), IIIB, or IIIC cutaneous melanoma, per American Joint Committee on Cancer 7th edition criteria, with a BRAF. Between Jan 31, 2013, and Dec 11, 2014, 870 patients were enrolled in the trial. Median follow-up at data cutoff (April 30, 2018) was 44 months (IQR 38-49) in the dabrafenib plus trametinib group and 42 months (21-49) in the placebo group. Intrinsic tumour genomic features were assessed in 368 patients (DNA sequencing set) and tumour microenvironment characteristics were assessed in 507 patients (NanoString biomarker set). MAPK pathway genomic alterations at baseline did not affect treatment benefit or clinical outcome. An IFNγ gene expression signature higher than the median was prognostic for prolonged relapse-free survival in both treatment groups. Tumour mutational burden was independently prognostic for relapse-free survival in the placebo group (high TMB, top third; hazard ratio [HR] 0·56, 95% CI 0·37-0·85, p=0·0056), but not in the dabrafenib plus trametinib group (0·83, 95% CI 0·53-1·32, p=0·44). Patients with tumour mutational burden in the lower two terciles seem to derive a substantial long-term relapse-free survival benefit from targeted therapy (HR [versus placebo] 0·49, 95% CI 0·35-0·68, p<0·0001). However, patients with high tumour mutational burden seem to have a less pronounced benefit with targeted therapy (HR [versus placebo] 0·75, 95% CI 0·44-1·26, p=0·27), especially if they had an IFNγ signature lower than the median (HR 0·88 [95% CI 0·40-1·93], p=0·74).. Tumour mutational burden alone or in combination with IFNγ gene expression signature or other markers for an adaptive immune response might be of relevance for identifying patients with stage III melanoma who might derive clinical benefit from targeted therapy. Further validation in prospective clinical trials is warranted.. Novartis Pharmaceuticals.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Double-Blind Method; Drug Resistance, Neoplasm; Female; Follow-Up Studies; Humans; Imidazoles; Male; Melanoma; Middle Aged; Mutation; Neoplasm Metastasis; Neoplasm Recurrence, Local; Oximes; Prognosis; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Salvage Therapy; Skin Neoplasms; Survival Rate; Young Adult

This study (NCT02083354) assessed the efficacy and safety of dabrafenib plus trametinib in East Asian patients with advanced BRAF V600-mutant cutaneous melanoma.. Overall, 77 patients of East Asian origin (including 61 from Mainland China) with unresectable or metastatic BRAF V600-mutant cutaneous melanoma were enrolled. Prior treatment was allowed except with BRAF/MEK inhibitors. Patients received dabrafenib 150 mg twice daily and trametinib 2 mg once daily. The primary end-point was objective response rate (ORR) using Response Evaluation Criteria in Solid Tumours 1.1. Secondary end-points were duration of response (DOR), progression-free survival (PFS), overall survival (OS), pharmacokinetics and safety.. These results support the efficacy and tolerability of dabrafenib in combination with trametinib in East Asian patients with unresectable or metastatic BRAF V600-mutant cutaneous melanoma.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Asia; Biomarkers, Tumor; Female; Humans; Imidazoles; Male; Melanoma; Middle Aged; Mutation; Oximes; Progression-Free Survival; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Time Factors

Effective treatments for patients with cholangiocarcinoma after progression on gemcitabine-based chemotherapy are urgently needed. Mutations in the BRAF gene have been found in 5% of biliary tract tumours. The combination of dabrafenib and trametinib has shown activity in several BRAF. This study is part of an ongoing, phase 2, open-label, single-arm, multicentre, Rare Oncology Agnostic Research (ROAR) basket trial in patients with BRAF. Between March 12, 2014, and July 18, 2018, 43 patients with BRAF. Dabrafenib plus trametinib combination treatment showed promising activity in patients with BRAF. GlaxoSmithKline and Novartis.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biliary Tract Neoplasms; Disease-Free Survival; Female; Humans; Imidazoles; Male; Middle Aged; Mutation; Neoplasm Recurrence, Local; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Treatment Outcome

In the previously reported primary analysis of this phase 3 trial, 12 months of adjuvant dabrafenib plus trametinib resulted in significantly longer relapse-free survival than placebo in patients with resected stage III melanoma with. We randomly assigned 870 patients who had resected stage III melanoma with. The minimum duration of follow-up was 59 months (median patient follow-up, 60 months for dabrafenib plus trametinib and 58 months for placebo). At 5 years, the percentage of patients who were alive without relapse was 52% (95% confidence interval [CI], 48 to 58) with dabrafenib plus trametinib and 36% (95% CI, 32 to 41) with placebo (hazard ratio for relapse or death, 0.51; 95% CI, 0.42 to 0.61). The percentage of patients who were alive without distant metastasis was 65% (95% CI, 61 to 71) with dabrafenib plus trametinib and 54% (95% CI, 49 to 60) with placebo (hazard ratio for distant metastasis or death, 0.55; 95% CI, 0.44 to 0.70). No clinically meaningful between-group difference in the incidence or severity of serious adverse events was reported during the follow-up period.. In the 5-year follow-up of a phase 3 trial involving patients who had resected stage III melanoma with

Topics: Adjuvants, Immunologic; Administration, Oral; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Double-Blind Method; Female; Follow-Up Studies; Humans; Imidazoles; Male; Melanoma; Middle Aged; Mutation; Neoplasm Metastasis; Neoplasm Staging; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Survival Analysis

Preclinical modeling suggests that intermittent BRAF inhibitor therapy may delay acquired resistance when blocking oncogenic BRAF

Topics: Administration, Oral; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Drug Administration Schedule; Female; Humans; Imidazoles; Male; MAP Kinase Kinase Kinases; Melanoma; Middle Aged; Mutation, Missense; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Survival Analysis; Treatment Outcome; Young Adult

Topics: Adult; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Cohort Studies; Disease Progression; Female; Humans; Imidazoles; Immune Checkpoint Inhibitors; Male; MAP Kinase Kinase Kinases; Melanoma; Middle Aged; Mutation, Missense; Neoplasm Metastasis; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Treatment Outcome; Young Adult

Combining PD-L1 blockade with inhibition of oncogenic mitogen-activated protein kinase (MAPK) signaling may result in long-lasting responses in patients with advanced melanoma. This phase 1, open-label, dose-escalation and -expansion study (NCT02027961) investigated safety, tolerability and preliminary efficacy of durvalumab (anti-PD-L1) combined with dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor) for patients with BRAF-mutated melanoma (cohort A, n = 26), or durvalumab and trametinib given concomitantly (cohort B, n = 20) or sequentially (cohort C, n = 22) for patients with BRAF-wild type melanoma. Adverse events and treatment discontinuation rates were more common than previously reported for these agents given as monotherapy. Objective responses were observed in 69.2% (cohort A), 20.0% (cohort B) and 31.8% (cohort C) of patients, with evidence of improved tumor immune infiltration and durable responses in a subset of patients with available biopsy samples. In conclusion, combined MAPK inhibition and anti-PD-L1 therapy may provide treatment options for patients with advanced melanoma.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; B7-H1 Antigen; Cohort Studies; Diarrhea; Exanthema; Female; Humans; Imidazoles; Male; Melanoma; Middle Aged; Mitogen-Activated Protein Kinases; Mutation; Oximes; Progression-Free Survival; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Young Adult

In the KEYNOTE-022 study, pembrolizumab with dabrafenib and trametinib (triplet) improved progression-free survival (PFS) versus placebo with dabrafenib and trametinib (doublet) without reaching statistical significance. Mature results on PFS, duration of response (DOR), and overall survival (OS) are reported.. The double-blind, phase 2 part of KEYNOTE-022 enrolled patients with previously untreated. Between November 30, 2015 and April 24, 2017, 120 patients were randomly assigned to triplet (n=60) or doublet (n=60) therapy. With 36.6 months of follow-up, median PFS was 16.9 months (95% CI 11.3 to 27.9) with triplet and 10.7 months (95% CI 7.2 to 16.8) with doublet (HR 0.53; 95% CI 0.34 to 0.83). With triplet and doublet, respectively, PFS at 24 months was 41.0% (95% CI 27.4% to 54.2%) and 16.3% (95% CI 8.1% to 27.1%); median DOR was 25.1 months (95% CI 14.1 to not reached) and 12.1 months (95% CI 6.0 to 15.7), respectively. Median OS was not reached with triplet and was 26.3 months with doublet (HR 0.64; 95% CI 0.38 to 1.06). With triplet and doublet, respectively, OS at 24 months was 63.0% (95% CI 49.4% to 73.9%) and 51.7% (95% CI 38.4% to 63.4%). Grade 3-5 treatment-related adverse events (TRAEs) occurred in 35 patients (58%, including one death) receiving triplet and 15 patients (25%) receiving doublet.. In

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Double-Blind Method; Female; Humans; Imidazoles; Male; Melanoma; Oximes; Pyridones; Pyrimidinones; Survival Analysis

To assess the potential ocular toxicity of a combined BRAF inhibition (BRAFi) + MEK inhibition (MEKi) + hydroxychloroquine (HCQ) regime used to treat metastatic BRAF mutant melanoma.. Patients with stage IV metastatic melanoma and BRAF V600E mutations (n = 11, 31-68 years of age) were included. Treatment was with oral dabrafenib, 150 mg bid, trametinib, 2 mg/day, and HCQ, 400 mg to 600 mg bid. An ophthalmic examination, spectral domain optical coherence tomography, near-infrared and short-wavelength fundus autofluorescence, and static perimetry were performed at baseline, 1 month, and q/6 months after treatment.. There were no clinically significant ocular events; there was no ocular inflammation. The only medication-related change was a separation of the photoreceptor outer segment tip from the apical retinal pigment epithelium that could be traced from the fovea to the perifoveal retina noted in 9/11 (82%) of the patients. There were no changes in retinal pigment epithelium melanization or lipofuscin content by near-infrared fundus autofluorescence and short-wavelength fundus autofluorescence, respectively. There were no inner retinal or outer nuclear layer changes. Visual acuities and sensitivities were unchanged.. BRAFi (trametinib) + MEKi (dabrafenib) + HCQ causes very frequent, subclinical separation of the photoreceptor outer segment from the apical retinal pigment epithelium without inner retinal changes or signs of inflammation. The changes suggest interference with the maintenance of the outer retinal barrier and/or phagocytic/pump functions of the retinal pigment epithelium by effective MEK inhibition.

Topics: Adult; Aged; Antineoplastic Agents; Enzyme Inhibitors; Female; Humans; Hydroxychloroquine; Imidazoles; Macula Lutea; Male; MAP Kinase Kinase 1; Melanoma; Middle Aged; Oximes; Photoreceptor Cells; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Retinal Diseases; Retinal Pigment Epithelium

The combination of a BRAF inhibitor dabrafenib and a MEK inhibitor trametinib (CombiDT) has improved outcomes compared with chemotherapy or BRAF inhibitor monotherapy in advanced BRAF V600E/K melanoma. However, CombiDT causes a high incidence of pyrexia and treatment interruptions. Pharmacokinetic analysis may provide an explanation for the pyrexia.. 34 patients with Stage 3 BRAF V600 melanoma were treated with CombiDT on a clinical trial between August 2014 and June 2017. Plasma concentrations of drugs and metabolites were determined using validated LC-MS assays, in addition to analysis of a panel of cytokines.. No apparent associations between pyrexia and exposure to the drugs or metabolites could be observed. Greater elevations in IL-1B and IL-6 were observed in patients with pyrexia during the first week of treatment compared to those without pyrexia.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Chromatography, Liquid; Cytokines; Drug Combinations; Female; Fever; Humans; Imidazoles; Interleukin-1beta; Interleukin-6; Male; Mass Spectrometry; Melanoma; Middle Aged; Neoplasm Staging; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Young Adult

Topics: Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Azetidines; CTLA-4 Antigen; Disease-Free Survival; Female; Humans; Imidazoles; Immunotherapy; Ipilimumab; Male; Melanoma; Middle Aged; Molecular Targeted Therapy; Mutation; Neoplasm Metastasis; Nivolumab; Oximes; Piperidines; Programmed Cell Death 1 Receptor; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Treatment Outcome; Vemurafenib

Comparison of clinical outcomes of nivolumab + ipilimumab versus BRAF + MEK inhibitors (dabrafenib + trametinib or vemurafenib + cobimetinib) in BRAF-mutant advanced melanoma.. Matching-adjusted indirect comparisons were conducted between nivolumab + ipilimumab (CheckMate 067/069 studies) and BRAF + MEK inhibitors (COMBI-d, COMBI-v and coBRIM studies). Overall survival (OS), progression-free survival and objective response rates were assessed.. After adjusting, nivolumab + ipilimumab showed improved OS versus dabrafenib + trametinib (hazard ratio [HR] = 0.64; 95% CI: 0.46-0.89) or vemurafenib + cobimetinib (HR = 0.56; 95% CI: 0.36-0.89); OS outcomes were similar at 1 year, with benefits emerging after 12 months; progression-free survival and objective response rates were similar. Grade 3/4 adverse events occurred in 54.1% with nivolumab + ipilimumab, 31.6% with dabrafenib + trametinib and 59.5% with vemurafenib + cobimetinib.. Nivolumab + ipilimumab had significantly improved clinical outcomes versus BRAF + MEK inhibitors, with benefits increasing after longer follow-up. Ongoing randomized trials directly comparing these treatments are necessary to prospectively validate these findings.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Azetidines; Female; Follow-Up Studies; Humans; Imidazoles; Immunotherapy; Ipilimumab; Male; Melanoma; Middle Aged; Molecular Targeted Therapy; Mutation; Neoplasm Staging; Nivolumab; Oximes; Piperidines; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Survival Analysis; Vemurafenib

In the phase 3 COMBI-AD study, patients with resected, stage III melanoma with BRAF. COMBI-AD was a randomised, double-blind, placebo-controlled, phase 3 study done at 169 sites in 25 countries. Study participants were aged 18 years or older and had complete resection of stage IIIA (lymph node metastases >1 mm), IIIB, or IIIC cutaneous melanoma as per American Joint Committee on Cancer 7th edition criteria, with BRAF. Between Jan 31, 2013, and Dec 11, 2014, 870 patients were enrolled and randomly assigned to receive dabrafenib plus trametinib (n=438) or matching placebos (n=432). Data were collected until the data cutoff for analyses of the primary endpoint (June 30, 2017). The median follow-up was 34 months (IQR 28-39) in the dabrafenib plus trametinib group and 33 months (20·5-39) in the placebo group. During the 12-month treatment phase, there were no significant or clinically meaningful changes from baseline between groups in EQ-5D-3L visual analogue scale (EQ-VAS) or utility scores. During treatment, there were no clinically meaningful differences in VAS scores or utility scores in the dabrafenib plus trametinib group between patients who did and did not experience the most common adverse events. During long-term follow-up (range 15-48 months), VAS and utility scores were similar between groups and did not differ from baseline scores. At recurrence, there were significant decreases in VAS scores in both the dabrafenib plus trametinib group (mean change -6·02, SD 20·57; p=0·0032) and the placebo group (-6·84, 20·86; p<0·0001); the mean change in utility score also differed significantly at recurrence for both groups (dabrafenib plus trametinib -0·0626, 0·1911, p<0·0001; placebo -0·0748, 0·2182, p<0·0001).. These findings show that dabrafenib plus trametinib did not affect patient-reported outcome scores during or after adjuvant treatment, and suggest that preventing or delaying relapse with adjuvant therapy could be beneficial in this setting.. Novartis.

Topics: Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Chemotherapy, Adjuvant; Dermatologic Surgical Procedures; Disease Progression; Humans; Imidazoles; Melanoma; Mutation; Neoplasm Recurrence, Local; Neoplasm Staging; Oximes; Patient Reported Outcome Measures; Progression-Free Survival; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Quality of Life; Risk Assessment; Risk Factors; Skin Neoplasms; Time Factors

Patients who have unresectable or metastatic melanoma with a. We analyzed pooled extended-survival data from two trials involving previously untreated patients who had received BRAF inhibitor dabrafenib (at a dose of 150 mg twice daily) plus MEK inhibitor trametinib (2 mg once daily) in the COMBI-d and COMBI-v trials. The median duration of follow-up was 22 months (range, 0 to 76). The primary end points in the COMBI-d and COMBI-v trials were progression-free survival and overall survival, respectively.. A total of 563 patients were randomly assigned to receive dabrafenib plus trametinib (211 in the COMBI-d trial and 352 in the COMBI-v trial). The progression-free survival rates were 21% (95% confidence interval [CI], 17 to 24) at 4 years and 19% (95% CI, 15 to 22) at 5 years. The overall survival rates were 37% (95% CI, 33 to 42) at 4 years and 34% (95% CI, 30 to 38) at 5 years. In multivariate analysis, several baseline factors (e.g., performance status, age, sex, number of organ sites with metastasis, and lactate dehydrogenase level) were significantly associated with both progression-free survival and overall survival. A complete response occurred in 109 patients (19%) and was associated with an improved long-term outcome, with an overall survival rate of 71% (95% CI, 62 to 79) at 5 years.. First-line treatment with dabrafenib plus trametinib led to long-term benefit in approximately one third of the patients who had unresectable or metastatic melanoma with a

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Female; Follow-Up Studies; Humans; Imidazoles; Male; MAP Kinase Kinase Kinases; Melanoma; Middle Aged; Mutation; Oximes; Progression-Free Survival; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Survival Rate; Young Adult

Adjuvant dabrafenib plus trametinib therapy improves relapse-free survival in patients with resected stage III melanoma. We aimed to ascertain the proportion of patients who would have a pathological response and a response according to Response Evaluation Criteria in Solid Tumors (RECIST) after neoadjuvant dabrafenib plus trametinib therapy for resectable clinical stage III melanoma.. NeoCombi was a single-arm, open-label, single-centre, phase 2 study done at Melanoma Institute Australia (Sydney, NSW, Australia). Eligible patients were adults (aged ≥18 years) with histologically confirmed, resectable, RECIST-measurable, clinical stage IIIB-C (American Joint Committee on Cancer [AJCC] 7th edition), BRAF. Between Aug 20, 2014, and April 19, 2017, 40 patients were screened, of whom 35 eligible patients were enrolled, received neoadjuvant dabrafenib plus trametinib, and underwent resection. At the data cutoff (Sept 24, 2018), median follow-up was 27 months (IQR 21-36). At resection, 30 (86%) patients achieved a RECIST response; 16 (46%; 95% CI 29-63) had a complete response and 14 (40%; 24-58) had a partial response. Five patients (14%; 95% CI 5-30) had stable disease, and no patients progressed. After resection and pathological evaluation, all 35 patients achieved a pathological response, of whom 17 (49%; 95% CI 31-66) patients had a complete pathological response and 18 (51%; 95% CI 34-69) had a non-complete pathological response. Treatment-related serious adverse events occurred in six (17%) of 35 patients and grade 3-4 adverse events occurred in ten (29%) patients. No treatment-related deaths were reported.. Neoadjuvant dabrafenib plus trametinib therapy could be considered in the management of RECIST-measurable resectable stage III melanoma as it led to a high proportion of patients achieving a complete response according to RECIST and a high proportion of patients achieving a complete pathological response, with no progression during neoadjuvant therapy.. GlaxoSmithKline; Novartis; National Health and Medical Research Council, Australia; and Melanoma Institute Australia.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Imidazoles; Male; Melanoma; Middle Aged; Mutation; Neoadjuvant Therapy; Neoplasm Staging; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Double-Blind Method; Female; Humans; Imidazoles; Kaplan-Meier Estimate; Male; MAP Kinase Kinase Kinases; Melanoma; Middle Aged; Mutation; Oximes; Programmed Cell Death 1 Receptor; Progression-Free Survival; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Young Adult

Purpose To report 5-year landmark analysis efficacy and safety outcomes in patients with BRAF V600-mutant metastatic melanoma (MM) who received BRAF inhibitor dabrafenib (D) and MEK inhibitor trametinib (T) combination therapy versus D monotherapy in the randomized phase II BRF113220 study part C. Patients and Methods BRAF inhibitor-naive patients with BRAF V600-mutant MM were randomly assigned 1:1:1 to receive D 150 mg twice a day, D 150 mg twice a day plus T 1 mg once daily, or D 150 mg twice a day plus T 2 mg once daily (D + T 150/2). Patients who received D monotherapy could cross over to D + T 150/2 postprogression. Efficacy and safety were analyzed 4 and 5 years after initiation in patients with ≥ 5 years of follow-up. Results As of October 13, 2016, 18 patients who received D + T 150/2 remained in the study (13 [24%] of 54 enrolled at this dose plus five [11%] of 45 initially administered D who crossed over to D + T). With D + T 150/2, overall survival (OS; 4 years, 30%; 5 years, 28%) and progression-free survival (4 and 5 years, both 13%) appeared to stabilize with extended follow-up. Increased OS was observed in patients who received D + T with baseline normal lactate dehydrogenase (5 years, 45%) and normal lactate dehydrogenase with fewer than three organ sites with metastasis (5 years, 51%). With extended follow-up, one additional patient who received D + T 150/2 improved from a partial to a complete response. No new safety signals were observed. Conclusion This 5-year analysis represents the longest follow-up to date with BRAF + MEK inhibitor combination therapy in BRAF V600-mutant MM. Consistent with trends observed in landmark analyses with shorter follow-up, this therapy elicits durable plateaus of long-term OS and progression-free survival that last ≥ 5 years in some patients with MM.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Imidazoles; Male; Melanoma; Middle Aged; Mutation; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Young Adult

Purpose We report the efficacy and safety of dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor) combination therapy in BRAF V600E-mutated anaplastic thyroid cancer, a rare, aggressive, and highly lethal malignancy with poor patient outcomes and no systemic therapies with clinical benefit. Methods In this phase II, open-label trial, patients with predefined BRAF V600E-mutated malignancies received dabrafenib 150 mg twice daily and trametinib 2 mg once daily until unacceptable toxicity, disease progression, or death. The primary end point was investigator-assessed overall response rate. Secondary end points included duration of response, progression-free survival, overall survival, and safety. Results Sixteen patients with BRAF V600E-mutated anaplastic thyroid cancer were evaluable (median follow-up, 47 weeks; range, 4 to 120 weeks). All patients had received prior radiation treatment and/or surgery, and six had received prior systemic therapy. The confirmed overall response rate was 69% (11 of 16; 95% CI, 41% to 89%), with seven ongoing responses. Median duration of response, progression-free survival, and overall survival were not reached as a result of a lack of events, with 12-month estimates of 90%, 79%, and 80%, respectively. The safety population was composed of 100 patients who were enrolled with seven rare tumor histologies. Common adverse events were fatigue (38%), pyrexia (37%), and nausea (35%). No new safety signals were detected. Conclusion Dabrafenib plus trametinib is the first regimen demonstrated to have robust clinical activity in BRAF V600E-mutated anaplastic thyroid cancer and was well tolerated. These findings represent a meaningful therapeutic advance for this orphan disease.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Fatigue; Female; Fever; Humans; Imidazoles; Male; Middle Aged; Mutation; Nausea; Neoplasm Metastasis; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Thyroid Carcinoma, Anaplastic; Young Adult

Explore the heterogeneity in dynamics of tumour response to vemurafenib, dabrafenib and trametinib using routinely collected clinical trial imaging data.. Time-series imaging data from the phase III studies of vemurafenib, dabrafenib and trametinib were collected through a data repository. A mathematical model based on basic mechanisms of tumour growth was placed within a statistical modelling framework to analyse the data.. The analysis revealed: (1) existence of homogeneity in drug response and resistance development within a patient; (2) tumour shrinkage rate does not relate to rate of resistance development; (3) vemurafenib and dabrafenib, two BRAF inhibitors, have different variability in tumour shrinkage rates.. Overall these results show how analysis of the dynamics of individual lesions can shed light on the within and between patient differences in tumour shrinkage and resistance rates, which could be used to gain a macroscopic understanding of tumour heterogeneity.

Topics: Algorithms; Antineoplastic Agents; Drug Resistance, Neoplasm; Humans; Imidazoles; Melanoma; Models, Theoretical; Neoplasm Metastasis; Neoplasm Recurrence, Local; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Vemurafenib

Dual BRAF and MEK inhibition produces a response in a large number of patients with stage IV BRAF-mutant melanoma. The existing standard of care for patients with clinical stage III melanoma is upfront surgery and consideration for adjuvant therapy, which is insufficient to cure most patients. Neoadjuvant targeted therapy with BRAF and MEK inhibitors (such as dabrafenib and trametinib) might provide clinical benefit in this high-risk p opulation.. We undertook this single-centre, open-label, randomised phase 2 trial at the University of Texas MD Anderson Cancer Center (Houston, TX, USA). Eligible participants were adult patients (aged ≥18 years) with histologically or cytologically confirmed surgically resectable clinical stage III or oligometastatic stage IV BRAF. Between Oct 23, 2014, and April 13, 2016, we randomly assigned seven patients to standard of care, and 14 to neoadjuvant plus adjuvant dabrafenib and trametinib. The trial was stopped early after a prespecified interim safety analysis that occurred after a quarter of the participants had been accrued revealed significantly longer event-free survival with neoadjuvant plus adjuvant dabrafenib and trametinib than with standard of care. After a median follow-up of 18·6 months (IQR 14·6-23·1), significantly more patients receiving neoadjuvant plus adjuvant dabrafenib and trametinib were alive without disease progression than those receiving standard of care (ten [71%] of 14 patients vs none of seven in the standard of care group; median event-free survival was 19·7 months [16·2-not estimable] vs 2·9 months [95% CI 1·7-not estimable]; hazard ratio 0·016, 95% CI 0·00012-0·14, p<0·0001). Neoadjuvant plus adjuvant dabrafenib and trametinib were well tolerated with no occurrence of grade 4 adverse events or treatment-related deaths. The most common adverse events in the neoadjuvant plus adjuvant dabrafenib and trametinib group were expected grade 1-2 toxicities including chills (12 patients [92%]), headache (12 [92%]), and pyrexia (ten [77%]). The most common grade 3 adverse event was diarrhoea (two patients [15%]).. Neoadjuvant plus adjuvant dabrafenib and trametinib significantly improved event-free survival versus standard of care in patients with high-risk, surgically resectable, clinical stage III-IV melanoma. Although the trial finished early, limiting generalisability of the results, the findings provide proof-of-concept and support the rationale for further investigation of neoadjuvant approaches in this disease. This trial is currently continuing accrual as a single-arm study of neoadjuvant plus adjuvant dabrafenib and trametinib.. Novartis Pharmaceuticals Corporation.

Topics: Academic Medical Centers; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cancer Care Facilities; Chemotherapy, Adjuvant; Confidence Intervals; Disease-Free Survival; Humans; Imidazoles; Melanoma; Middle Aged; Mohs Surgery; Neoadjuvant Therapy; Neoplasm Invasiveness; Neoplasm Staging; Oximes; Prognosis; Pyridones; Pyrimidinones; Risk Assessment; Skin Neoplasms; Standard of Care; Survival Analysis; Texas; Treatment Outcome

The combination of dabrafenib and trametinib demonstrated encouraging antitumor activity and tolerability, at initial analysis, in Japanese patients with BRAF V600 mutant advanced melanoma warranting further investigation. This study evaluated the safety and tolerability, pharmacokinetics (PK) and preliminary efficacy of dabrafenib 150 mg b.i.d. plus trametinib 2 mg q.d. in Japanese patients with BRAF V600E/K mutant solid tumors (phase 1) and melanoma (phase 2). Phase 1 was primarily intended to assess safety and tolerability as assessed by adverse events (AE), and the primary end-point in phase 2 was to assess confirmed overall response rate (ORR). The secondary end-points in phase 1 included PK, confirmed/unconfirmed ORR and duration of response (DOR). The secondary end-points in phase 2 were PK, unconfirmed ORR, DOR, safety and tolerability. A total of 12 cutaneous melanoma patients were enrolled in the study (six in phase 1 and six in phase 2) and received the combination therapy of dabrafenib and trametinib. Common AE (≥50.0%) included pyrexia (75%), increased aspartate aminotransferase (67%), peripheral edema (50%) and nasopharyngitis (50%). The investigator-assessed ORR was reported in five patients (83%) in phase 1 and was also reported in five patients (83%; 95% confidence interval, 35.9-99.6; P < 0.0001) in phase 2. Plasma concentrations of both dabrafenib and trametinib seemed to a reach steady state by week 3. Overall, efficacy and PK properties for the dabrafenib plus trametinib combination in Japanese patients were comparable with those seen in global studies.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Female; Humans; Imidazoles; Japan; Kaplan-Meier Estimate; Male; Melanoma; Middle Aged; Mutation; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Treatment Outcome; Young Adult

Although BRAF inhibitor monotherapy yields response rates >50% in

Topics: Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Drug Resistance, Neoplasm; ErbB Receptors; Female; Humans; Imidazoles; Male; MAP Kinase Signaling System; Mitogen-Activated Protein Kinase Kinases; Oximes; Panitumumab; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

Longer time to progression (TTP) is associated with prolonged post-progression survival (PPS) in anaplastic lymphoma kinase+non-small cell lung cancer (NSCLC). This study evaluated whether TTP is associated with PPS among previously treated patients with metastatic v-Raf murine sarcoma viral oncogene homolog B V600E NSCLC receiving dabrafenib as monotherapy or in combination with trametinib.. Secondary analysis of phase II clinical trial data.. Patients who experienced disease progression treated with dabrafenib monotherapy or in combination with trametinib as second line or later in an open-label, non-randomised, phase II study.. The primary outcome was the TTP-PPS association. PPS was assessed with Kaplan-Meier analysis among patients with shorter versus longer TTP (< or ≥6 months). The TTP-PPS association was quantified in the Cox models adjusting for clinical covariates.. Of the 84 included patients who progressed on dabrafenib monotherapy (n=57) or combination therapy (n=27), 60 (71%) died during post-progression follow-up. Patients with TTP ≥6 months experienced significantly longer PPS compared with those with TTP <6 months (median PPS: 9.5 vs 2.7 months, log-rank p<0.001). Each 3 months of longer TTP was associated with a 32% lower hazard of death following progression (HR 0.68, 95% CI 0.52 to 0.88) in the multivariable Cox model. Similar associations were seen in each treatment arm.. A longer TTP duration after treatment with dabrafenib monotherapy or combination therapy was associated with significantly longer PPS duration.. NCT01336634; Post-results.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Disease Progression; Female; Humans; Imidazoles; Lung Neoplasms; Male; Mutation; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

Dabrafenib plus trametinib improved relapse-free survival (RFS) versus placebo (hazard ratio [HR], 0.47;. In this phase III trial, patients with resected. At median follow-up of 44 months (dabrafenib plus trametinib) and 42 months (placebo), 3- and 4-year RFS rates were 59% (95% CI, 55% to 64%) and 54% (95% CI, 49% to 59%) in the dabrafenib plus trametinib arm and 40% (95% CI, 35% to 45%) and 38% (95% CI, 34% to 44%) in the placebo arm, respectively (HR, 0.49; 95% CI, 0.40 to 0.59). Distant metastasis-free survival also favored dabrafenib plus trametinib (HR, 0.53; 95% CI, 0.42 to 0.67). The estimated cure rate was 54% (95% CI, 49% to 59%) in the dabrafenib plus trametinib arm compared with 37% (95% CI, 32% to 42%) in the placebo arm. Subgroup analysis of RFS demonstrated similar treatment benefit regardless of baseline factors, including disease stage, nodal metastatic burden, and ulceration.. Longer follow-up confirmed RFS benefit with dabrafenib plus trametinib. Subgroup analysis suggested that dabrafenib plus trametinib benefited patients regardless of baseline factors.

Topics: Adjuvants, Immunologic; Adult; Age Factors; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Imidazoles; Internationality; Male; Melanoma; Melanoma, Cutaneous Malignant; Middle Aged; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Sex Factors; Skin Neoplasms; Time Factors; Treatment Outcome

Previous analysis of COMBI-d (NCT01584648) demonstrated improved progression-free survival (PFS) and overall survival (OS) with combination dabrafenib and trametinib versus dabrafenib monotherapy in BRAF V600E/K-mutant metastatic melanoma. This study was continued to assess 3-year landmark efficacy and safety after ≥36-month follow-up for all living patients.. This double-blind, phase 3 study enrolled previously untreated patients with BRAF V600E/K-mutant unresectable stage IIIC or stage IV melanoma. Patients were randomized to receive dabrafenib (150 mg twice daily) plus trametinib (2 mg once daily) or dabrafenib plus placebo. The primary endpoint was PFS; secondary endpoints were OS, overall response, duration of response, safety, and pharmacokinetics.. Between 4 May and 30 November 2012, a total of 423 of 947 screened patients were randomly assigned to receive dabrafenib plus trametinib (n = 211) or dabrafenib monotherapy (n = 212). At data cut-off (15 February 2016), outcomes remained superior with the combination: 3-year PFS was 22% with dabrafenib plus trametinib versus 12% with monotherapy, and 3-year OS was 44% versus 32%, respectively. Twenty-five patients receiving monotherapy crossed over to combination therapy, with continued follow-up under the monotherapy arm (per intent-to-treat principle). Of combination-arm patients alive at 3 years, 58% remained on dabrafenib plus trametinib. Three-year OS with the combination reached 62% in the most favourable subgroup (normal lactate dehydrogenase and <3 organ sites with metastasis) versus only 25% in the unfavourable subgroup (elevated lactate dehydrogenase). The dabrafenib plus trametinib safety profile was consistent with previous clinical trial observations, and no new safety signals were detected with long-term use.. These data demonstrate that durable (≥3 years) survival is achievable with dabrafenib plus trametinib in patients with BRAF V600-mutant metastatic melanoma and support long-term first-line use of the combination in this setting.

Topics: Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Disease Progression; Disease-Free Survival; Double-Blind Method; Drug Administration Schedule; Humans; Imidazoles; Kaplan-Meier Estimate; Melanoma; Mutation; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Risk Factors; Skin Neoplasms; Time Factors; Treatment Outcome

Dabrafenib plus trametinib improves clinical outcomes in BRAF. This ongoing, multicentre, multicohort, open-label, phase 2 study evaluated oral dabrafenib (150 mg twice per day) plus oral trametinib (2 mg once per day) in four patient cohorts with melanoma brain metastases enrolled from 32 hospitals and institutions in Europe, North America, and Australia: (A) BRAF. Between Feb 28, 2014, and Aug 5, 2016, 125 patients were enrolled in the study: 76 patients in cohort A; 16 patients in cohort B; 16 patients in cohort C; and 17 patients in cohort D. At the data cutoff (Nov 28, 2016) after a median follow-up of 8·5 months (IQR 5·5-14·0), 44 (58%; 95% CI 46-69) of 76 patients in cohort A achieved an intracranial response. Intracranial response by investigator assessment was also achieved in nine (56%; 95% CI 30-80) of 16 patients in cohort B, seven (44%; 20-70) of 16 patients in cohort C, and ten (59%; 33-82) of 17 patients in cohort D. The most common serious adverse events related to study treatment were pyrexia for dabrafenib (eight [6%] of 125 patients) and decreased ejection fraction (five [4%]) for trametinib. The most common grade 3 or worse adverse events, regardless of study drug relationship, were pyrexia (four [3%] of 125) and headache (three [2%]).. Dabrafenib plus trametinib was active with a manageable safety profile in this melanoma population that was consistent with previous dabrafenib plus trametinib studies in patients with BRAF. Novartis.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Female; Fever; Headache; Humans; Imidazoles; Magnetic Resonance Imaging; Male; Melanoma; Middle Aged; Mutation; Oximes; Prospective Studies; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Stroke Volume; Young Adult

Understanding predictors of long-term benefit with currently available melanoma therapies is the key for optimising individualised treatments. A prior pooled analysis of dabrafenib plus trametinib (D + T)-randomised trials (median follow-up, 20.0 months) identified baseline lactate dehydrogenase (LDH) and number of organ sites with metastasis as predictive factors for progression-free (PFS) and overall (OS) survival. However, longer-term follow-up analyses are needed to confirm which patients treated with D + T can achieve maximum benefit.. Three-year landmark data were retrospectively pooled for D + T patients in phase 3 trials (COMBI-d [NCT01584648]; COMBI-v [NCT01597908]). Univariate and multivariate analyses assessed prognostic values of predefined baseline factors; regression tree analysis determined hierarchy and interactions between variables.. Long-term pooled outcomes were consistent with individual trial results (N = 563; 3-year PFS, 23%; 3-year OS, 44%). Baseline LDH level and number of organ sites remained strongly associated with and/or predictive of PFS and OS. In addition, baseline sum of lesion diameters (SLD) was identified as a predictor for progression. In the most favourable prognostic group (normal LDH, SLD <66 mm, <3 organ sites; n = 183/563 [33%]), 3-year PFS was 42%. Baseline number of organ sites was also predictive of outcomes in patients with PFS ≥ 6 months.. Using the largest phase 3 data set available for BRAF/MEK inhibitor combination therapy in melanoma, these results demonstrate that durable responses lasting ≥3 years are possible in subsets of patients with BRAF-mutant melanoma receiving D + T. Although the best predictive model evolved with longer follow-up, factors predicting clinical outcomes with the combination remained consistent with previous analyses.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Imidazoles; L-Lactate Dehydrogenase; Male; Melanoma; Middle Aged; Neoplasm Metastasis; Oximes; Predictive Value of Tests; Prognosis; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Risk Factors; Survival Analysis

Stage III malignant melanoma is a heterogeneous disease where those cases deemed marginally resectable or irresecatble are frequently incurable by surgery alone. Targeted therapy takes advantage of the high incidence of BRAF mutations in melanomas, most notably the V600E mutation. These agents have rarely been used in a neoadjuvant setting prior to surgery.. Thirteen consecutive patients with confirmed BRAF. Overall, 12/13 patients showed a marked clinical responsiveness to medical treatment, enabling a macroscopically successful resection in all cases. Four patients had a complete pathological response with no viable tumor evident in the resected specimens and eight patients showed evidence of minimally residual tumor with extensive tumoral necrosis and fibrosis. One patient progressed and died before surgery. At a median follow up of 20 months, 10 patients remain free of disease.. Perioperative treatment with BRAF inhibiting agents in BRAFV600E mutated Stage III melanoma patients facilitates surgical resection and affords satisfactory disease free survival.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Disease-Free Survival; Female; Humans; Imidazoles; Indoles; Male; Melanoma; Middle Aged; Neoadjuvant Therapy; Neoplasm Staging; Oximes; Perioperative Care; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Sulfonamides; Vemurafenib

Combination therapy with the BRAF inhibitor dabrafenib plus the MEK inhibitor trametinib improved survival in patients with advanced melanoma with BRAF V600 mutations. We sought to determine whether adjuvant dabrafenib plus trametinib would improve outcomes in patients with resected, stage III melanoma with BRAF V600 mutations.. In this double-blind, placebo-controlled, phase 3 trial, we randomly assigned 870 patients with completely resected, stage III melanoma with BRAF V600E or V600K mutations to receive oral dabrafenib at a dose of 150 mg twice daily plus trametinib at a dose of 2 mg once daily (combination therapy, 438 patients) or two matched placebo tablets (432 patients) for 12 months. The primary end point was relapse-free survival. Secondary end points included overall survival, distant metastasis-free survival, freedom from relapse, and safety.. At a median follow-up of 2.8 years, the estimated 3-year rate of relapse-free survival was 58% in the combination-therapy group and 39% in the placebo group (hazard ratio for relapse or death, 0.47; 95% confidence interval [CI], 0.39 to 0.58; P<0.001). The 3-year overall survival rate was 86% in the combination-therapy group and 77% in the placebo group (hazard ratio for death, 0.57; 95% CI, 0.42 to 0.79; P=0.0006), but this level of improvement did not cross the prespecified interim analysis boundary of P=0.000019. Rates of distant metastasis-free survival and freedom from relapse were also higher in the combination-therapy group than in the placebo group. The safety profile of dabrafenib plus trametinib was consistent with that observed with the combination in patients with metastatic melanoma.. Adjuvant use of combination therapy with dabrafenib plus trametinib resulted in a significantly lower risk of recurrence in patients with stage III melanoma with BRAF V600E or V600K mutations than the adjuvant use of placebo and was not associated with new toxic effects. (Funded by GlaxoSmithKline and Novartis; COMBI-AD ClinicalTrials.gov, NCT01682083 ; EudraCT number, 2012-001266-15 .).

Topics: Adjuvants, Immunologic; Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Double-Blind Method; Female; Humans; Imidazoles; Male; Melanoma; Melanoma, Cutaneous Malignant; Middle Aged; Mutation; Neoplasm Recurrence, Local; Neoplasm Staging; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Survival Analysis; Young Adult

BRAF. In this phase 2, sequentially enrolled, multicohort, multicentre, non-randomised, open-label study, adults (≥18 years of age) with previously untreated metastatic BRAF. Between April 16, 2014, and Dec 28, 2015, 36 patients were enrolled and treated with first-line dabrafenib plus trametinib. Median follow-up was 15·9 months (IQR 7·8-22·0) at the data cutoff (April 28, 2017). The proportion of patients with investigator-assessed confirmed overall response was 23 (64%, 95% CI 46-79), with two (6%) patients achieving a complete response and 21 (58%) a partial response. All patients had one or more adverse event of any grade, and 25 (69%) had one or more grade 3 or 4 event. The most common (occurring in more than two patients) grade 3 or 4 adverse events were pyrexia (four [11%]), alanine aminotransferase increase (four [11%]), hypertension (four [11%]), and vomiting (three [8%]). Serious adverse events occurring in more than two patients included alanine aminotransferase increase (five [14%]), pyrexia (four [11%]), aspartate aminotransferase increase (three [8%]), and ejection fraction decrease (three [8%]). One fatal serious adverse event deemed unrelated to study treatment was reported (cardiorespiratory arrest).. Dabrafenib plus trametinib represents a new therapy with clinically meaningful antitumour activity and a manageable safety profile in patients with previously untreated BRAF. Novartis.

Topics: Administration, Oral; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Confidence Intervals; Disease-Free Survival; Dose-Response Relationship, Drug; Drug Administration Schedule; Gene Expression Regulation, Neoplastic; Humans; Imidazoles; Lung Neoplasms; Maximum Tolerated Dose; Middle Aged; Mutation; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasm Staging; Oximes; Prognosis; Prospective Studies; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Survival Rate

Raman spectroscopy is a noninvasive and label-free optical technique that provides detailed information about the molecular composition of a sample. In this study, we evaluated the potential of Raman spectroscopy to predict skin toxicity due to tyrosine kinase inhibitors treatment. We acquired Raman spectra of skin of patients undergoing treatment with MEK, EGFR, or BRAF inhibitors, which are known to induce severe skin toxicity; for this pilot study, three patients were included for each inhibitor. Our algorithm, based on partial least squares-discriminant analysis (PLS-DA) and cross-validation by bootstrapping, discriminated to variable degrees spectra from patient suffering and not suffering cutaneous adverse events. For MEK and EGFR inhibitors, discriminative power was more than 90% in the viable epidermis skin layer; whereas for BRAF inhibitors, discriminative power was 71%. There was a 81.5% correlation between blood drug concentration and Raman signature of skin in the case of EGFR inhibitors and viable epidermis skin layer. Our results demonstrate the power of Raman spectroscopy to detect apparition of skin toxicity in patients treated with tyrosine kinase inhibitors at levels not detectable via dermatological inspection and histological evaluation. Cancer Res; 77(2); 557-65. ©2016 AACR.

Topics: Aged; Algorithms; Antineoplastic Agents; Area Under Curve; Biomarkers; Drug Eruptions; Erlotinib Hydrochloride; Female; Humans; Imidazoles; Indoles; Male; Middle Aged; Oximes; Pilot Projects; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; ROC Curve; Sensitivity and Specificity; Skin; Spectrum Analysis, Raman; Sulfonamides; Vemurafenib

To report the overall survival (OS) and clinical characteristics of BRAF inhibitor-naive long-term responders and survivors treated with dabrafenib plus trametinib in a phase I and II study of patients with BRAF V600 mutation-positive metastatic melanoma.. BRAF inhibitor-naive patients treated with dabrafenib 150 mg twice daily plus trametinib 2 mg daily (the 150/2 group) from the non-randomly assigned (part B) and randomly assigned (part C) cohorts of the study were analyzed for progression-free and OS separately. Baseline characteristics and factors on treatment were analyzed for associations with durable responses and OS.. For BRAF inhibitor-naive patients in the 150/2 groups (n = 78), the progression-free survival at 1, 2, and 3 years was 44%, 22%, and 18%, respectively, for part B (n = 24) and 41%, 25%, and 21%, respectively, for part C (n = 54). Median OS was 27.4 months in part B and 25 months in part C. OS at 1, 2, and 3 years was 72%, 60%, and 47%, respectively, for part B and 80%, 51%, and 38%, respectively, for part C. Prolonged survival was associated with metastases in fewer than three organ sites and lower baseline lactate dehydrogenase. OS at 3 years was 62% in patients with normal baseline lactate dehydrogenase and 63% in patients with a complete response.. Dabrafenib plus trametinib results in a median OS of more than 2 years in BRAF inhibitor-naive patients with BRAF V600 mutation-positive metastatic melanoma, and approximately 20% were progression free at 3 years. Durable responses occurred in patients with good prognostic features at baseline, which may be predictive.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Imidazoles; Male; Melanoma; Middle Aged; Mutation; Neoplasm Metastasis; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Survival Rate

Inhibitors of the mitogen-activated protein kinase (MAPK) signal pathway have decisively improved the prognosis of metastatic cutaneous melanoma in patients with an activating mutation in position V600 of the BRAF gene. We report on a patient who was regularly examined in our clinic while participating in a randomized blinded clinical trial. The aim of this trial was to examine the effectiveness and tolerability of a combination of the BRAF inhibitor dabrafenib and the MAPK kinase (MEK) inhibitor trametinib compared with a monotherapy with dabrafenib (plus placebo). During therapy the patient developed a diffuse neuroretinal detachment which could not be completely reversed after discontinuation of the study medication.

Topics: Antineoplastic Combined Chemotherapy Protocols; Central Serous Chorioretinopathy; Diagnosis, Differential; Female; Humans; Imidazoles; Melanoma; Middle Aged; Oximes; Pyridones; Pyrimidinones; Single-Blind Method; Skin Neoplasms; Treatment Outcome

Targeted therapies for melanoma have shown clinical benefit in increasing the survival of metastatic patients. Cutaneous adverse events have been reported, but hair and nail data have been rarely detailed. Patients treated with BRAF and MEK inhibitors for metastatic melanoma underwent dermatological evaluation before the start of each treatment and after every four weeks. Pull test, global photography, dermoscopy/trichoscopy and scalp biopsy were performed. Appendages adverse events were graded using the National Cancer Institute's Common Terminology Criteria. Of the 24 patients included, 14 underwent treatment with a selective BRAF inhibitor; 10 received a combined treatment (dabrafenib/trametinib). Adnexal adverse events were common in the group of patients receiving vemurafenib, and included hair kinking, acute hair loss, and hair colour changes, often present in association, classified as G2 in three patients and G1 in eight. Dabrafenib alone induced hair kinking and colour changes in 60% of the patients. Combined treatment with dabrafenib/trametinib did not induce hair changes. Onycholysis was the most common nail side effect, and the unique side effect of dabrafenib (alone or in combination). Vemurafenib also induced acute paronychia and brittle nails. All nail side effects were graded as G1. Hair and nail side effects during targeted therapy for melanoma are not rare. The early recognition and cure of such side effects by dermatologists is of benefit to ensure the need for dose reduction or drug discontinuation.

Topics: Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Drug Eruptions; Female; Hair Diseases; Humans; Imidazoles; Indoles; Male; Melanoma; Middle Aged; Mitogen-Activated Protein Kinase Kinases; Molecular Targeted Therapy; Nail Diseases; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; raf Kinases; Skin Neoplasms; Sulfonamides; Vemurafenib

Combined treatment with dabrafenib and trametinib (CombiDT) achieves clinical responses in only about 15% of patients with BRAF inhibitor (BRAFi)-refractory metastatic melanoma in contrast to the higher response rate observed in BRAFi-naïve patients. Identifying correlates of response and mechanisms of resistance in this population will facilitate clinical management and rational therapeutic development.. To determine correlates of benefit from CombiDT therapy in patients with BRAFi-refractory metastatic melanoma.. Single-center, single-arm, open-label phase 2 trial of CombiDT treatment in patients with BRAF V600 metastatic melanoma resistant to BRAFi monotherapy conducted between September 2012 and October 2014 at the University of Texas MD Anderson Cancer Center. Key eligibility criteria for participants included BRAF V600 metastatic melanoma, prior BRAFi monotherapy, measurable disease (RECIST 1.1), and tumor accessible for biopsy.. Patients were treated with dabrafenib (150 mg, twice daily) and trametinib (2 mg/d) continuously until disease progression or intolerance. All participants underwent a mandatory baseline biopsy, and optional biopsy specimens were obtained on treatment and at disease progression. Whole-exome sequencing, reverse transcription polymerase chain reaction analysis for BRAF splicing, RNA sequencing, and immunohistochemical analysis were performed on tumor samples, and blood was analyzed for levels of circulating BRAF V600.. The primary end point was overall response rate (ORR). Progression-free survival (PFS) and overall survival (OS) were secondary clinical end points.. A total of 28 patients were screened, and 23 enrolled. Among evaluable patients, the confirmed ORR was 10%; disease control rate (DCR) was 45%, and median PFS was 13 weeks. Clinical benefit was associated with duration of prior BRAFi therapy greater than 6 months (DCR, 73% vs 11% for ≤6 months; P = .02) and decrease in circulating BRAF V600 at day 8 of cycle 1 (DCR, 75% vs 18% for no decrease; P = .02) but not with pretreatment mitogen-activated protein kinase (MAPK) pathway mutations or activation. Biopsy specimens obtained during treatment demonstrated that CombiDT therapy failed to achieve significant MAPK pathway inhibition or immune infiltration in most patients.. The baseline presence of MAPK pathway alterations was not associated with benefit from CombiDT in patients with BRAFi-refractory metastatic melanoma. Failure to inhibit the MAPK pathway provides a likely explanation for the limited clinical benefit of CombiDT in this setting. Circulating BRAF V600 is a promising early biomarker of clinical response.. clinicaltrials.gov Identifier: NCT01619774.

Topics: Adaptor Proteins, Signal Transducing; Adult; Antineoplastic Agents; B7-H1 Antigen; CD8 Antigens; Disease-Free Survival; Drug Resistance, Neoplasm; Female; Humans; Imidazoles; Immunohistochemistry; Male; MAP Kinase Signaling System; Melanoma; Middle Aged; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinases; Oximes; Phosphorylation; Prospective Studies; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Ribosomal Protein S6; Signal Transduction; Skin Neoplasms; Treatment Outcome

BRAF mutations act as an oncogenic driver via the mitogen-activated protein kinase (MAPK) pathway in non-small cell lung cancer (NSCLC). BRAF inhibition has shown antitumour activity in patients with BRAF(V600E)-mutant NSCLC. Dual MAPK pathway inhibition with BRAF and MEK inhibitors in BRAF(V600E)-mutant NSCLC might improve efficacy over BRAF inhibitor monotherapy based on observations in BRAF(V600)-mutant melanoma. We aimed to assess the antitumour activity and safety of dabrafenib plus trametinib in patients with BRAF(V600E)-mutant NSCLC.. In this phase 2, multicentre, non-randomised, open-label study, we enrolled adult patients (aged ≥18 years) with pretreated metastatic stage IV BRAF(V600E)-mutant NSCLC who had documented tumour progression after at least one previous platinum-based chemotherapy and had had no more than three previous systemic anticancer therapies. Patients with previous BRAF or MEK inhibitor treatment were ineligible. Patients with brain metastases were allowed to enrol only if the lesions were asymptomatic, untreated (or stable more than 3 weeks after local therapy if treated), and measured less than 1 cm. Enrolled patients received oral dabrafenib (150 mg twice daily) plus oral trametinib (2 mg once daily) in continuous 21-day cycles until disease progression, unacceptable adverse events, withdrawal of consent, or death. The primary endpoint was investigator-assessed overall response, which was assessed by intention to treat in the protocol-defined population (patients who received second-line or later treatment); safety was also assessed in this population and was assessed at least once every 3 weeks, with adverse events, laboratory values, and vital signs graded according to the Common Terminology Criteria for Adverse Events version 4.0. The study is ongoing but no longer recruiting patients. This trial is registered with ClinicalTrials.gov, number NCT01336634.. Between Dec 20, 2013, and Jan 14, 2015, 59 patients from 30 centres in nine countries across North America, Europe, and Asia met eligibility criteria. Two patients who had previously been untreated due to protocol deviation were excluded; thus, 57 eligible patients were enrolled. 36 patients (63·2% [95% CI 49·3-75·6]) achieved an investigator-assessed overall response. Serious adverse events were reported in 32 (56%) of 57 patients and included pyrexia in nine (16%), anaemia in three (5%), confusional state in two (4%), decreased appetite in two (4%), haemoptysis in two (4%), hypercalcaemia in two (4%), nausea in two (4%), and cutaneous squamous cell carcinoma in two (4%). The most common grade 3-4 adverse events were neutropenia in five patients (9%), hyponatraemia in four (7%), and anaemia in three (5%). Four patients died during the study from fatal adverse events judged to be unrelated to treatment (one retroperitoneal haemorrhage, one subarachnoid haemorrhage, one respiratory distress, and one from disease progression that was more severe than typical progression, as assessed by the investigator).. Dabrafenib plus trametinib could represent a new targeted therapy with robust antitumour activity and a manageable safety profile in patients with BRAF(V600E)-mutant NSCLC.. GlaxoSmithKline.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Carcinoma, Large Cell; Carcinoma, Non-Small-Cell Lung; Female; Follow-Up Studies; Humans; Imidazoles; Lung Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Mutation; Neoplasm Recurrence, Local; Neoplasm Staging; Oximes; Prognosis; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Survival Rate

BRAF inhibitor-based therapies have been shown to induce cutaneous toxicities, with onset generally in the first 8-26 weeks of therapy.. To determine whether cutaneous toxicities persist in patients who have remained on BRAF inhibitor-based therapies for longer than 52 weeks, and therefore whether ongoing dermatology assessment is required.. All patients treated with the BRAF inhibitors vemurafenib or dabrafenib or combination BRAF inhibitor and mitogen-activated protein kinase kinase (MEK) inhibitor therapy at Westmead Hospital, Sydney, Australia underwent regular dermatological assessments for the duration of therapy. All patients enrolled in a clinical trial, and 18% of patients in the compassionate access scheme underwent a baseline assessment prior to commencement of therapy and every 4-8 weeks thereafter. Patients' adverse events were recorded in a specific database.. Patients continued to develop cutaneous adverse events after 52 weeks of continuous therapy. Patients on single-agent BRAF inhibitor therapy suffered from Grover disease (45%), plantar hyperkeratosis (45%), verrucal keratosis (18%) and even cutaneous squamous cell carcinoma (16%). The most frequent adverse event seen in patients in the combination BRAF and MEK inhibitor group was an acneiform eruption (40%).. Patients on BRAF inhibitor-based therapies need to continue to have regular dermatological follow-up independent of the duration of their therapy.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Drug Eruptions; Female; Humans; Imidazoles; Indoles; Male; MAP Kinase Kinase Kinases; Melanoma; Middle Aged; Neoplasm Metastasis; Oximes; Prospective Studies; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Skin Neoplasms; Sulfonamides; Vemurafenib

The BRAF inhibitors vemurafenib and dabrafenib have shown efficacy as monotherapies in patients with previously untreated metastatic melanoma with BRAF V600E or V600K mutations. Combining dabrafenib and the MEK inhibitor trametinib, as compared with dabrafenib alone, enhanced antitumor activity in this population of patients.. In this open-label, phase 3 trial, we randomly assigned 704 patients with metastatic melanoma with a BRAF V600 mutation to receive either a combination of dabrafenib (150 mg twice daily) and trametinib (2 mg once daily) or vemurafenib (960 mg twice daily) orally as first-line therapy. The primary end point was overall survival.. At the preplanned interim overall survival analysis, which was performed after 77% of the total number of expected events occurred, the overall survival rate at 12 months was 72% (95% confidence interval [CI], 67 to 77) in the combination-therapy group and 65% (95% CI, 59 to 70) in the vemurafenib group (hazard ratio for death in the combination-therapy group, 0.69; 95% CI, 0.53 to 0.89; P=0.005). The prespecified interim stopping boundary was crossed, and the study was stopped for efficacy in July 2014. Median progression-free survival was 11.4 months in the combination-therapy group and 7.3 months in the vemurafenib group (hazard ratio, 0.56; 95% CI, 0.46 to 0.69; P<0.001). The objective response rate was 64% in the combination-therapy group and 51% in the vemurafenib group (P<0.001). Rates of severe adverse events and study-drug discontinuations were similar in the two groups. Cutaneous squamous-cell carcinoma and keratoacanthoma occurred in 1% of patients in the combination-therapy group and 18% of those in the vemurafenib group.. Dabrafenib plus trametinib, as compared with vemurafenib monotherapy, significantly improved overall survival in previously untreated patients with metastatic melanoma with BRAF V600E or V600K mutations, without increased overall toxicity. (Funded by GlaxoSmithKline; ClinicalTrials.gov number, NCT01597908.).

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Imidazoles; Indoles; Intention to Treat Analysis; Kaplan-Meier Estimate; Male; Melanoma; Middle Aged; Mitogen-Activated Protein Kinase Kinases; Mutation; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Sulfonamides; Survival Analysis; Vemurafenib; Young Adult

Pyrexia is a frequent adverse event with combined dabrafenib and trametinib therapy (CombiDT), but little is known of its clinical associations, etiology, or appropriate management.. All patients on the BRF133220 phase I/II trial of CombiDT treated at the standard dose (150/2) were included for assessment of pyrexia (n = 201). BRAF and MEK inhibitor-naïve patients (n = 117) were included for efficacy analyses. Pyrexia was defined as temperature ≥38°C (≥100.4(°)F) or related symptoms.. Fifty-nine percent of patients developed pyrexia during treatment, 24% of which had pyrexia symptoms without a recorded elevation in body temperature. Pyrexia was grade 2+ in 60% of pyrexia patients. Median time to onset of first pyrexia was 19 days, with a median duration of 9 days. Pyrexia patients had a median of two pyrexia events, but 21% had three or more events. Various pyrexia management approaches were conducted in this study. A trend was observed between dabrafenib and hydroxy-dabrafenib exposure and pyrexia. No baseline clinical characteristics predicted pyrexia, and pyrexia was not statistically significantly associated with treatment outcome.. Pyrexia is a frequent and recurrent toxicity with CombiDT treatment. No baseline features predict pyrexia, and it is not associated with clinical outcome. Dabrafenib and metabolite exposure may contribute to the etiology of pyrexia. The optimal secondary prophylaxis for pyrexia is best studied in a prospective trial.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Female; Fever; Humans; Imidazoles; Male; Melanoma; Middle Aged; Mutation; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

Hairy cell leukemia (HCL) shows unique clinicopathological and biological features. HCL responds well to purine analogs but relapses are frequent and novel therapies are required. BRAF-V600E is the key driver mutation in HCL and distinguishes it from other B-cell lymphomas, including HCL-like leukemias/lymphomas (HCL-variant and splenic marginal zone lymphoma). The kinase-activating BRAF-V600E mutation also represents an ideal therapeutic target in HCL. Here, we investigated the biological and therapeutic importance of the activated BRAF-mitogen-activated protein kinase kinase (MEK)-extracellular signal-regulated kinase (ERK) pathway in HCL by exposing in vitro primary leukemic cells purified from 26 patients to clinically available BRAF (vemurafenib; dabrafenib) or MEK (trametinib) inhibitors. Results were validated in vivo in samples from vemurafenib-treated HCL patients within a phase 2 clinical trial. BRAF and MEK inhibitors caused, specifically in HCL (but not HCL-like) cells, marked MEK/ERK dephosphorylation, silencing of the BRAF-MEK-ERK pathway transcriptional output, loss of the HCL-specific gene expression signature, downregulation of the HCL markers CD25, tartrate-resistant acid phosphatase, and cyclin D1, smoothening of leukemic cells' hairy surface, and, eventually, apoptosis. Apoptosis was partially blunted by coculture with bone marrow stromal cells antagonizing MEK-ERK dephosphorylation. This protective effect could be counteracted by combined BRAF and MEK inhibition. Our results strongly support and inform the clinical use of BRAF and MEK inhibitors in HCL.

Topics: Antineoplastic Agents; Gene Expression Regulation, Leukemic; Humans; Imidazoles; Indoles; Leukemia, Hairy Cell; MAP Kinase Kinase Kinases; MAP Kinase Signaling System; Oximes; Phosphorylation; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Sulfonamides; Transcriptome; Tumor Cells, Cultured; Vemurafenib

To present the impact of treatments on health-related quality of life (HRQoL) from the double-blind, randomised phase III COMBI-d study that investigated the combination of dabrafenib and trametinib versus dabrafenib monotherapy in patients with BRAF V600E/K-mutant metastatic melanoma. COMBI-d showed significantly prolonged progression-free survival for the combination.. HRQoL was evaluated using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-C30, a generic cancer questionnaire (completed at baseline, during study treatment, at progression and post progression) assessing various dimensions (global health/QoL, functional status, and symptom impact). A mixed-model, repeated-measures analyses of covariance evaluated differences between arms.. Questionnaire completion rates were >95% at baseline, >85% to week 40 and >70% at disease progression. Baseline scores across both arms were comparable for all dimensions. Global health dimension scores were significantly better at weeks 8, 16 and 24 for patients receiving the combination during treatment and at progression. The majority of functional dimension scores (physical, social, role, emotional and cognitive functioning) trended in favour of the combination. Pain scores were significantly improved and clinically meaningful (6-13 point difference) for patients receiving the combination for all follow-up assessments versus those receiving dabrafenib monotherapy. For other symptom dimensions (nausea and vomiting, diarrhoea, dyspnoea, and constipation), scores trended in favour of dabrafenib monotherapy.. This analysis demonstrates that the combination of dabrafenib and trametinib provides better preservation of HRQoL and pain improvements versus dabrafenib monotherapy while also delaying progression. (Clinicaltrials.gov registration number: NCT01584648).

Topics: Amino Acid Substitution; Antineoplastic Combined Chemotherapy Protocols; Health Status; Humans; Imidazoles; Melanoma; Neoplasm Metastasis; Oximes; Pain Measurement; Proto-Oncogene Mas; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Quality of Life; Skin Neoplasms; Valine

We conducted a prospective trial of BRAF and mitogen-activated protein kinase kinase (MEK) targeted therapy in advanced, operable BRAF mutation-positive melanoma to determine feasibility, tumor response rates, and biomarkers of response and resistance.. Thirteen patients with locally or regionally advanced BRAF mutation-positive melanoma received dabrafenib 150 mg po bid for 14 days, followed by dabrafenib plus trametinib 2 mg po daily for 14 days before operation. Biopsies and tumor measurements were obtained at baseline and days 14 and 28. Formalin-fixed paraffin embedded specimens were analyzed with hematoxylin and eosin, Ki-67, cleaved caspase-3, CD8, phosphorylated extracellular signal-regulated kinase (ERK), and phosphorylated MEK immunostains.. Therapy was tolerated well, with toxicity ≥ grade 3 in 2 of 13 (15%) patients. All 12 patients receiving >14 days of therapy had substantial reduction in tumor volume (65% at day 14 and 78% at day 28) and underwent resection. After 14 days of dabrafenib therapy, there was a marked reduction in viable melanoma cells and a CD8 T-cell--rich infiltrate. Proliferation of the residual melanoma cells was reduced and apoptosis was increased. The cells continued to express phosphorylated ERK and phosphorylated MEK consistent with incomplete mitogen-activated protein kinase pathway inhibition.. Preoperative targeted therapy of advanced BRAF-mutant melanoma is feasible, well tolerated, induces brisk tumor responses, and facilitates correlative science. A CD8 T-cell-rich infiltrate indicates a potential immune-mediated mechanism of action. Both proliferation and apoptosis were inhibited, but the mitogen-activated protein kinase pathway remained activated, suggesting intrinsic resistance in a subset of tumor cells. Additional investigation of the anti-tumor immune response during targeted therapy and the mechanisms of intrinsic resistance can yield novel therapeutic strategies.

Topics: Administration, Oral; Adult; Aged; Biomarkers, Tumor; Biopsy; DNA Mutational Analysis; DNA, Neoplasm; Dose-Response Relationship, Drug; Drug Therapy, Combination; Feasibility Studies; Female; Follow-Up Studies; Humans; Imidazoles; Male; MAP Kinase Kinase 1; Melanoma; Middle Aged; Mitogen-Activated Protein Kinases; Mutation; Oximes; Preoperative Care; Prospective Studies; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Young Adult

Previously, a study of ours showed that the combination of dabrafenib and trametinib improves progression-free survival compared with dabrafenib and placebo in patients with BRAF Val600Lys/Glu mutation-positive metastatic melanoma. The study was continued to assess the secondary endpoint of overall survival, which we report in this Article.. We did this double-blind phase 3 study at 113 sites in 14 countries. We enrolled previously untreated patients with BRAF Val600Glu or Val600Lys mutation-positive unresectable stage IIIC or stage IV melanoma. Participants were computer-randomised (1:1) to receive a combination of dabrafenib (150 mg orally twice daily) and trametinib (2 mg orally once daily), or dabrafenib and placebo. The primary endpoint was progression-free survival and overall survival was a secondary endpoint. This study is registered with ClinicalTrials.gov, number NCT01584648.. Between May 4, 2012, and Nov 30, 2012, we screened 947 patients for eligibility, of whom 423 were randomly assigned to receive dabrafenib and trametinib (n=211) or dabrafenib only (n=212). The final data cutoff was Jan 12, 2015, at which time 222 patients had died. Median overall survival was 25·1 months (95% CI 19·2-not reached) in the dabrafenib and trametinib group versus 18·7 months (15·2-23·7) in the dabrafenib only group (hazard ratio [HR] 0·71, 95% CI 0·55-0·92; p=0·0107). Overall survival was 74% at 1 year and 51% at 2 years in the dabrafenib and trametinib group versus 68% and 42%, respectively, in the dabrafenib only group. Based on 301 events, median progression-free survival was 11·0 months (95% CI 8·0-13·9) in the dabrafenib and trametinib group and 8·8 months (5·9-9·3) in the dabrafenib only group (HR 0·67, 95% CI 0·53-0·84; p=0·0004; unadjusted for multiple testing). Treatment-related adverse events occurred in 181 (87%) of 209 patients in the dabrafenib and trametinib group and 189 (90%) of 211 patients in the dabrafenib only group; the most common was pyrexia (108 patients, 52%) in the dabrafenib and trametinib group, and hyperkeratosis (70 patients, 33%) in the dabrafenib only group. Grade 3 or 4 adverse events occurred in 67 (32%) patients in the dabrafenib and trametinib group and 66 (31%) patients in the dabrafenib only group.. The improvement in overall survival establishes the combination of dabrafenib and trametinib as the standard targeted treatment for BRAF Val600 mutation-positive melanoma. Studies assessing dabrafenib and trametinib in combination with immunotherapies are ongoing.. GlaxoSmithKline.

Topics: Adult; Aged; Aged, 80 and over; Disease-Free Survival; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Imidazoles; Male; Melanoma; Middle Aged; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Treatment Outcome; Young Adult

The treatment of patients with metastatic melanomas that harbour BRAF V600E or V600K mutations with trametinib plus dabrafenib appears to be superior to treatment with vemurafenib alone. This treatment regimen is likely to become available in Switzerland in the near future.. To determine the cost-effectiveness of trametinib plus dabrafenib.. A Markov cohort simulation was conducted to model the clinical course of typical patients with metastatic melanoma. Information on response rates, clinical condition and follow-up treatments were derived and transition probabilities estimated based on the results of a clinical trial that compared treatment with trametinib plus dabrafenib vs. vemurafenib alone.. Treatment with trametinib plus dabrafenib was estimated to cost an additional CHF199 647 (Swiss francs) on average and yield a gain of 0·52 quality-adjusted life years (QALYs), resulting in an incremental cost-effectiveness ratio of CHF385 603 per QALY. Probabilistic sensitivity analyses showed that a willingness-to-pay threshold of CHF100 000 per QALY would not be reached at the current US price of trametinib.. The introduction of trametinib in Switzerland at US market prices for the treatment of metastatic BRAF V600-mutated melanoma with trametinib plus dabrafenib is unlikely to be cost-effective compared with vemurafenib monotherapy. A reduction in the total price of the combination therapy is required to achieve an acceptable cost-effectiveness ratio for this clinically promising treatment.

Topics: Administration, Oral; Antineoplastic Combined Chemotherapy Protocols; Cost-Benefit Analysis; Disease Progression; Drug Administration Schedule; Drug Costs; Humans; Imidazoles; Melanoma; Mutation; Neoplasm Metastasis; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Quality of Life; Quality-Adjusted Life Years; Skin Neoplasms; Switzerland; Treatment Outcome

Patients with BRAF V600E mutation-positive melanoma who were assigned to 150 mg dabrafenib twice daily combined with 2 mg trametinib once daily in a phase I/II study showed a median overall survival (OS) of 23.8 months, compared with 20.2 months for patients assigned to dabrafenib alone [hazard ratio (HR)=0.73, 95% confidence interval (CI) 0.43-1.24; data cutoff March 2013], on the basis of an intention-to-treat analysis. Because patients assigned to dabrafenib monotherapy were allowed to switch to combination therapy upon disease progression, we attempted to adjust for confounding effects on OS. Randomization-based adjustment methods, Rank Preserving Structural Failure Time Models and the Iterative Parameter Estimation algorithm, were used. Two analyses, 'treatment group' (assumes that treatment effect continues beyond treatment discontinuation) and 'on treatment' (assumes that the treatment effect disappears upon treatment discontinuation), were used to test assumptions on the durability of the treatment effect. A total of 45/54 (83%) patients assigned to dabrafenib monotherapy switched to the trametinib/dabrafenib combination. Adjusted OS HRs ranged from 0.47 to 0.50, depending on the analysis, compared with the unadjusted OS HR of 0.73. CIs continued to cross 1.00; thus, adjusted estimates did not provide statistically significant evidence of a treatment benefit on survival. Reduction of HRs after adjusting for the effect of treatment switching suggests that the intention-to-treat analysis underestimates the effect of dabrafenib plus trametinib on OS, although several factors, such as small trial size and methodological assumptions, affect the certainty of the conclusions.

Topics: Algorithms; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Drug Substitution; Humans; Imidazoles; Kaplan-Meier Estimate; Melanoma; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

To evaluate dabrafenib, a selective BRAF inhibitor, combined with trametinib, a selective MEK inhibitor, in patients with BRAF V600-mutant metastatic colorectal cancer (mCRC).. A total of 43 patients with BRAF V600-mutant mCRC were treated with dabrafenib (150 mg twice daily) plus trametinib (2 mg daily), 17 of whom were enrolled onto a pharmacodynamic cohort undergoing mandatory biopsies before and during treatment. Archival tissues were analyzed for microsatellite instability, PTEN status, and 487-gene sequencing. Patient-derived xenografts were established from core biopsy samples.. Of 43 patients, five (12%) achieved a partial response or better, including one (2%) complete response, with duration of response > 36 months; 24 patients (56%) achieved stable disease as best confirmed response. Ten patients (23%) remained in the study > 6 months. All nine evaluable during-treatment biopsies had reduced levels of phosphorylated ERK relative to pretreatment biopsies (average decrease ± standard deviation, 47% ± 24%). Mutational analysis revealed that the patient achieving a complete response and two of three evaluable patients achieving a partial response had PIK3CA mutations. Neither PTEN loss nor microsatellite instability correlated with efficacy. Responses to dabrafenib plus trametinib were comparable in patient-derived xenograft-bearing mice and the biopsied lesions from each corresponding patient.. The combination of dabrafenib plus trametinib has activity in a subset of patients with BRAF V600-mutant mCRC. Mitogen-activated protein kinase signaling was inhibited in all patients evaluated, but to a lesser degree than observed in BRAF-mutant melanoma with dabrafenib alone. PIK3CA mutations were identified in responding patients and thus do not preclude response to this regimen. Additional studies targeting the mitogen-activated protein kinase pathway in this disease are warranted.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Biopsy; Cohort Studies; Colorectal Neoplasms; Female; Follow-Up Studies; Humans; Imidazoles; Male; MAP Kinase Kinase 1; Mice; Microsatellite Instability; Middle Aged; Mutation; Neoplasm Staging; Oximes; Prognosis; Proto-Oncogene Proteins B-raf; PTEN Phosphohydrolase; Pyridones; Pyrimidinones; Xenograft Model Antitumor Assays

In the COMBI-v trial, patients with previously untreated BRAF Val600Glu or Val600Lys mutant unresectable or metastatic melanoma who were treated with the combination of dabrafenib and trametinib had significantly longer overall and progression-free survival than those treated with vemurafenib alone. Here, we present the effects of treatments on health-related quality of life (HRQoL), an exploratory endpoint in the COMBI-v study.. COMBI-v was an open-label, randomised phase 3 study in which 704 patients with metastatic melanoma with a BRAF Val600 mutation were randomly assigned (1:1) by an interactive voice response system to receive either a combination of dabrafenib (150 mg twice-daily) and trametinib (2 mg once-daily) or vemurafenib monotherapy (960 mg twice-daily) orally as first-line therapy. The primary endpoint was overall survival. In this pre-specified exploratory analysis, we prospectively assessed HRQoL in the intention-to-treat population with the European Organisation for Research and Treatment of Cancer quality of life (EORTC QLQ-C30), EuroQoL-5D (EQ-5D), and Melanoma Subscale of the Functional Assessment of Cancer Therapy-Melanoma (FACT-M), completed at baseline, during study treatment, at disease progression, and after progression. We used a mixed-model, repeated measures ANCOVA to assess differences in mean scores between groups with baseline score as covariate; all p-values are descriptive. The COMBI-v trial is registered with ClinicalTrials.gov, number NCT01597908, and is ongoing for the primary endpoint, but is not recruiting patients.. From June 4, 2012, to Oct 7, 2013, 1645 patients at 193 centres worldwide were screened for eligibility, and 704 patients were randomly assigned to dabrafenib plus trametinib (n=352) or vemurafenib (n=352). Questionnaire completion rates for both groups were high (>95% at baseline, >80% at follow-up assessments, and >70% at disease progression) with similar HRQoL and symptom scores reported at baseline in both treatment groups for all questionnaires. Differences in mean scores between treatment groups were significant and clinically meaningful in favour of the combination compared with vemurafenib monotherapy for most domains across all three questionnaires during study treatment and at disease progression, including EORTC QLQ-C30 global health (7·92, 7·62, 6·86, 7·47, 5·16, 7·56, and 7·57 at weeks 8, 16, 24, 32, 40, 48, and disease progression, respectively; p<0·001 for all assessments except p=0·005 at week 40), EORTC QLQ-C30 pain (-13·20, -8·05, -8·82, -12·69, -12·46, -11·41, and -10·57 at weeks 8, 16, 24, 32, 40, 48, and disease progression, respectively; all p<0·001), EQ-5D thermometer scores (7·96, 8·05, 6·83, 11·53, 7·41, 9·08, and 10·51 at weeks 8, 16, 24, 32, 40, 48, and disease progression, respectively; p<0·001 for all assessments except p=0·006 at week 32), and FACT-M Melanoma Subscale score (3·62, 2·93, 2·45, 3·39, 2·85, 3·00, and 3·68 at weeks 8, 16, 24, 32, 40, 48, and disease progression, respectively; all p<0·001).. From the patient's perspective, which integrates not only survival advantage but also disease-associated and adverse-event-associated symptoms, treatment with the combination of a BRAF inhibitor plus a MEK inhibitor (dabrafenib plus trametinib) adds a clear benefit over monotherapy with the BRAF inhibitor vemurafenib and supports the combination therapy as standard of care in this population.

Topics: Administration, Oral; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Disease Progression; Disease-Free Survival; DNA Mutational Analysis; Drug Administration Schedule; Genetic Predisposition to Disease; Humans; Imidazoles; Indoles; Intention to Treat Analysis; MAP Kinase Kinase Kinases; Melanoma; Mutation; Oximes; Phenotype; Prospective Studies; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Quality of Life; Risk Factors; Skin Neoplasms; Sulfonamides; Surveys and Questionnaires; Time Factors; Treatment Outcome; Vemurafenib

A 61-year-old man was diagnosed with stage IIIB BRAF V600E mutant melanoma in October 2012. He was treated with a combination therapy of dabrafenib and trametinib. He remained in complete remission for 18 months and the treatment was well tolerated after dose reduction because of pyrexia. In March 2013, he developed bilateral pitting edema of the legs with an erythematous, slightly infiltrated rash on his back and upper arms. His face was edematous, with a heliotrope rash-like aspect. Eye examination showed bilateral blepharitis. Additional blood test showed inflammation and acute kidney injury Rifle category failure. A skin and kidney biopsy indicated a granulomatous inflammation. A complete workup for other causes of granulomatous inflammation was negative. Treatment with dabrafenib and trametinib was stopped and corticosteroids were initiated, with a rapid beneficial effect on both the kidney function and skin rash. When corticosteroids were halted after 1 month, a rapid decline in the kidney function was observed. After reintroduction of corticosteroids, kidney function normalized and steroids could be tapered gradually over 6 months. To our knowledge, interstitial nephritis has not been described in patients on BRAF-targeted nor MEK-targeted therapy for melanoma, although it has been described in a melanoma patient treated with the immune checkpoint inhibitor, ipilimumab. Currently, the patient has no sign of local or distal recurrence of melanoma, notwithstanding that treatment with dabrafenib and trametinib has been stopped for 10 months and no other antimelanoma therapy was initiated.

Topics: Adrenal Cortex Hormones; Anti-Inflammatory Agents; Antineoplastic Combined Chemotherapy Protocols; Drug Eruptions; Granuloma; Humans; Imidazoles; Male; Melanoma; Middle Aged; Nephritis, Interstitial; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms

Treatment of BRAF-mutant melanoma with combined dabrafenib and trametinib, which target RAF and the downstream MAP-ERK kinase (MEK)1 and MEK2 kinases, respectively, improves progression-free survival and response rates compared with dabrafenib monotherapy. Mechanisms of clinical resistance to combined RAF/MEK inhibition are unknown. We performed whole-exome sequencing (WES) and whole-transcriptome sequencing (RNA-seq) on pretreatment and drug-resistant tumors from five patients with acquired resistance to dabrafenib/trametinib. In three of these patients, we identified additional mitogen-activated protein kinase (MAPK) pathway alterations in the resistant tumor that were not detected in the pretreatment tumor, including a novel activating mutation in MEK2 (MEK2(Q60P)). MEK2(Q60P) conferred resistance to combined RAF/MEK inhibition in vitro, but remained sensitive to inhibition of the downstream kinase extracellular signal-regulated kinase (ERK). The continued MAPK signaling-based resistance identified in these patients suggests that alternative dosing of current agents, more potent RAF/MEK inhibitors, and/or inhibition of the downstream kinase ERK may be needed for durable control of BRAF-mutant melanoma.

Topics: Aged; Antineoplastic Agents; Drug Resistance, Neoplasm; Humans; Imidazoles; Male; Melanoma; Middle Aged; Mitogen-Activated Protein Kinase Kinases; Mitogen-Activated Protein Kinases; Mutation; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; raf Kinases; Signal Transduction; Skin Neoplasms

While response rates to BRAF inhibitiors (BRAFi) are high, disease progression emerges quickly. One strategy to delay the onset of resistance is to target anti-apoptotic proteins such as BCL-2, known to be associated with a poor prognosis. We analyzed BCL-2 family member expression levels of 34 samples from 17 patients collected before and 10 to 14 days after treatment initiation with either vemurafenib or dabrafenib/trametinib combination. The observed changes in mRNA and protein levels with BRAFi treatment led us to hypothesize that combining BRAFi with a BCL-2 inhibitor (the BH3-mimetic navitoclax) would improve outcome. We tested this hypothesis in cell lines and in mice. Pretreatment mRNA levels of BCL-2 negatively correlated with maximal tumor regression. Early increases in mRNA levels were seen in BIM, BCL-XL, BID and BCL2-W, as were decreases in MCL-1 and BCL2A. No significant changes were observed with BCL-2. Using reverse phase protein array (RPPA), significant increases in protein levels were found in BIM and BID. No changes in mRNA or protein correlated with response. Concurrent BRAF (PLX4720) and BCL2 (navitoclax) inhibition synergistically reduced viability in BRAF mutant cell lines and correlated with down-modulation of MCL-1 and BIM induction after PLX4720 treatment. In xenograft models, navitoclax enhanced the efficacy of PLX4720. The combination of a selective BRAF inhibitor with a BH3-mimetic promises to be an important therapeutic strategy capable of enhancing the clinical efficacy of BRAF inhibition in many patients that might otherwise succumb quickly to de novo resistance. Trial registrations: ClinicalTrials.gov NCT01006980; ClinicalTrials.gov NCT01107418; ClinicalTrials.gov NCT01264380; ClinicalTrials.gov NCT01248936; ClinicalTrials.gov NCT00949702; ClinicalTrials.gov NCT01072175.

Topics: Adult; Aged; Aniline Compounds; Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Drug Resistance, Neoplasm; Humans; Imidazoles; Indoles; Melanoma; Mice; Middle Aged; Mutation, Missense; Neoplasm Metastasis; Oximes; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins c-bcl-2; Pyridones; Pyrimidinones; Sulfonamides; Vemurafenib

The combination of dabrafenib and trametinib (CombiDT) is an effective treatment for BRAF-mutant metastatic melanoma; however, over 70% of patients develop drug-related pyrexia, and little is known about this toxicity. We sought to examine the features and management of CombiDT pyrexia. The association between pyrexia and patient demographics, disease characteristics and outcome variables was assessed in patients treated with CombiDT at a single institution. The clinicopathological features of pyrexic events were analysed. Fourteen of 32 (44%) patients developed pyrexia (temperature≥38.5°C). Pyrexia was recurrent in 11/14 (79%). The median time to pyrexia was 38 days. Pyrexia was not associated with age, sex nor disease burden, and did not correlate with RECIST response, progression-free nor overall survival. Paracetamol, NSAIDs and/or dose reduction (DR) were ineffective secondary prophylaxis for pyrexia, whereas corticosteroids were effective in all patients (n=8), including two with multiple previous pyrexic events despite several DRs. In patients with previous DRs who commenced steroids (n=3), CombiDT doses were re-escalated without pyrexia. Pyrexia is a frequent and recurrent toxicity with CombiDT, with no predictive clinical characteristics. Pyrexia does not correlate with clinical outcome. Neither DR nor antipyretics are effective secondary prophylaxis, whereas corticosteroids are effective, prevent DR and enable re-escalation of CombiDT dosing.

Topics: Acetaminophen; Adrenal Cortex Hormones; Adult; Aged; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Female; Fever; Humans; Imidazoles; Male; Melanoma; Middle Aged; Oximes; Pyridones; Pyrimidinones; Retrospective Studies; Temperature; Treatment Outcome

Combined BRAF and MEK inhibition, as compared with BRAF inhibition alone, delays the emergence of resistance and reduces toxic effects in patients who have melanoma with BRAF V600E or V600K mutations.. In this phase 3 trial, we randomly assigned 423 previously untreated patients who had unresectable stage IIIC or stage IV melanoma with a BRAF V600E or V600K mutation to receive a combination of dabrafenib (150 mg orally twice daily) and trametinib (2 mg orally once daily) or dabrafenib and placebo. The primary end point was progression-free survival. Secondary end points included overall survival, response rate, response duration, and safety. A preplanned interim overall survival analysis was conducted.. The median progression-free survival was 9.3 months in the dabrafenib-trametinib group and 8.8 months in the dabrafenib-only group (hazard ratio for progression or death in the dabrafenib-trametinib group, 0.75; 95% confidence interval [CI], 0.57 to 0.99; P=0.03). The overall response rate was 67% in the dabrafenib-trametinib group and 51% in the dabrafenib-only group (P=0.002). At 6 months, the interim overall survival rate was 93% with dabrafenib-trametinib and 85% with dabrafenib alone (hazard ratio for death, 0.63; 95% CI, 0.42 to 0.94; P=0.02). However, a specified efficacy-stopping boundary (two-sided P=0.00028) was not crossed. Rates of adverse events were similar in the two groups, although more dose modifications occurred in the dabrafenib-trametinib group. The rate of cutaneous squamous-cell carcinoma was lower in the dabrafenib-trametinib group than in the dabrafenib-only group (2% vs. 9%), whereas pyrexia occurred in more patients (51% vs. 28%) and was more often severe (grade 3, 6% vs. 2%) in the dabrafenib-trametinib group.. A combination of dabrafenib and trametinib, as compared with dabrafenib alone, improved the rate of progression-free survival in previously untreated patients who had metastatic melanoma with BRAF V600E or V600K mutations. (Funded by GlaxoSmithKline; Clinical Trials.gov number, NCT01584648.).

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Double-Blind Method; Female; Fever; Humans; Imidazoles; Kaplan-Meier Estimate; Male; Melanoma; Middle Aged; Mitogen-Activated Protein Kinase Kinases; Mutation; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

Preclinical and early clinical studies have demonstrated that initial therapy with combined BRAF and MEK inhibition is more effective in BRAF(V600)-mutant melanoma than single-agent BRAF inhibitors. This study assessed the safety and efficacy of dabrafenib and trametinib in patients who had received prior BRAF inhibitor treatment.. In this open-label phase I/II study, we evaluated the pharmacology, safety, and efficacy of dabrafenib and trametinib. Here, we report patients treated with combination therapy after disease progression with BRAF inhibitor treatment administered before study enrollment (part B; n = 26) or after cross-over at progression with dabrafenib monotherapy (part C; n = 45).. In parts B and C, confirmed objective response rates (ORR) were 15% (95% CI, 4% to 35%) and 13% (95% CI, 5% to 27%), respectively; an additional 50% and 44% experienced stable disease ≥ 8 weeks, respectively. In part C, median progression-free survival (PFS) was 3.6 months (95% CI, 2 to 4), and median overall survival was 11.8 months (95% CI, 8 to 25) from cross-over. Patients who previously received dabrafenib ≥ 6 months had superior outcomes with the combination compared with those treated < 6 months; median PFS was 3.9 (95% CI, 3 to 7) versus 1.8 months (95% CI, 2 to 4; hazard ratio, 0.49; P = .02), and ORR was 26% (95% CI, 10% to 48%) versus 0% (95% CI, 0% to 15%).. Dabrafenib plus trametinib has modest clinical efficacy in patients with BRAF inhibitor-resistant melanoma. This regimen may be a therapeutic strategy for patients who previously benefited from BRAF inhibitor monotherapy ≥ 6 months but demonstrates minimal efficacy after rapid progression with BRAF inhibitor therapy.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Disease Progression; Disease-Free Survival; Female; Humans; Imidazoles; Male; Melanoma; Middle Aged; Mitogen-Activated Protein Kinase Kinases; Mutation; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

Inhibitors of the mitogen-activated protein kinases (MAPK), BRAF, and MAP-ERK kinase (MEK) induce tumor regression in the majority of patients with BRAF-mutant metastatic melanoma. The clinical benefit of MAPK inhibitors is restricted by the development of acquired resistance with half of those who benefit having progressed by 6 to 7 months and long-term responders uncommon. There remains no agreed treatment strategy on disease progression in these patients. Without published evidence, fears of accelerated disease progression on inhibitor withdrawal have led to the continuation of drugs beyond formal disease progression. We now show that treatment with MAPK inhibitors beyond disease progression can provide significant clinical benefit, and the withdrawal of these inhibitors led to a marked increase in the rate of disease progression in two patients. We also show that MAPK inhibitors retain partial activity in acquired resistant melanoma by examining drug-resistant clones generated to dabrafenib, trametinib, or the combination of these drugs. All resistant sublines displayed a markedly slower rate of proliferation when exposed to MAPK inhibitors, and this coincided with a reduction in MAPK signaling, decrease in bromodeoxyuridine incorporation, and S-phase inhibition. This cytostatic effect was also associated with diminished levels of cyclin D1 and p-pRb. Two short-term melanoma cultures generated from resistant tumor biopsies also responded to MAPK inhibition, with comparable inhibitory changes in proliferation and MAPK signaling. These data provide a rationale for the continuation of BRAF and MEK inhibitors after disease progression and support the development of clinical trials to examine this strategy.

Topics: Apoptosis; Cell Line, Tumor; Drug Resistance, Neoplasm; Gene Expression; Humans; Imidazoles; Male; Melanoma; Middle Aged; Mitogen-Activated Protein Kinase Kinases; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

Resistance to therapy with BRAF kinase inhibitors is associated with reactivation of the mitogen-activated protein kinase (MAPK) pathway. To address this problem, we conducted a phase 1 and 2 trial of combined treatment with dabrafenib, a selective BRAF inhibitor, and trametinib, a selective MAPK kinase (MEK) inhibitor.. In this open-label study involving 247 patients with metastatic melanoma and BRAF V600 mutations, we evaluated the pharmacokinetic activity and safety of oral dabrafenib (75 or 150 mg twice daily) and trametinib (1, 1.5, or 2 mg daily) in 85 patients and then randomly assigned 162 patients to receive combination therapy with dabrafenib (150 mg) plus trametinib (1 or 2 mg) or dabrafenib monotherapy. The primary end points were the incidence of cutaneous squamous-cell carcinoma, survival free of melanoma progression, and response. Secondary end points were overall survival and pharmacokinetic activity.. Dose-limiting toxic effects were infrequently observed in patients receiving combination therapy with 150 mg of dabrafenib and 2 mg of trametinib (combination 150/2). Cutaneous squamous-cell carcinoma was seen in 7% of patients receiving combination 150/2 and in 19% receiving monotherapy (P=0.09), whereas pyrexia was more common in the combination 150/2 group than in the monotherapy group (71% vs. 26%). Median progression-free survival in the combination 150/2 group was 9.4 months, as compared with 5.8 months in the monotherapy group (hazard ratio for progression or death, 0.39; 95% confidence interval, 0.25 to 0.62; P<0.001). The rate of complete or partial response with combination 150/2 therapy was 76%, as compared with 54% with monotherapy (P=0.03).. Dabrafenib and trametinib were safely combined at full monotherapy doses. The rate of pyrexia was increased with combination therapy, whereas the rate of proliferative skin lesions was nonsignificantly reduced. Progression-free survival was significantly improved. (Funded by GlaxoSmithKline; ClinicalTrials.gov number, NCT01072175.).

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Drug Therapy, Combination; Female; Fever; Humans; Imidazoles; Male; MAP Kinase Signaling System; Melanoma; Middle Aged; Mitogen-Activated Protein Kinase Kinases; Mutation; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

BRAF V600E is the key oncogenic driver mutation in hairy cell leukemia (HCL). We report the efficacy and safety of dabrafenib plus trametinib in patients with relapsed/refractory BRAF V600E mutation-positive HCL. This open-label, phase 2 study enrolled patients with BRAF V600E mutation-positive HCL refractory to first-line treatment with a purine analog or relapsed after ≥2 prior lines of treatment. Patients received dabrafenib 150 mg twice daily plus trametinib 2 mg once daily until disease progression, unacceptable toxicity, or death. The primary endpoint was investigator-assessed objective response rate (ORR) per criteria adapted from National Comprehensive Cancer Network-Consensus Resolution guidelines. Secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Fifty-five patients with BRAF V600E mutation-positive HCL were enrolled. The investigator-assessed ORR was 89.0% (95% confidence interval, 77.8%-95.9%); 65.5% of patients had a complete response (without minimal residual disease [MRD]: 9.1% [negative immunohistochemistry of bone marrow {BM} biopsy], 12.7% [negative BM aspirate flow cytometry {FC}], 16.4% [negative immunohistochemistry and/or FC results]; with MRD, 49.1%), and 23.6% had a partial response. The 24-month DOR was 97.7% with 24-month PFS and OS rates of 94.4% and 94.5%, respectively. The most common treatment-related adverse events were pyrexia (58.2%), chills (47.3%), and hyperglycemia (40.0%). Dabrafenib plus trametinib demonstrated durable responses with a manageable safety profile consistent with previous observations in other indications and should be considered as a rituximab-free therapeutic option for patients with relapsed/refractory BRAF V600E mutation-positive HCL. This trial is registered at www.clinicaltrials.gov as #NCT02034110.

Topics: Antineoplastic Combined Chemotherapy Protocols; Humans; Leukemia, Hairy Cell; Mutation; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

Patients with melanoma with activating BRAF mutations (BRAF V600E/K) initially respond to combination therapy of BRAF and MEK inhibitors. However, their clinical efficacy is limited by acquired resistance, in some cases driven by amplification of the mutant BRAF gene and subsequent reactivation of the MAPK pathway. DS03090629 is a novel and orally available MEK inhibitor that inhibits MEK in an ATP-competitive manner. In both in vitro and in vivo settings, potent inhibition of MEK by DS03090629 or its combination with the BRAF inhibitor dabrafenib was demonstrated in a mutant BRAF-overexpressing melanoma cell line model that exhibited a higher MEK phosphorylation level than the parental cell line and then became resistant to dabrafenib and the MEK inhibitor trametinib. DS03090629 also exhibited superior efficacy against a melanoma cell line-expressing mutant MEK1 protein compared with dabrafenib and trametinib. Biophysical analysis revealed that DS03090629 retained its affinity for the MEK protein regardless of its phosphorylation status, whereas the affinity of trametinib declined when the MEK protein was phosphorylated. These results suggest that DS03090629 may be a novel therapeutic option for patients who acquire resistance to the current BRAF- and MEK-targeting therapies.

Topics: Adenosine Triphosphate; Drug Resistance, Neoplasm; Humans; MAP Kinase Kinase 1; Melanoma; Mitogen-Activated Protein Kinase Kinases; Mutation; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

Topics: Antineoplastic Combined Chemotherapy Protocols; Humans; Melanoma; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms

Combination BRAF and MEK inhibitor therapy is an active regimen in patients who have BRAF V600E-mutated tumors; however, the clinical efficacy of this therapy is limited by resistance. Preclinically, the addition of heat shock protein 90 (HSP90) inhibition improves the efficacy of BRAF inhibitor therapy in both BRAF inhibitor-sensitive and BRAF inhibitor-resistant mutant cell lines.. Cancer Therapy Evaluation Program study 9557 (ClinicalTrials.gov identifier NCT02097225) is a phase 1 study that was designed to assess the safety and efficacy of the small-molecule HSP90 inhibitor, AT13387, in combination with dabrafenib and trametinib in BRAF V600E/K-mutant solid tumors. Correlative analyses evaluated the expression of HSP90 client proteins and chaperones.. Twenty-two patients with metastatic, BRAF V600E-mutant solid tumors were enrolled using a 3 + 3 design at four dose levels, and 21 patients were evaluable for efficacy assessment. The most common tumor type was colorectal cancer (N = 12). Dose-limiting toxicities occurred in one patient at dose level 3 and in one patient at dose level 4; specifically, myelosuppression and fatigue, respectively. The maximum tolerated dose was oral dabafenib 150 mg twice daily, oral trametinib 2 mg once daily, and intravenous AT13387 260 mg/m. HSP90 inhibition combined with BRAF/MEK inhibition was safe and produced evidence of modest disease control in a heavily pretreated population. Additional translational work may identify tumor types and resistance mechanisms that are most sensitive to this approach.

Topics: Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Humans; Melanoma; Mitogen-Activated Protein Kinase Kinases; Mutation; Oximes; Protein Kinase Inhibitors; Proteomics; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

Dabrafenib and trametinib are oral targeted agents indicated for BRAF mutated non-small cell lung cancer and melanoma. There is little data to support the administration of these two agents via enteral feeding tube. This case series describes three patients who received compounded dabrafenib and trametinib suspensions through enteral feeding tubes.. We present three patients who required dabrafenib and trametinib to be prepared as a non-standard compound for the medications to be administered via feeding tube. The patients were diagnosed with with BRAF mutated cancers including melanoma, non-small-cell lung carcinoma, and anaplastic thyroid cancer. In all three cases, there was evidence of initial disease response on imaging, and there were no unexpected toxicities secondary to dabrafenib and trametinib.. There are patients that are unable to tolerate medications by mouth due to dysphagia, anatomical malfunctions, or other digestive disorders. There is limited literature that describes preparation of trametinib and dabrafenib into an enteral suspension. Identifying a safe and efficacious method of administering these two medications via feeding tube ensures that these patients continue to be able to receive them as part of their anti-cancer therapy.. Despite the lack of available data, compounding of dabrafenib and trametinib may be clinically appropriate when benefits outweigh the risk of unconventional administration. Further studies are warranted to assess for the pharmacokinetics, pharmacodynamics, stability, and storage for these liquid medications.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms; Melanoma; Mutation; Oximes; Proto-Oncogene Proteins B-raf; Pyrimidinones

Brain metastases (BM) and lactate dehydrogenase (LDH) levels above the upper limit of normal (ULN) are associated with poor prognosis in patients with melanoma. Although treatment with the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib have demonstrated long-term clinical benefit in patients with melanoma, data on their efficacy in patients with BM are limited.. DESCRIBE Italy is an observational, retrospective, real-world study evaluating dabrafenib plus trametinib in 499 patients with. Overall, 325 evaluable patients were on first-line therapy and are the focus of this analysis; of these, 76 patients (23.4%) had BM at baseline. mPFS was lower for patients with BM at baseline compared with overall patients (8.7 months vs 9.3 months, respectively). Patients with BM at diagnosis and LDH >ULN had a considerably shorter mPFS compared with patients with LDH ⩽ULN (5.3 months vs 9.9 months, respectively). mPFS was noticeably longer for patients with cerebral metastases only compared with patients with cerebral and other metastases (15.0 months vs 8.7 months, respectively).. Dabrafenib plus trametinib showed effectiveness in a real-world population of patients with advanced

Topics: Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Humans; Melanoma; Mutation; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Retrospective Studies; Skin Neoplasms

The Food and Drug Administration (FDA) has approved MAPK inhibitors as a treatment for melanoma patients carrying a mutation in codon V600 of the BRAF gene exclusively. However, BRAF mutations outside the V600 codon may occur in a small percentage of melanomas. Although these rare variants may cause B-RAF activation, their predictive response to B-RAF inhibitor treatments is still poorly understood. We exploited an integrated approach for mutation detection, tumor evolution tracking, and assessment of response to treatment in a metastatic melanoma patient carrying the rare p.T599dup B-RAF mutation. He was addressed to Dabrafenib/Trametinib targeted therapy, showing an initial dramatic response. In parallel, in-silico ligand-based homology modeling was set up and performed on this and an additional B-RAF rare variant (p.A598_T599insV) to unveil and justify the success of the B-RAF inhibitory activity of Dabrafenib, showing that it could adeptly bind both these variants in a similar manner to how it binds and inhibits the V600E mutant. These findings open up the possibility of broadening the spectrum of BRAF inhibitor-sensitive mutations beyond mutations at codon V600, suggesting that B-RAF V600 WT melanomas should undergo more specific investigations before ruling out the possibility of targeted therapy.

Topics: Humans; Imidazoles; Male; Melanoma; Mutation; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms

Topics: Antineoplastic Combined Chemotherapy Protocols; Humans; Melanoma; Mutation; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Vitiligo

Topics: Fever; Humans; Imidazoles; Neoplasms; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

Topics: Fever; Humans; Imidazoles; Neoplasms; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

Melanoma has benefited in recent years from therapeutic innovations, which have improved overall survival of patients. France has developed a regulatory arsenal allowing faster access to innovative drugs before marketing authorization: temporary authorization for use (ATU) and temporary recommendation for use (RTU).. We describe here the decision-making processes that led to the non-publication of the decree on the funding of three RTU in adjuvant melanoma therapy: nivolumab, pembrolizumab and the combination of dabrafenib and trametinib, and we analyse the fate of these drugs in order to quantify the potential loss of chance.. On 03AUG2018, the French National Agency for Medicines and Health Product Safety (ANSM) published 3 RTU in order to give rapid access to major innovations in adjuvant melanoma therapy: nivolumab, pembrolizumab and the combination of dabrafenib and trametinib. These drugs have respectively demonstrated reductions in the risk of recurrence by 35 %, 43% and 55% for target populations of 2200, 1900 and 650 patients per year. Despite a favourable opinion on reimbursement from the French National Authority for Health (HAS), the decrees on reimbursement will never be published, prohibiting the use of these products before the marketing authorisation, and depriving many patients of a potential cure.. Despite a favourable opinion from scientists and health agencies for the rapid availability of a drug, the French public health code does not systematically imply access to a therapeutic innovation. The reform of access to innovation implemented on 01JUL2021 may help tackle this issue.

Topics: Adult; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Agents, Immunological; Chemotherapy, Adjuvant; Clinical Trials as Topic; Decision Making; Drug Approval; Drug Combinations; France; Humans; Imidazoles; Insurance, Health, Reimbursement; Ipilimumab; Melanoma; Neoplasm Recurrence, Local; Nivolumab; Oximes; Pyridones; Pyrimidinones; Skin Neoplasms

Topics: Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Carbamates; Humans; Imidazoles; Lactate Dehydrogenases; Melanoma; Mutation; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Sulfonamides

Combined treatment with dabrafenib, a B-RAF inhibitor, and trametinib, a mitogen-activated protein kinase inhibitor, is an effective option for patients with metastatic melanoma. A few cases of acute kidney injury associated with tubulointerstitial nephritis and 1 case of nephrotic syndrome have been reported in patients on this drug combination; however, progressive renal injury has not been reported. In this case study, we report a patient with metastatic melanoma who developed glomerular capillary endothelial toxicity and progressive glomerular sclerosis during combination therapy.. Our patient was an 80-year-old woman with a history of type 2 diabetes and chronic kidney disease.. She was diagnosed with metastatic melanoma and commenced combination therapy with dabrafenib and trametinib.. Her renal function progressively deteriorated; by month 20 after treatment commencement, her serum creatinine level had increased from 1.59 to 3.74 mg/dL. The first kidney biopsy revealed marked glomerular and endothelial cell damage. Her medication was stopped, but no improvement was evident. At 5 months after the first biopsy, her serum creatinine level had increased to 5.46 mg/dL; a second kidney biopsy revealed focal segmental glomerular sclerosis and marked tubulointerstitial fibrosis. She was started on hemodialysis.. We describe a patient with a metastatic melanoma who developed progressive kidney failure during treatment with dabrafenib and trametinib. The most prominent microscopy findings were glomerular endothelial damage in the initial kidney biopsy and accelerated glomerular sclerosis and tubulointerstitial fibrosis in the follow-up biopsy. We hypothesize that a decreased renal reserve and impairment of kidney repair capacity caused by inhibition of B-RAF, a downstream mediator of vascular endothelial growth factor, may explain the progressive kidney injury.

Topics: Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Creatinine; Diabetes Mellitus, Type 2; Female; Fibrosis; Humans; Imidazoles; Melanoma; Mitogen-Activated Protein Kinase Kinases; Nephritis, Interstitial; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Vascular Endothelial Growth Factor A

BRAF V600E mutations are detected in 3%-10% of patients with multiple myeloma (MM) and are associated with more aggressive disease, higher frequency of extramedullary growth and shorter survival. Monotherapy with the BRAF inhibitor vemurafenib has been disappointing in MM. In patients with BRAF-mutated melanoma, MEK and BRAF inhibition has been a successful approach. Here we describe a very good partial response and possible mechanisms of resistance to a combination of the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib in a patient with BRAF V600E-mutant refractory MM.

Topics: Antineoplastic Combined Chemotherapy Protocols; Humans; Imidazoles; Mitogen-Activated Protein Kinase Kinases; Multiple Myeloma; Mutation; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

Efficacy and safety of dabrafenib and trametinib in metastatic melanoma have been demonstrated in two-phase III and one-phase I/II clinical trials. However, patients at least 75 years old (y.o.) were largely underrepresented. Additionally, the safety profile of dabrafenib and trametinib based on age is unknown. ELDERLYMEL is a retrospective noninterventional multicenter study, describing the effectiveness and safety of at least 75 y.o. patients compared with less than 75 y.o. patients with advanced BRAF V600-mutated melanoma treated with dabrafenib plus trametinib or dabrafenib monotherapy. A total of 159 patients were included, 130 less than 75 y.o. and 29 at least 75 y.o. Clinical features were similar between the groups, except in the number of comorbidities, number of metastatic sites, Eastern Cooperative Oncology Group (ECOG) performance status, and BRAF V600-mutation type. Five patients per group received dabrafenib monotherapy. There were no differences in adverse events (AEs) rate or grade between the groups. However, AE profiles were different between the groups, being pyrexia infrequent in patients at least 75 y.o. (13.8% vs. 42.3%; P = 0.005). Dabrafenib and trametinib dose intensities were lower in at least 75 y.o. patients ( P = 0.018 and P = 0.020), but there were no differences in effectiveness between the groups. Finally, in a multivariate analysis, sex (female) was the only variable independently associated with an increased risk of AE grade ≥3. Data from the ELDERLYMEL study demonstrate that dabrafenib plus trametinib is safe and effective in at least 75 y.o. patients with advanced BRAF V600-mutated melanoma without increasing toxicity. Additionally, we describe a different safety profile depending on age and sex.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Data Analysis; Female; Humans; Imidazoles; Male; Melanoma; Mutation; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Retrospective Studies; Skin Neoplasms

Recently, targeted therapies using BRAFV600E and MEK inhibitors (dabrafenib and trametinib, respectively) have been recommended in BRAF-mutated anaplastic thyroid carcinoma (ATC). Considering the fast development of ATC, droplet digital PCR (ddPCR) performed on fine-needle aspirate (FNA), which is a rapid, reliable, and low-cost method, appears interesting for the detection of BRAFV600E mutation in these patients and allows early initiation of targeted therapies.. In our two patients, both presenting extensive cervical masses inaccessible to surgery, ddPCR results were available in less than 24 h. Therefore, dabrafenib and trametinib were started only a few days after first contact.. We suggest that ddPCR on FNA be used in non-resectable cervical masses for rapid BRAFV600E mutation detection in the hope that starting targeted therapies early might improve outcomes.

Topics: Antineoplastic Combined Chemotherapy Protocols; Humans; Imidazoles; Mutation; Oximes; Polymerase Chain Reaction; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms

Pyrexia is a frequent adverse event of BRAF/MEK-inhibitor combination therapy in patients with metastasized malignant melanoma (MM). The study's objective was to identify laboratory changes which might correlate with the appearance of pyrexia. Initially, data of 38 MM patients treated with dabrafenib plus trametinib, of which 14 patients developed pyrexia, were analysed retrospectively. Graphical visualization of time series of laboratory values suggested that a rise in C-reactive-protein, in parallel with a fall of leukocytes and thrombocytes, were indicative of pyrexia. Additionally, statistical analysis showed a significant correlation between lactate dehydrogenase (LDH) and pyrexia. An algorithm based on these observations was designed using a deductive and heuristic approach in order to calculate a pyrexia score (PS) for each laboratory assessment in treated patients. A second independent data set of 28 MM patients, 8 with pyrexia, was used for the validation of the algorithm. PS based on the four parameters CRP, LDH, leukocyte and thrombocyte numbers, were statistically significantly higher in pyrexia patients, differentiated between groups (F = 20.8; p = <0.0001) and showed a significant predictive value for the diagnosis of pyrexia (F = 6.24; p = 0.013). We provide first evidence that pyrexia in patients treated with BRAF/MEK-blockade can be identified by an algorithm that calculates a score.

Topics: Algorithms; Antineoplastic Combined Chemotherapy Protocols; Fever; Humans; Imidazoles; L-Lactate Dehydrogenase; Melanoma; Melanoma, Cutaneous Malignant; Mitogen-Activated Protein Kinase Kinases; Mutation; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Retrospective Studies; Skin Neoplasms

Limited data are available to assist the selection between immune checkpoint inhibitors and BRAF/mitogen-activated protein kinase kinase inhibitors as first-line treatment for patients with BRAF-mutant advanced malignant melanoma.. To investigate the outcomes associated with first-line pembrolizumab or dabrafenib/trametinib treatment for advanced melanoma with activating BRAF V600 mutation.. Data of patients with BRAF V600-mutant melanoma who were treated with first-line pembrolizumab (n = 40) or dabrafenib/trametinib (n = 32) were analyzed. Tumor response, progression-free survival, and overall survival were evaluated. Immune evasion accompanied with emerging resistance to BRAF/mitogen-activated protein kinase kinase inhibitors was assessed.. A longer overall survival was observed after first-line pembrolizumab treatment than after first-line dabrafenib/trametinib treatment (hazard ratio = 2.910, 95% CI: 1.552-5.459), although there were no significant differences in progression-free survival (P = .375) and response rate (P = .123). Emergence of resistance to dabrafenib/trametinib co-occurred with immune evasion, enabling melanoma cells to escape recognition and killing by Melan-A-specific CD8. Analysis was conducted in a retrospective manner.. Pembrolizumab may be recommended over BRAF/mitogen-activated protein kinase kinase inhibitors as the first-line treatment in patients with advanced BRAF V600-mutant melanoma.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; CD8-Positive T-Lymphocytes; Humans; Imidazoles; Immune Checkpoint Inhibitors; MART-1 Antigen; Melanoma; Mitogen-Activated Protein Kinase Kinases; Mutation; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Retrospective Studies; Skin Neoplasms

We report a case of ocular drug toxicity consistent with bilateral Vogt-Koyanagi-Harada (VKH) like disease in a patient with cutaneous melanoma treated with Dabrafenib/Trametinib therapy. A 53-year-old man with a history of metastatic cutaneous melanoma, treated with Dabrafenib/Trametinib, developed a severe acute panuveitis with granulomatous anterior uveitis and multiple serous retinal detachments. The ocular inflammatory reaction was classified as a bilateral Vogt-Koyanagi-Harada disease. Intraocular inflammation resolved after discontinuation of chemotherapeutic agents and aggressive topical and systemic corticosteroid therapy. The present case outlines the importance of recognizing VKH-like syndrome as a possible consequence of therapy with dabrafenib and trametinib.

Topics: Humans; Imidazoles; Male; Melanoma; Middle Aged; Oximes; Pyridones; Pyrimidinones; Skin Neoplasms; Uveitis; Uveomeningoencephalitic Syndrome

Our objective was to characterize the incidence, risk factors and clinical features of acute kidney injury (AKI) in patients receiving dabrafenib and trametinib.. We performed a retrospective cohort study examining the kidney outcomes of patients in a large healthcare system who received dabrafenib/trametinib between 2010 and 2019. The primary outcome was AKI, defined as a 1.5-fold increase in serum creatinine from baseline within a 12-month study period. AKI severity and etiology was determined for each case by chart review. Logistic regression was used to evaluate baseline predictors of AKI.. A total of 199 patients who received dabrafenib in our healthcare system from 2010 to 2019 were included in the analysis. Forty-two patients (21%) experienced AKI within 12 months; 10 patients (5% of the total cohort, 24% of AKI patients) experienced AKI occurring during a dabrafenib/trametinib-induced febrile syndrome characterized by fever, chills, gastrointestinal symptoms and elevated liver enzymes. Preexisting liver disease was the only significant predictor of AKI in the cohort. One patient had biopsy-proven granulomatous acute interstitial nephritis that resolved with corticosteroids.. Oncologists and nephrologists should be aware that AKI is common after dabrafenib/trametinib and a substantial number of cases occur in the setting of treatment-induced pyrexia.

Topics: Acute Kidney Injury; Antineoplastic Combined Chemotherapy Protocols; Humans; Imidazoles; Melanoma; Mutation; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Retrospective Studies

Topics: Antineoplastic Combined Chemotherapy Protocols; Facial Nerve Diseases; Humans; Imidazoles; Immunotherapy; Melanoma; Mutation; Neoadjuvant Therapy; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms

We analysed PCD/T in patients treated with D+T for metastatic melanoma. We collected data of tumour response (RECIST 1.1) and AE (CTCAE 4.0) blinded to PCD/T results.. We analysed 71 D and 58T assays from 34 patients. High inter-individual variability of PCD (median: 65.0ng/mL; interquartile range (IQR) [4-945]) and of PCT (median: 8.6ng/mL; IQR [5-39]) was observed. We found a weak relationship between PCD and progression-free survival, taking follow-up time into account (hazard ratio 0.991; 95%CI, 0.981 to 1.000; P=0.06). However, no difference was observed between mean PCD/T of progressing patients (n=21; 125±183ng/mL and 9.3±3.6ng/mL, respectively) and responders (complete, partial or stable response) (n=13; 159±225ng/mL, P=0.58 and 10.6±24.4ng/mL, P=0.29, respectively). No significant relationship was found between PCD/T and most common AEs (fever, lymphopenia, CPK increase, and hepatic cytolysis), body mass index, or age. Mean CPT (n=16) was significantly higher for female subjects (n=18; 11.5±4.8ng/mL) than for male subjects (8.8ng/mL±2.9, P=0.01), but no difference was observed between sex and CPD (P=0.32).. Our study showed a weak relationship between PCD and progression-free survival, but no relationship between PCD/T and AE was found. Monitoring PCD and PCT alone is unlikely to be useful in assessing response to treatment.

Topics: Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Imidazoles; Male; Melanoma; Mutation; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms

Malignant adenomyoepithelioma (AME) of the breast is an exceptionally rare form of breast cancer, with a significant metastatic potential. Chemotherapy has been used in the management of advanced AME patients, however the majority of treatments are not effective. Recent studies report recurrent mutations in the HRAS Q61 hotspot in small series of AMEs, but there are no preclinical or clinical data showing H-Ras protein as a potential therapeutic target in malignant AMEs. We performed targeted sequencing of tumours' samples from new series of 13 AMEs, including 9 benign and 4 malignant forms. Samples from the breast tumour and the matched axillary metastasis of one malignant HRAS mutated AME were engrafted and two patient-derived xenografts (PDX) were established that reproduced the typical AME morphology. The metastasis-derived PDX was treated in vivo by different chemotherapies and a combination of MEK and BRAF inhibitors (trametinib and dabrafenib). All malignant AMEs presented a recurrent mutation in the HRAS G13R or G12S hotspot. Mutation of PIK3CA were found in both benign and malignant AMEs, while AKT1 mutations were restricted to benign AMEs. Treatment of the PDX by the MEK inhibitor trametinib, resulted in a marked anti-tumor activity, in contrast to the BRAF inhibitor and the different chemotherapies that were ineffective. Overall, these findings further expand on the genetic features of AMEs and suggest that patients carrying advanced HRAS-mutated AMEs could potentially be treated with MEK inhibitors.

Topics: Adenomyoepithelioma; Aged; Aged, 80 and over; Antineoplastic Agents; Breast; Breast Neoplasms; Drug Resistance, Neoplasm; Female; Humans; Imidazoles; Middle Aged; Oximes; Point Mutation; Protein Kinase Inhibitors; Proto-Oncogene Proteins p21(ras); Pyridones; Pyrimidinones

Crizotinib, a multitargeted MET/ALK/ROS1 tyrosine kinase inhibitor, has been approved for the treatment of ROS1 fusion-positive non-small cell lung cancers (NSCLCs). However, "on-target" or "off-target" resistance alterations often emerge that confer the drug resistance. Patients with ROS1-rearranged NSCLC who develop crizotinib resistance, especially those acquiring "off-target" resistance mutations, still lack effective therapeutic options for after crizotinib treatment. Herein, we reported a patient with stage IVb lung adenocarcinoma harboring ROS1 fusion, who acquired a BRAF V600E and lost the ROS1 fusion after progression on crizotinib. It was deduced that the V600E may originate from a subclone with an extremely low fraction that was independent of ROS1 fusion-positive cells. The patient was subsequently treated with dabrafenib and trametinib combination and achieved a partial response lasting for more than 6 months. Our study revealed that BRAF V600E can confer the crizotinib resistance in ROS1 fusion-positive NSCLC and presented the first case showing that the treatment with dabrafenib and trametinib can serve as an effective option for later-line treatment for this molecular-defined subgroup. KEY POINTS: Patients with ROS1-rearranged non-small cell lung cancer (NSCLC) who acquire "off-target" resistance mutations to crizotinib still lack effective therapeutic options for after crizotinib treatment. This report describes the case of a patient with ROS1-rearranged NSCLC who acquired a BRAF V600E and lost the ROS1 fusion after crizotinib failure. The case was subsequently treated with dabrafenib and trametinib combination and achieved a partial response lasting for more than 6 months. This is the first article reporting that treatment with dabrafenib and trametinib may serve as an effective option for later-line treatment for patients harboring resistant BRAF V600E.

Topics: Carcinoma, Non-Small-Cell Lung; Crizotinib; Drug Resistance, Neoplasm; Humans; Imidazoles; Lung Neoplasms; Oximes; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

Patients with resected stage IIIB, IIIC and IIID melanomas have a high risk of recurrence. Therefore, an appropriate protocol for stage III melanoma is needed. Since adjuvant dabrafenib plus trametinib (D+T) combined therapy and anti-PD1 antibody (Ab) therapy reduce the risk of recurrence in patients with resected stage III BRAF-mutated melanoma, selecting the adjuvant therapy for BRAF-mutated melanoma is controversial. The efficacy and safety profiles of D+T combined therapy in the adjuvant setting were retrospectively analyzed in 36 Japanese. BRAF-mutated advanced melanoma patients. The relapse-free rate (RFR) at 12 months was 82.1% (95% confidential interval (CI), 63.9-92.6%). In the 21 patients who completed the protocol, the RFR at 12 months was 85.7% (95% CI, 64.5-95.9%). In the seven patients whose protocol was interrupted by adverse events, the RFR was 71.4% (95% CI, 35.2-92.4%). The incidence rate of any AEs for all patients was 69.7% (95% CI, 52.5-82.8%), including 13 cases of pyrexia, five cases of skin rash and four cases of liver dysfunction. The present study suggested that D+T therapy in the adjuvant setting is a useful and very tolerable protocol for BRAF-mutated melanoma in the Japanese population.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Female; Humans; Imidazoles; Japan; Male; Melanoma; Middle Aged; Oximes; Pyridones; Pyrimidinones; Retrospective Studies; Survival Analysis

The combination of dabrafenib and trametinib is a well-established treatment for BRAF-mutated melanoma. However, the effectiveness of this approach may be hindered by the development of treatment-related pyrexia syndrome, which occurs in at least 50% of treated patients. Without appropriate intervention, pyrexia syndrome has the potential to worsen and can result in hypotension secondary to dehydration and associated organ-related complications. Furthermore, premature treatment discontinuation may result in a reduction in progression-free and overall survival. Despite existing guidance, there is still a wide variety of therapeutic approaches suggested in the literature for both the definition and management of dabrafenib and trametinib-related pyrexia. This is reflected in the practice variation of its prevention and treatment within and between Canadian cancer centres. A Canadian working group was formed and consensus statements were constructed based on evidence and finalised through a two-round modified Delphi approach. The statements led to the development of a pyrexia treatment algorithm that can easily be applied in routine practice. The Canadian working group consensus statements serve to provide practical guidance for the management of dabrafenib and trametinib-related pyrexia, hopefully leading to reduced discontinuation rates, and ultimately improve patients' quality of life and cancer-related outcomes.

Topics: Antineoplastic Combined Chemotherapy Protocols; Canada; Consensus; Fever; Humans; Imidazoles; Mutation; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Quality of Life

The combination of BRAF and MEK inhibitors, such as dabrafenib and trametinib, respectively, is an established treatment option for patients with advanced BRAFV600-mutated melanoma. With the wide adoption of these therapies, a range of cutaneous adverse effects has been reported. We describe the case of a 47-year-old woman with BRAFV600E-mutated stage IV melanoma treated with dabrafenib and trametinib for 30 months who presented to our attention for painful skin lesions that had been present on her limbs since the start of targeted therapy. We also observed vitiligo-like lesions on the extensor surface of both legs. Despite achieving a complete oncological response, the patient had to discontinue the treatment because of persisting fever, nausea and painful skin nodules that significantly impaired her quality of life. The recognition of cutaneous signs of efficacy of such drugs for advanced melanoma is of primary importance in order to identify patients with potential long-term clinical benefits.

Topics: Combined Modality Therapy; Female; Humans; Imidazoles; Melanoma; Middle Aged; Neoplasm Staging; Oximes; Panniculitis; Pyridones; Pyrimidinones; Skin Neoplasms; Vitiligo

Simultaneous inhibition of multiple components of the BRAF-MEK-ERK cascade (vertical inhibition) has become a standard of care for treating BRAF-mutant melanoma. However, the molecular mechanism of how vertical inhibition synergistically suppresses intracellular ERK activity, and consequently cell proliferation, are yet to be fully elucidated.. We develop a mechanistic mathematical model that describes how the mutant BRAF inhibitor, dabrafenib, and the MEK inhibitor, trametinib, affect BRAFV600E-MEK-ERK signalling. The model is based on a system of chemical reactions that describes cascade signalling dynamics. Using mass action kinetics, the chemical reactions are re-expressed as ordinary differential equations that are parameterised by in vitro data and solved numerically to obtain the temporal evolution of cascade component concentrations.. The model provides a quantitative method to compute how dabrafenib and trametinib can be used in combination to synergistically inhibit ERK activity in BRAFV600E-mutant melanoma cells. The model elucidates molecular mechanisms of vertical inhibition of the BRAFV600E-MEK-ERK cascade and delineates how elevated BRAF concentrations generate drug resistance to dabrafenib and trametinib. The computational simulations further suggest that elevated ATP levels could be a factor in drug resistance to dabrafenib.. The model can be used to systematically motivate which dabrafenib-trametinib dose combinations, for treating BRAFV600E-mutated melanoma, warrant experimental investigation.

Topics: Extracellular Signal-Regulated MAP Kinases; Humans; Imidazoles; MAP Kinase Signaling System; Melanoma; Mitogen-Activated Protein Kinase Kinases; Models, Biological; Models, Chemical; Mutation; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

Advanced melanoma accounts for 4% of malignant skin tumors, and approximately 80% of deaths are attributed to it. The most frequent mutation of the RAF gene is BRAFV600, which has been associated with a worse prognosis. The objective of the research was to evaluate the cost-effectiveness of the combined regimen of dabrafenib plus trametinib (D + T) compared with other targeted therapies, immunotherapy, and dacarbazine for the treatment of unresectable/metastatic melanoma with BRAFV600 mutation from the perspective of the Colombian health system.. A partitioned survival model with 3 states (progression-free survival, progression, and death) was used to evaluate the cost-effectiveness for a time horizon of 20 years. Owing to the perspective of the analysis, only direct medical costs were taken into account. The efficacy of the evaluated treatment and the comparators were measured in terms of overall survival and progression-free survival. All costs were expressed in Colombian pesos as of 2018, and outcomes and costs were discounted at 5% annually. Two analysis scenarios were considered, one in which only monitoring and follow-up costs were included in the progression phase and another in which costs of acquisition of possible treatment sequences were also included.. In the first scenario (without postprogression medication costs), the combined D + T regimen was a dominant alternative to vemurafenib + cobimetinib but was not a cost-effective option compared with vemurafenib, nivolumab, ipilimumab, nivolumab + ipilimumab, pembrolizumab, and dacarbazine. In the second scenario (with drug costs in postprogression), D + T was dominant compared with vemurafenib + cobimetinib and cost-effective compared with nivolumab and pembrolizumab. Compared with other schemes, the incremental cost-effectiveness ratio was above the threshold of 3 gross domestic product per capita. Probabilistic sensitivity analyses showed that a willingness-to-pay threshold of Col$56 484 300 (US$19 108) per quality-adjusted life-year would not be reached at the current price of schema in Colombia.. The combined scheme could be a cost-effective and even a cost-saving alternative to vemurafenib + cobimetinib, nivolumab, and pembrolizumab if the costs associated with the use of other medications are taken into account after progression to the first line of treatment. Compared with the other comparators, it produces a greater number of quality-adjusted life-years, but the incremental cost-effectiveness ratio is above that of the willingness to pay.

Topics: Colombia; Cost-Benefit Analysis; Dacarbazine; Humans; Imidazoles; Immunotherapy; Melanoma; Mutation; Oximes; Pyridones; Pyrimidinones

Virtually all metastatic patients with metastatic melanoma who progress after initial treatment with PD-1 or CTLA-4 directed antibodies will die of their disease. Salvage options are urgently needed. It is theoretically attractive to combine immunotherapy with targeted agents in progressing patients with BRAF mutation positive melanoma, but the toxicity of combined treatment has proven challenging.. We performed a retrospective analysis of our patient database and identified 23 patients who progressed on initial checkpoint inhibitor treatment, who subsequently had cautious addition of BRAF±MEK inhibitor therapy to continued PD-1 antibody treatment.. We found an objective response rate of 55% in second line therapy, with a median progression-free survival of 33.4 months and median overall survival of 34.1 months, with 40% of patients in unmaintained remission at over 3 years. Ten of 12 responding patients were able to discontinue all therapy and continue in unmaintained remission. Toxicity of this approach was generally manageable (21.7% grade 3-5 toxicity). There was 1 early sudden death for unknown reasons in a responding patient.. Our results suggest that 2nd line therapy with PD-1 inhibitors plus BRAF±MEK inhibitors has substantial activity and manageable toxicity. This treatment can induce additional durable complete responses in patients who have progressed on initial immunotherapy. These results suggest further evaluation be performed of sequential PD-1 antibody treatment with cautious addition of targeted therapy in appropriate patients.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Combined Modality Therapy; Disease Progression; Feasibility Studies; Female; Humans; Imidazoles; Immune Checkpoint Inhibitors; Ipilimumab; Male; Melanoma; Middle Aged; Mitogen-Activated Protein Kinase Kinases; Molecular Targeted Therapy; Mutation; Nivolumab; Oximes; Progression-Free Survival; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Retrospective Studies; Skin Neoplasms; Time Factors; Treatment Outcome; Young Adult

Real-world data on extended follow-up of patients with BRAF V600-mutant metastatic melanoma are limited. We investigated dabrafenib plus trametinib (dab + tram) outside of a clinical trial setting (Individual Patient Program; DESCRIBE Italy).. To describe the baseline features, treatment patterns, efficacy, and safety outcomes in patients with BRAF V600-mutant unresectable or metastatic melanoma who had received dab + tram as part of the Managed Access Program (MAP) in Italy.. An observational, retrospective chart review was conducted in Italian patients with BRAF V600-mutant unresectable stage III/IV melanoma receiving dab + tram as part of the MAP. Baseline features, treatment patterns, efficacy, and safety outcomes were evaluated.. Overall, 499 patients were included in this analysis. BRAF V600E mutation was seen in 81.4% of patients. Overall response rate achieved in 243 of the 390 evaluable patients was 62.3% (95% CI 57.5-67.1). Median progression-free survival (PFS) was 9.3 months (95% CI 8.6-10.6). Subgroup analyses revealed that patients with normal lactate dehydrogenase (LDH) and ≤ three metastatic sites without brain metastases at baseline had better outcomes. With normal LDH at baseline, median PFS for patients with one or two metastatic sites other than cerebral was 18 months. No new safety signals were observed. Treatment was permanently discontinued because of treatment-emergent adverse events (TEAEs) in 9.2% of patients, and pyrexia (27.3%) was the most common TEAE, with a lower incidence than that in the phase 3 studies of dab + tram.. Treatment of BRAF V600E-mutant metastatic melanoma with dab + tram in the real-world setting was effective and safe, including the unselected population with several patients having a high tumor burden - concordant with the results of the pivotal phase 3 studies of dab + tram.

Topics: Antineoplastic Combined Chemotherapy Protocols; Humans; Imidazoles; Melanoma; Melanoma, Cutaneous Malignant; Mutation; Neoplasms, Second Primary; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Retrospective Studies; Skin Neoplasms

Topics: Aged; Antineoplastic Agents; Drug-Related Side Effects and Adverse Reactions; Epiretinal Membrane; Female; Glucocorticoids; Humans; Imidazoles; Liver Neoplasms; Lymphatic Metastasis; Melanoma; Neoplasm Staging; Oximes; Prednisolone; Pyridones; Pyrimidinones; Skin Neoplasms; Tomography, Optical Coherence; Uveitis

Topics: Adenocarcinoma of Lung; Antineoplastic Combined Chemotherapy Protocols; Azetidines; Drug Substitution; Humans; Imidazoles; Lung Neoplasms; Male; Middle Aged; Mutation; Oximes; Piperidines; Prognosis; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Vemurafenib

Approximately 50% of melanomas are characterized by BRAF mutation (V600E in 90% of cases), that predicts more aggressive behaviour. This mutation is the target of dabrafenib, an anti-BRAF tyrosine-kinase inhibitor (TKI), that together with trametinib, anti-MEK TKI, is approved for first-line treatment of metastatic melanoma due to significant benefit in overall and progression-free survival. Most common treatment-related adverse events are pyrexia, chills, fatigue, rash, nausea, vomiting, and diarrhoea. This case report aims to present another less common adverse event of combined anti-BRAF and anti-MEK treatment. Our patient, after 4 months on target-therapy, experienced sudden deep abdominal pain. At the initial work-out at the emergency department, increase in serum lipase was detected and radiological findings were consistent with acute pancreatitis. Admitted to the hospital, other causes were ruled out and target-therapy was discontinued with symptoms improvement. Radiological and clinical follow-up was performed and a diagnosis of drug-induced pancreatitis was made. After few days of medical support with analgesia and antibiotic, the patient felt better and was discharged; target-therapy was permanently interrupted. Searching the literature, not so many cases of iatrogenic pancreatitis are described with this TKI combination, therefore, we have reported it as a rare but life-threatening adverse event that should be investigated whenever conceivable.

Topics: Aged, 80 and over; Humans; Imidazoles; Male; Melanoma; Neoplasm Metastasis; Oximes; Pancreatitis; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms

Topics: Antineoplastic Combined Chemotherapy Protocols; Humans; Imidazoles; Melanoma; Mutation; Neoplasm Metastasis; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms

Topics: Antineoplastic Combined Chemotherapy Protocols; Humans; Imidazoles; Melanoma; Mutation; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Renal Dialysis; Skin Neoplasms

A new liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the simultaneous quantification of dabrafenib (DAB), its main metabolite hydroxy-dabrafenib (OHD) and trametinib (TRA) in human plasma has been developed and validated. After addition of internal standard (dabrafenib-d9), extraction was achieved after protein precipitation with acetonitrile containing 1 % (v/v) formic acid. Chromatographic separation was performed on an Accucore® C18 (2.1 × 50 mm; 2.6 μm) column using a gradient elution of water acidified with 0.1 % (v/v) formic acid (A) and acetonitrile containing 0.1 % (v/v) formic acid (B) at a flow rate of 500 μL/min. The calibration ranged from 10 to 2000 ng/mL for DAB and OHD and from 5 to 50 ng/mL for TRA. This method was validated with satisfactory results including good precision (intra- and inter-assay coefficient of variation from 2.0 %-14.9 %) and good accuracy (inter- and intra-day bias between -1.2 % and 10.9 %), as well as long term stability in unprocessed plasma at -20 °C. This newly proposed method is useful for clinical research purposes as well as therapeutic drug monitoring for patients with a Rapidly Accelerated Fibrosarcoma kinase B (BRAF)-mutated cancer.

Topics: Chromatography, Liquid; Humans; Imidazoles; Oximes; Pyridones; Pyrimidinones; Reproducibility of Results; Tandem Mass Spectrometry

Various adverse events (AEs) have been reported to occur at a high rate in patients treated with dabrafenib plus trametinib (D + T) combination therapy. Among such AEs, the incidence of pyrexia was highest among the series of AEs in patients treated with D + T combination therapy. Although little is known about the mechanisms of pyrexia caused by D + T combination therapy, a recent report suggested that sCD163, as well as interferon-inducible chemokines (CXCL9, CXCL10, CXCL11), might correlate with pyrexia caused by encorafenib plus binimetinib combination therapy. In addition to these soluble factors, CXCL5 is a biomarker for predicting immune-related AEs in melanoma patients treated with nivolumab. From the above findings, we hypothesized that these soluble factors might also correlate with the onset of AEs in D + T combination therapy. The serum levels of sCD163 were increased in patients with pyrexia in parallel with their severity, whereas the serum levels of CXCL5 were increased in patients without pyrexia. Moreover, increased levels of CXCL9, CXCL10, and CXCL11 were prominent in patients with AEs over G2 levels. As these chemokines recruit Th1, Th17, and activated CD8+ T cells, increased serum levels of these chemokines might correlate with the positive feedback of inflammatory reactions related to AEs.

Topics: Antineoplastic Combined Chemotherapy Protocols; Biomarkers; Chemokines; Humans; Imidazoles; Melanoma; Mutation; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms

Topics: Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; COVID-19; COVID-19 Nucleic Acid Testing; Diagnosis, Differential; Female; Fever; Humans; Imidazoles; Lung; Melanoma; Oximes; Pyridones; Pyrimidinones; RNA, Viral; SARS-CoV-2; Skin Neoplasms; Tomography, X-Ray Computed

Topics: Adolescent; Brain Neoplasms; Ganglioglioma; Humans; Imidazoles; Mitogen-Activated Protein Kinase Kinases; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Vemurafenib

Dabrafenib and trametinib therapy for BRAF V600E-mutant non-small cell lung cancer (NSCLC) has demonstrated strong antitumor effects in clinical trials and has been approved for use in clinical practice. However, the efficacy and safety of this combination therapy in elderly patients remain unclear. An 86-year-old male patient, who had been diagnosed with lung adenocarcinoma with the BRAF V600E mutation, received dabrafenib and trametinib combination chemotherapy. The tumor shrunk rapidly; however, therapy was discontinued after 40 days because adverse events (hypoalbuminemia, peripheral edema, and pneumonia) developed. Although this targeted combination therapy seemed to cause relatively severe adverse events compared with single-agent targeted therapy in this "oldest old" elderly patient, the marked tumor shrinkage prolonged the patient's life and helped him to maintain a good general condition. Active targeted therapy may therefore be considered with appropriate drug dose reduction instead of conservative treatment, even if a patient is extremely old.

Topics: Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Humans; Imidazoles; Lung Neoplasms; Male; Mutation; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

Topics: Adolescent; Brain Neoplasms; Chemoradiotherapy; Fatal Outcome; Glioma; Humans; Imidazoles; Male; MAP Kinase Kinase Kinases; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Re-Irradiation

Topics: Carcinoma, Non-Small-Cell Lung; Humans; Imidazoles; Lung Neoplasms; Mitogen-Activated Protein Kinase Kinases; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

Topics: Choroid; Choroid Neoplasms; Drug Therapy, Combination; Follow-Up Studies; Humans; Imidazoles; Immunotherapy; Injections, Intralesional; Male; Melanoma; Melanoma, Cutaneous Malignant; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Oximes; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Skin Neoplasms; Tomography, Optical Coherence

Topics: Antineoplastic Combined Chemotherapy Protocols; Biliary Tract Neoplasms; Humans; Imidazoles; Mutation; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

Topics: Antineoplastic Combined Chemotherapy Protocols; Humans; Imidazoles; Melanoma; Oximes; Proto-Oncogene Proteins B-raf; Psoriasis; Pyridones; Pyrimidinones; Skin Neoplasms

The outcomes of patients with metastatic melanoma (MM) have significantly improved after the introduction of BRAF-specific inhibitors. Herein is reported a patient with MM and non-V600-BRAF mutation who responded to iBRAF/iMEK therapy. In July 2014, a 63-year-old man presented with a 4.1mm-thick V600E-BRAF wild type melanoma on the back. Metastases were identified in one sentinel node and two of 11 subsequently excised lymph nodes, with no signs of distant metastatic disease. In September 2017, lung metastasis was observed and pembrolizumab was started. Progressive disease was apparent at cycle 10 and therapy was switched to ipilimumab. After four cycles, an asymmetric response was observed. In November 2017, next generation sequencing genomic profiling disclosed a rare L597K-BRAF mutation and vemurafenib plus cobimetinib therapy was initiated in January 2018. Seven days after treatment start, a remarkable clinical improvement was observed. In April 2018, the patient achieved partial response, which was sustained until October 2018. Cases of patients with non-V600-BRAF mutations responding to iBRAF/iMEK therapy have been reported over the last years. To the best of our knowledge, this is the first case reporting response to combined iBRAF/iMEK therapy in a patient with metastatic melanoma harboring L597K mutation.

Topics: Antineoplastic Combined Chemotherapy Protocols; Azetidines; Back; Dacarbazine; Humans; Imidazoles; Male; Melanoma; Middle Aged; Mutation; Oximes; Piperidines; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Vemurafenib

Anaplastic thyroid carcinoma is the rarest tumor of the thyroid gland, representing less than 2% of clinically recognized thyroid cancers. Typically, it has an extremely rapid onset, fatal outcomes in most cases, and a median overall survival of 3 to 10 months despite aggressive multidisciplinary management. The presence of targetable mutations in anaplastic thyroid carcinoma patients is an opportunity for treatment when conventional therapeutics approaches are not effective, a frequent situation in the majority of patients. We present our experience in the management of a patient with unresectable anaplastic thyroid cancer who had a remarkable and rapid response to treatment with dabrafenib and trametinib during the COVID-19 pandemic. After four weeks of dabrafenib 150 mg twice daily plus trametinib 2 mg daily, he showed a dramatic reduction of the cervical mass around 90%. Nearly eight weeks under treatment with dabrafenib plus trametinib, the patient remains with minimal locoregional disease without distant metastases.

Topics: Antineoplastic Combined Chemotherapy Protocols; COVID-19; Humans; Imidazoles; Male; Mutation; Oximes; Pandemics; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; SARS-CoV-2; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms

Topics: Circulating Tumor DNA; Humans; Imidazoles; Melanoma; Oximes; Pyridones; Pyrimidinones

Pneumatosis intestinalis (PI) is a rare entity which refers to the presence of gas within the wall of the small bowel or colon which is a radiographic sign. The etiology and clinical presentation are variable. Patients with PI may present either with chronic mild non-specific symptoms or with acute abdominal pain with peritonitis. Some cases of intestinal pneumatosis have been reported as adverse events of new oncological treatments such as targeted therapies that are widely used in multiple tumors.. A 59-year-old caucasian female with radioactive iodine-refractory metastatic thyroid papillary carcinoma with BRAF. This case report is, in our knowledge, the first description of PI in a patient treated with dabrafenib-trametinib. Conservative treatment is feasible if there are no abdominal symptoms.

Topics: Emphysema; Female; Humans; Imidazoles; Intestinal Diseases; Iodine Radioisotopes; Middle Aged; Oximes; Positron Emission Tomography Computed Tomography; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skull Base Neoplasms; Thyroid Cancer, Papillary; Thyroid Neoplasms

Immunotherapy (IT) and targeted therapy (TT) are both effective against melanoma, but their combination is frequently toxic. Here, we investigated whether the sequence of IT (anti-PD-1)→ TT (ceritinib-trametinib or dabrafenib-trametinib) was associated with improved antitumor responses in mouse models of

Topics: Animals; Antineoplastic Agents; CD8-Positive T-Lymphocytes; Cell Line, Tumor; Disease Models, Animal; Female; Imidazoles; Immunotherapy; Melanoma; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Molecular Targeted Therapy; Monomeric GTP-Binding Proteins; Mutation; Oximes; Programmed Cell Death 1 Receptor; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidines; Pyrimidinones; Skin Neoplasms; Sulfones; T-Lymphocytes, Regulatory

Researchers often aim to incorporate microenvironmental variables such as the dimensionality and composition of the extracellular matrix into their cell-based assays. A technical challenge created by introduction of these variables is quantification of single-cell measurements and control of environmental reproducibility. Here, we detail a methodology to quantify viability and proliferation of melanoma cells in 3D collagen-based culture platforms by automated microscopy and 3D image analysis to yield robust, high-throughput results of single-cell responses to drug treatment.

Topics: Antineoplastic Agents; Cell Culture Techniques; Cell Proliferation; Cell Survival; Collagen; Image Processing, Computer-Assisted; Imidazoles; Melanoma; Oximes; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Single-Cell Analysis; Spheroids, Cellular

The emerging role of BRAF and MEK tyrosine-kinase inhibitors has shown new opportunities of treatment for patients with advanced melanoma and BRAF mutations. Its use is associated with some toxicities, as pyrexia, that clinicians may not be familiarized with. We present the case of a patient diagnosed with stage IV melanoma BRAF Val600E mutated who was started on dabrafenib and trametinib and developed three severe episodes of fever, hypotension and acute phase reactants elevation during the first 3 months of therapy, in the absence of microbiological demonstration of infection. The episodes were initially managed as a septic shock with broad-spectrum antibiotics and vasoactive drugs, while treatment with dabrafenib and trametinib was withheld. After two subsequent dose reduction of dabrafenib, the patient did not experience new episodes of fever.

Topics: Acute-Phase Proteins; Antineoplastic Combined Chemotherapy Protocols; Humans; Imidazoles; Male; Middle Aged; Oximes; Pyridones; Pyrimidinones; Shock; Survival Analysis

Anaplastic thyroid cancer (ATC) has dismal prognosis and there is no effective treatment. We aimed to evaluate the efficacy of tyrosine kinase inhibitor (TKI) therapy in real-world clinic and to suggest the most effective treatment modality according to the combination of treatments.. This retrospective study evaluated clinical outcomes and cause of death with multimodal treatments in patients with ATC at Samsung Medical Center.. A total of 120 patients received anti-cancer treatment for ATC. Seventy-seven (64.2%) patients underwent surgery, 64 (53.3%) received radiotherapy, 29 (24.2%) received cytotoxic chemotherapy, and 19 (15.8%) received TKI therapy. In the TKI therapy group, eight achieved partial response (three with lenvatinib and five with dabrafenib plus trametinib), and two patients with lenvatinib showed stable disease. Median progression-free survival (PFS) of the TKI therapy group was 2.7 months (range: 0.1-12.7) and their median overall survival (OS) was 12.4 months (range: 1.7-47.7). Patients who received surgery or radiotherapy for local control showed superior OS than those who did not. In a multivariate analysis, surgery, TKI therapy, younger age, and no distant metastasis were associated with favorable OS. The combination of surgery, radiotherapy, and TKI therapy (median OS: 34.3 months, 6-month survival rates: 77.8%) was the most effective. Compared to the era without TKI therapy, distant metastasis has recently become the major cause of death in ATC over airway problems.. Multimodality treatment including TKI therapy demonstrated prolonged survival with dabrafenib plus trametinib as the most effective therapeutic option demonstrated for BRAF mutant ATC patients.

Topics: Age Factors; Aged; Antineoplastic Agents; Combined Modality Therapy; Female; Humans; Imidazoles; Male; Middle Aged; Oximes; Phenylurea Compounds; Prognosis; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Quinolines; Retrospective Studies; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms; Treatment Outcome

Cardiovascular adverse events (CVAEs) associated with BRAF inhibitors alone versus combination BRAF/MEK inhibitors are not fully understood.. This study included all adult patients who received BRAF inhibitors (vemurafenib, dabrafenib, encorafenib) or combinations BRAF/MEK inhibitors (vemurafenib/cobimetinib; dabrafenib/trametinib; encorafenib/binimetinib). We utilized the cross-sectional FDA's Adverse Events Reporting System (FAERS) and longitudinal Truven Health Analytics/IBM MarketScan database from 2011 to 2018. Various CVAEs, including arterial hypertension, heart failure (HF), and venous thromboembolism (VTE), were studied using adjusted regression techniques.. In FAERS, 7752 AEs were reported (40% BRAF and 60% BRAF/MEK). Median age was 60 (IQR 49-69) years with 45% females and 97% with melanoma. Among these, 567 (7.4%) were cardiovascular adverse events (mortality rate 19%). Compared with monotherapy, combination therapy was associated with increased risk for HF (reporting odds ratio [ROR] = 1.62 (CI = 1.14-2.30); p = 0.007), arterial hypertension (ROR = 1.75 (CI = 1.12-2.89); p = 0.02) and VTE (ROR = 1.80 (CI = 1.12-2.89); p = 0.02). Marketscan had 657 patients with median age of 53 years (IQR 46-60), 39.3% female, and 88.7% with melanoma. There were 26.2% CVAEs (CI: 14.8%-36%) within 6 months of medication start in those receiving combination therapy versus 16.7% CVAEs (CI: 13.1%-20.2%) among those receiving monotherapy. Combination therapy was associated with CVAEs compared to monotherapy (adjusted HR: 1.56 (CI: 1.01-2.42); p = 0.045).. In two independent real-world cohorts, combination BRAF/MEK inhibitors were associated with increased CVAEs compared to monotherapy, especially HF, and hypertension.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Azetidines; Benzimidazoles; Carbamates; Carcinoma, Non-Small-Cell Lung; Cardiotoxicity; Cardiovascular Diseases; Colonic Neoplasms; Cross-Sectional Studies; Female; Heart Failure; Humans; Hypertension; Imidazoles; Lung Neoplasms; Male; Melanoma; Middle Aged; Mitogen-Activated Protein Kinase Kinases; Oximes; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Registries; Regression Analysis; Skin Neoplasms; Sulfonamides; Vemurafenib; Venous Thromboembolism; Young Adult

Gastrointestinal perforation related to mitogen-activated protein kinase kinase (MEK) inhibitors has been reported previously; however, there has been no case report of such a condition in patients with non-small cell lung cancer (NSCLC). Herein, we report a case of small intestinal perforation secondary to dabrafenib and trametinib administration, but not related to tumor regression. A 62-year-old man with non-small cell lung cancer harboring BRAF V600E mutation was treated with dabrafenib and trametinib. Four months after the initiation of treatment, a small intestinal perforation was diagnosed. Dabrafenib and trametinib rechallenge was performed after gastrointestinal perforation. The patient responded well to therapy and did not experience recurrence of gastrointestinal perforation. To the best of our knowledge, this is the first report of gastrointestinal perforation in a patient with NSCLC treated with a MEK inhibitor. The mechanism and risk factors of trametinib-induced perforation are currently unknown. Physicians should be aware of such severe gastrointestinal side effects of trametinib.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Humans; Imidazoles; Intestinal Perforation; Lung Neoplasms; Male; Middle Aged; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

Dabrafenib plus trametinib combination has greatly improved survival in BRAFV600. BRAFV600. Fifty patients (comprising 4 AJCC stage IIIc and 46 stage IV) were included. Median PFS reached 11.4 months, and overall response rate 70%. Fifty percent of patients experienced ARAE (G3 n = 10, G4 n = 0). In univariate analysis, median dabrafenib C. In this study, exposure-efficacy and tolerance analysis highlighted the interest of therapeutic drug monitoring to optimize therapeutic management in BRAFV600

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Area Under Curve; Bayes Theorem; Drug Monitoring; Female; Humans; Imidazoles; Male; Melanoma; Middle Aged; Mutation; Neoplasm Staging; Oximes; Progression-Free Survival; Prospective Studies; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Treatment Outcome

Although patients with unresectable or metastatic melanoma can experience long-term survival with BRAF- and MEK-targeted agents or immune checkpoint inhibitors over 5 years, resistance develops in most patients. There is a distinct lack of pretherapeutic biomarkers to identify which patients are likely to benefit from each therapy type. Most research has focused on the predictive role of T cells in antitumor responses as opposed to B cells.. We conducted prespecified exploratory biomarker analysis using gene expression profiling and digital pathology in 146 patients with previously untreated. B cells may serve as a potential biomarker to predict clinical outcome in patients with advanced melanoma treated with dabrafenib plus trametinib. As separate studies have shown an opposite effect for B-cell levels and response to immunotherapy, B cells may serve as a potential biomarker to facilitate treatment selection. Further validation in a larger patient cohort is needed.

Topics: Antineoplastic Combined Chemotherapy Protocols; B-Lymphocytes; Humans; Imidazoles; Melanoma; Oximes; Pyridones; Pyrimidinones; Skin Neoplasms; Treatment Outcome

Therapy resistance arises from heterogeneous drug-tolerant persister cells or minimal residual disease (MRD) through genetic and nongenetic mechanisms. A key question is whether specific molecular features of the MRD ecosystem determine which of these two distinct trajectories will eventually prevail. We show that, in melanoma exposed to mitogen-activated protein kinase therapeutics, emergence of a transient neural crest stem cell (NCSC) population in MRD concurs with the development of nongenetic resistance. This increase relies on a glial cell line-derived neurotrophic factor-dependent signaling cascade, which activates the AKT survival pathway in a focal adhesion kinase (FAK)-dependent manner. Ablation of the NCSC population through FAK inhibition delays relapse in patient-derived tumor xenografts. Strikingly, all tumors that ultimately escape this treatment exhibit resistance-conferring genetic alterations and increased sensitivity to extracellular signal-regulated kinase inhibition. These findings identify an approach that abrogates the nongenetic resistance trajectory in melanoma and demonstrate that the cellular composition of MRD deterministically imposes distinct drug resistance evolutionary paths.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Drug Resistance, Neoplasm; Female; Focal Adhesion Kinase 1; Gene Expression Regulation, Neoplastic; Glial Cell Line-Derived Neurotrophic Factor; Humans; Imidazoles; Melanoma; Mice, SCID; Mitogen-Activated Protein Kinase Kinases; Neoplasm Recurrence, Local; Neoplastic Stem Cells; Neural Crest; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Xenograft Model Antitumor Assays

Topics: Brain Diseases; Brain Stem; Humans; Imidazoles; Melanoma; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

Malignant melanoma is a well-known diagnostic pitfall, given its propensity to metastasize to different sites and mimic various entities. In this report, we present a fine-needle aspiration biopsy (FNA) of a metastatic melanoma with basaloid features that is occurring in the preauricular/parotid area. The patient is a 17-year-old male with a history of excision of melanoma of the left temple, and was undergoing adjuvant treatment with nivolumab. The prior excision was positive for S100, HMB-45, melan-A, and tyrosinase. On follow-up, he presented with non-FDG avid left preauricular area lesions. FNA was performed, and on-site evaluation demonstrated a cellular basaloid neoplasm with focal fibrillary stroma. Immunohistochemical stains revealed that the tumor cells were positive for SOX-10, S100, MITF, and HMGA2, and were negative for HMB-45, melan-A, tyrosinase, p63, cam 5.2 and PLAG1. The positive S100, SOX-10, and MITF results and negative cam 5.2 result supported the diagnosis of melanoma. Nivolumab was then stopped, Dabrafenib/Trametinib were started, and the patient underwent excision of the nodules. Nine-months later, he developed a rib metastasis that was positive for S100, SOX-10, melan-A, and tyrosinase. This report emphasizes that melanoma involving the parotid gland region has the potential to be misdiagnosed by FNA as a salivary gland neoplasm because of overlapping cytologic features and immunophenotypes. This pitfall is avoided by careful morphologic analysis and judicious use of ancillary studies.

Topics: Adolescent; Antineoplastic Agents; Biomarkers, Tumor; Biopsy, Fine-Needle; Diagnosis, Differential; Humans; Imidazoles; Male; Melanoma; Neoplasm Metastasis; Nivolumab; Oximes; Pyridones; Pyrimidinones; Salivary Gland Neoplasms

Topics: Antineoplastic Combined Chemotherapy Protocols; Child; Humans; Imidazoles; Mutation; Nervous System Neoplasms; Oximes; Pyridones; Pyrimidinones

Topics: Antineoplastic Combined Chemotherapy Protocols; China; Cost-Benefit Analysis; Humans; Imidazoles; Melanoma; Mutation; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Vemurafenib

Dabrafenib plus trametinib has demonstrated clinical benefit across multiple BRAF-mutant tumours, leading to approval for resected stage III and metastatic melanoma, non-small-cell lung cancer (NSCLC) and anaplastic thyroid cancer. Pyrexia is a common adverse event in patients treated with dabrafenib plus trametinib. Here, we characterise the incidence, patterns and management of pyrexia in patients receiving dabrafenib plus trametinib in clinical trials.. Patients (N = 1076) included in the analysis received dabrafenib plus trametinib in the following clinical trials: phase II registration trial in advanced NSCLC (N = 82), phase III COMBI-AD study in resectable stage III melanoma (N = 435) and phase III COMBI-d and COMBI-v studies in unresectable or metastatic melanoma (N = 209 and N = 350, respectively).. Among the 1076 patients enrolled in the clinical trials, 61.3% developed pyrexia, 5.7% developed grade 3/4 pyrexia and 15.6% developed a protocol-defined serious pyrexia event. Among the 660 patients with pyrexia, 33.0% had 1 occurrence, 19.8% had 2 occurrences and 47.1% had ≥3 occurrences. The incidence of pyrexia was highest early in treatment and decreased with time on treatment. Temporary dose interruption of dabrafenib or trametinib was the most common and effective management strategy.. Pyrexia is the most common adverse event associated with dabrafenib plus trametinib but is manageable with dose interruption.. ClinicalTrials.gov (Phase II NSCLC, NCT01336634; COMBI-AD, NCT01682083; COMBI-d, NCT01584648; COMBI-v, NCT01597908).

Topics: Antineoplastic Combined Chemotherapy Protocols; Female; Fever; Humans; Imidazoles; Male; Neoplasms; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

Acute kidney injury (AKI) associated with cancer chemotherapy can be life-threatening. Inhibitors of rapidly accelerated fibrosarcoma kinase B (BRAF)-mutants and mitogen-activated extracellular signal-regulated kinase (MEK) administered as combination therapy are effective against BRAF-mutant melanoma, but drug-associated AKI events were reported after marketing. Here, we examined the nephrotoxicity of two BRAF inhibitors, vemurafenib and dabrafenib, and two MEK inhibitors, cobimetinib and trametinib, in a real-world setting and human kidney cells. Target drug-associated AKI signals were detected by reporting odds ratio (ROR) derived from report data in the Food and Drug Administration Adverse Events Reporting System database. In-vitro cytotoxicity was evaluated in proximal renal tubular epithelial cells (RPTEC), glomerular endothelial cells (GEnC), and glomerular epithelial cells (GEpC). AKI RORs associated with vemurafenib [ROR, 3.28; confidence interval (CI), 2.91-3.69] and cobimetinib (ROR, 4.40; CI, 3.55-5.45) were higher than those associated with dabrafenib (ROR, 1.35; CI, 1.15-1.60) and trametinib (ROR, 1.32; CI, 1.11-1.56). Vemurafenib reduced cell viability and increased cell death in RPTEC and GEpC at 10 μM, which was below the mean maximum concentration in blood under steady-state condition [115.7 μM (56.7 μg/mL)]. No vemurafenib-associated cytotoxicity was detected in GEnC. Mean maximum concentrations of cobimetinib, dabrafenib and trametinib did not induce cell death. This work revealed that vemurafenib had stronger cytotoxic effects on tubular and glomerular epithelial cells than the other BRAF and MEK inhibitors. Hence, we recommend careful monitoring for clinical signs of kidney injury in patients treated with vemurafenib.

Topics: Acute Kidney Injury; Antineoplastic Agents; Azetidines; Cell Death; Cell Line; Cell Survival; Dose-Response Relationship, Drug; Humans; Imidazoles; Mitogen-Activated Protein Kinase Kinases; Oximes; Piperidines; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Vemurafenib

Patients with BRAF-mutated colorectal cancer (CRC) have a poor prognosis despite recent therapeutic advances such as combination therapy with BRAF, MEK, and epidermal growth factor receptor (EGFR) inhibitors. To identify microRNAs (miRNAs) that can improve the efficacy of BRAF inhibitor dabrafenib (DAB) and MEK inhibitor trametinib (TRA), we screened 240 miRNAs in BRAF-mutated CRC cells and identified five candidate miRNAs. Overexpression of miR-193a-3p, one of the five screened miRNAs, in CRC cells inhibited cell proliferation by inducing apoptosis. Reverse-phase protein array analysis revealed that proteins with altered phosphorylation induced by miR-193a-3p were involved in several oncogenic pathways including MAPK-related pathways. Furthermore, overexpression of miR-193a-3p in BRAF-mutated cells enhanced the efficacy of DAB and TRA through inhibiting reactivation of MAPK signaling and inducing inhibition of Mcl1. Inhibition of Mcl1 by siRNA or by Mcl1 inhibitor increased the antiproliferative effect of combination therapy with DAB, TRA, and anti-EGFR antibody cetuximab. Collectively, our study demonstrated the possibility that miR-193a-3p acts as a tumor suppressor through regulating multiple proteins involved in oncogenesis and affects cellular sensitivity to MAPK-related pathway inhibitors such as BRAF inhibitors, MEK inhibitors, and/or anti-EGFR antibodies. Addition of miR-193a-3p and/or modulation of proteins involved in the miR-193a-3p-mediated pathway, such as Mcl1, to EGFR/BRAF/MEK inhibition may be a potential therapeutic strategy against BRAF-mutated CRC.

Topics: Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Cetuximab; Colorectal Neoplasms; Drug Therapy, Combination; ErbB Receptors; Genes, Tumor Suppressor; Humans; Imidazoles; MicroRNAs; Mitogen-Activated Protein Kinase Kinases; Mutation; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; RNA, Small Interfering; Signal Transduction; Transfection

Topics: Antineoplastic Combined Chemotherapy Protocols; Antiviral Agents; Benzimidazoles; Fluorenes; Hepatitis C, Chronic; Humans; Imidazoles; Melanoma; Oximes; Pyridones; Pyrimidinones; Skin Neoplasms; Sofosbuvir; Uridine Monophosphate

The majority of papillary thyroid cancers are driven by acquired mutations typically in the BRAF or RAS genes that aberrantly activate the mitogen-activated protein kinase pathway. This process leads to malignant transformation, dedifferentiation, and a decrease in the expression of the sodium-iodide symporter (NIS; SLC5A5), which results in resistance to radioactive iodine therapy. We sought to determine whether inhibition of aberrant mitogen-activated protein kinase-signaling can restore NIS expression.. We prospectively developed cultures of papillary thyroid cancers derived from operative specimens and applied drug treatments for 24 hours. Samples were genotyped to identify BRAF and RAS mutations. We performed quantitative PCR to measure NIS expression after treatment.. We evaluated 24 patient papillary thyroid cancer specimens; BRAF. Dual treatment with BRAF and MEK inhibitors upregulated NIS expression, suggesting that this treatment regimen may increase tumor iodine uptake. The effect was greatest in tumor cells from younger patients.

Topics: Adult; Age Factors; Aged; Antineoplastic Combined Chemotherapy Protocols; Chemoradiotherapy; Female; Gene Expression Regulation, Neoplastic; Humans; Imidazoles; Iodine Radioisotopes; Male; MAP Kinase Signaling System; Middle Aged; Mitogen-Activated Protein Kinase Kinases; Mutation; Oximes; Primary Cell Culture; Prospective Studies; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins p21(ras); Pyridones; Pyrimidinones; Radiation Tolerance; Symporters; Thyroid Cancer, Papillary; Thyroid Neoplasms; Tumor Cells, Cultured; Up-Regulation

Topics: Antineoplastic Agents; Dermatologic Agents; Erythema Nodosum; Female; Humans; Imidazoles; Melanoma; Middle Aged; Mutation; Oximes; Potassium Iodide; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms

Topics: Acrylamides; Aniline Compounds; ErbB Receptors; Humans; Imidazoles; Liquid Biopsy; Lung Neoplasms; Mutation; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

A patient who was initially considered to have a glioblastoma (GBM) had molecular analysis, showing that it was a pleomorphic xanthoastrocytoma (PXA). Up to 78% of PXA tumors have BRAF V600E mutations. Primary brain tumors with BRAF mutations can have a good response to BRAF MEK inhibitors (BRAF MEKi), and there may be a synergistic response when combined with autophagy inhibitors.. A 20-year-old man found to have a large brain mass with midline shift underwent resection. He was diagnosed with "GBM" and treated with radiation and temozolomide with subsequent disease recurrence. Review of histology showed malignant PXA with BRAF V600E mutation. Treatment with Dabrafenib and Trametinib was started, and tumor size increased in size after 14 months of treatment. Given studies showing that resistance to BRAF inhibition can be overcome by autophagy inhibition, chloroquine was added. Patient has been on "triple" therapy for 15 months and has radiographically Stable Disease. At MCC, 3% of patients with gliomas have BRAF mutations who could potentially benefit from this combination therapy.. This is the first report of a PXA patient receiving therapy with BRAF MEKi and an autophagy inhibitor with prolonged stable disease. This patient highlights the importance of a molecular interrogation in gliomas to provide an integrated diagnosis and effective treatment. This may be useful in up to 3% of glioma patients with BRAF mutations. Molecular testing in neuro-oncology is providing new avenues of diagnosis and treatment, and detailed molecular interrogation should be considered routine.

Topics: Antineoplastic Combined Chemotherapy Protocols; Astrocytoma; Brain Neoplasms; Chloroquine; Drug Resistance, Neoplasm; Humans; Imidazoles; Male; Oximes; Precision Medicine; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Young Adult

The recent publication of randomized trials investigating the efficacy of adjuvant therapy and completion lymph node dissection at microscopic stage III melanoma calls for a reappraisal of melanoma management from different angles: indications for sentinel lymph node biopsy, indications for completion lymph node dissection in microscopic-stage disease, and adjuvant therapies. Our objective was to evaluate current practices and to question French onco-dermatologists about any changes they envisaged in their practices in the light of recent publications.. We conducted a national survey among members of the Cutaneous Oncology Group of the French Society of Dermatology in October 2017.. Forty French health centers were included, and 53 individual responses were collected. Sentinel lymph node biopsy for melanoma was performed at 75 % of the centers. Before the summer of 2017 and the publication of MSLT-II (proving the absence of any therapeutic benefits for complete lymph node dissection in microscopic stage III melanoma), when a positive sentinel lymph node was diagnosed, immediate completion lymph node dissection was performed at 90 % of the centers. After the publication of MSLT-II, 45 % of the respondents considered stopping this practice. The risk-benefit ratio prompted prescription of nivolumab and of combined dabrafenib+trametinib as adjuvant therapy by respectively 96 % and 79 % of respondents, while the corresponding rates for interferon and ipilimumab were only 21 % and 15 %.. Early melanoma management stands on the verge of major changes thanks to the arrival of efficient adjuvant therapies and a decrease in immediate completion lymph node dissections for patients with microscopic stage III is also anticipated.

Topics: Antineoplastic Agents; Chemotherapy, Adjuvant; France; Health Care Surveys; Humans; Imidazoles; Interferons; Ipilimumab; Lymph Node Excision; Lymphatic Metastasis; Melanoma; Oximes; Pyridones; Pyrimidinones; Randomized Controlled Trials as Topic; Risk Assessment; Sentinel Lymph Node; Sentinel Lymph Node Biopsy; Skin Neoplasms

Topics: Antineoplastic Combined Chemotherapy Protocols; Biomarkers; Fibrinolysis; Humans; Imidazoles; Lung; Lung Neoplasms; Male; Melanoma; Mutation; Oximes; Procalcitonin; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Young Adult

Topics: Chemotherapy, Adjuvant; Disease-Free Survival; Humans; Imidazoles; Lymph Node Excision; Melanoma; Molecular Targeted Therapy; Neoadjuvant Therapy; Neoplasm Staging; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Sentinel Lymph Node; Sentinel Lymph Node Biopsy; Skin Neoplasms; Survival Rate; Tumor Burden

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Imidazoles; Immunotherapy; Ipilimumab; Melanoma; Nivolumab; Oximes; Posterior Leukoencephalopathy Syndrome; Pyridones; Pyrimidinones; Skin Neoplasms

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Asymptomatic Diseases; Biopsy, Fine-Needle; Female; Humans; Imidazoles; Liver Neoplasms; Melanoma; Mitogen-Activated Protein Kinase Kinases; Oximes; Pancreas; Pancreatic Neoplasms; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Tomography, X-Ray Computed; Treatment Outcome; Ultrasonography

We conducted a retrospective investigation of the efficacy and safety of dabrafenib and trametinib combination therapy in Japanese patients with BRAF V600 mutation-positive advanced melanoma in real-world clinical practise. The study analyzed 50 patients who received dabrafenib and trametinib combination therapy for BRAF V600 mutation-positive advanced melanoma in our hospital (26 men and 24 women, aged 21-86 years, inclusive; median age, 53 years). The response rate was 72.3%, with complete response (CR) achieved in eight cases (17.0%), partial response in 26 (55.3%), stable disease in nine (19.1%) and progressive disease in four (8.5%). Median progression-free survival (PFS) was 12 months, and median overall survival (OS) was 23 months. Disease progression occurred in 29 of the 50 patients during the study period, and 25 patients died. Baseline lactate dehydrogenase and the number of organs with metastasis were important predictive factors for PFS and OS, and CR to combination therapy was a predictive factor for long-term remission. Adverse events occurred in 88% of cases; 16% were grade 3 or worse. The adverse events observed in 50% of more of patients were rash (56%) and pyrexia (52%). The efficacy of dabrafenib and trametinib combination therapy in Japanese patients was similar to that reported in global studies, and the same adverse events were generally reported; however, rash tended to occur more frequently in the patients in our study.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Disease Progression; Drug Eruptions; Exanthema; Female; Fever; Humans; Imidazoles; Japan; L-Lactate Dehydrogenase; Male; Melanoma; Middle Aged; Mutation; Oximes; Progression-Free Survival; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Response Evaluation Criteria in Solid Tumors; Retrospective Studies; Skin Neoplasms; Survival Rate; Young Adult

Topics: Aged; Antineoplastic Agents; Humans; Imidazoles; Male; Melanoma; Myasthenia Gravis; Neoplasm Metastasis; Oximes; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Scalp; Skin Neoplasms

In clinical trials, dabrafenib plus trametinib improved overall survival (OS) compared with single-agent BRAF inhibitors (BRAFi) in patients with BRAF V600-mutant unresectable or metastatic melanoma. We investigated dabrafenib plus trametinib therapy in a compassionate-use setting [Named Patient Program (NPP); DESCRIBE II]. A retrospective chart review of patients with BRAF V600-mutated unresectable stage III/IV melanoma receiving dabrafenib plus trametinib as compassionate use was conducted. Treatment patterns and duration, clinical outcomes, and tolerability were evaluated. Of 271 patients, 92.6% had stage IV melanoma, including 36.5% with brain metastases. Overall, 162 patients (59.8%) were BRAFi naive and 171 (63.1%) received first-line dabrafenib plus trametinib. Among BRAFi-naive patients, the overall response rate (ORR) was 67.3%, median OS (mOS) was 20.0 months, and median progression-free survival (mPFS) was 7.5 months. In BRAFi-naive patients with known brain metastases (n = 62), ORR was 61.3%, mOS was 15.5 months, and mPFS was 6.2 months. Eighty-four patients received BRAFi monotherapy for >30 days and switched to dabrafenib plus trametinib prior to progression. Of these 84 patients, 63 had known disease status at the time of switch, and 22 improved with the combination therapy. No new safety signals were identified, and dabrafenib plus trametinib was well tolerated. Dabrafenib plus trametinib showed substantial clinical activity in NPP patients with BRAF V600-mutated unresectable or metastatic melanoma. Analysis of treatment patterns demonstrated the effectiveness of the combination in patients with brain metastases and across lines of therapy with a well tolerated and manageable safety profile.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Compassionate Use Trials; Disease-Free Survival; Female; Humans; Imidazoles; Male; Melanoma; Melanoma, Cutaneous Malignant; Middle Aged; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Retrospective Studies; Skin Neoplasms; Treatment Outcome

Topics: Biomarkers; Humans; Imidazoles; Melanoma; Oximes; Pyridones; Pyrimidinones; Skin Neoplasms

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Cell Transdifferentiation; Head and Neck Neoplasms; Histiocytic Sarcoma; Humans; Imidazoles; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Oximes; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins p21(ras); Pyridones; Pyrimidinones

Topics: Amino Acid Substitution; Histiocytic Sarcoma; Humans; Imidazoles; Infant; Male; Mutation, Missense; Neoplasms, Second Primary; Oximes; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

Paired fresh tumor biopsies were acquired at baseline and on day 15 of treatment from all consenting patients with BM colorectal cancer enrolled in a phase II clinical trial of dabrafenib, trametinib, and panitumumab. For each sample, BM subtype, cell cycle, and immune gene signature expression were determined using RNA-sequencing (RNA-seq), and a Cox proportional hazards model was applied to determine association with progression-free survival (PFS).. Confirmed response rates, median PFS, and median overall survival (OS) were higher in BM1 subtype patients compared with BM2 subtype patients. Evaluation of immune contexture identified greater immune reactivity in BM1, whereas cell-cycle signatures were more highly expressed in BM2. A multivariate model of PFS incorporating BM subtype plus immune and cell-cycle signatures revealed that BM subtype encompasses the majority of the effect.. BM subtype is significantly associated with the outcome of combination dabrafenib, trametinib, and panitumumab therapy and may serve as a standalone predictive biomarker beyond mutational status. Our findings support a more nuanced approach to targeted therapeutic decisions that incorporates assessment of transcriptional context.

Topics: Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Colorectal Neoplasms; ErbB Receptors; Gene Expression Regulation, Neoplastic; Humans; Imidazoles; MAP Kinase Kinase 1; Mutation; Oximes; Panitumumab; Prognosis; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Survival Rate

Combined BRAF and MEK inhibition is one of the first-line treatment strategies for patients with advanced BRAF-mutant melanoma. Sarcoid-like reactions (SLRs) have occasionally been described with melanoma systemic treatments such as immunotherapy or the BRAF inhibitor vemurafenib, but very few cases have been reported with dabrafenib and trametinib. Our aim was to better characterize SLR induced by this combination. We conducted a monocentric retrospective observational study among patients treated with dabrafenib and trametinib for BRAF-mutant advanced melanoma from January 2015 to March 2019. Patients presenting with histologically proven SLR were included. We also searched Medline database for all reported cases of SLR induced by targeted therapy. Of 63 patients on dabrafenib/trametinib combination, seven were diagnosed with a SLR. They all had specific cutaneous involvement, and one also displayed mediastinal and salivary glands involvement. None required systemic corticosteroids or dabrafenib/trametinib discontinuation. Three of them (43%) reached melanoma complete remission and are still on targeted therapy; and four patients progressed and died. A literature review yielded 22 additional cases of SLR induced by targeted therapy: the main affected organ was the skin, 11 patients (50%) had systemic involvement, five patients (23%) required systemic corticosteroids to reach partial or complete remission of SLR, 12 (55%) reached partial or complete response of melanoma while six (27%) progressed. BRAF and MEK inhibitors are potential triggers of SLR, although pathological mechanisms remain unclear. The mainstay of treatment is systemic or topical corticotherapy; targeted therapy discontinuation is usually not necessary.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Imidazoles; Male; Melanoma; Melanoma, Cutaneous Malignant; Middle Aged; Oximes; Pyridones; Pyrimidinones; Retrospective Studies; Sarcoidosis; Skin Neoplasms

A BRAF V600E mutation is found as driver oncogene in patients with non-small cell lung cancer. Although combined treatment with dabrafenib and trametinib is highly effective, the efficacy of reduced doses of the drugs in combination therapy has not yet been reported.. A Japanese man in his mid-sixties was diagnosed with unresectable lung adenocarcinoma and was unresponsive to cytotoxic chemotherapy and immune checkpoint inhibitors. The BRAF V600E mutation was detected by next generation sequencing, and the patient was subjected to treatment with dabrafenib and trametinib in combination. Although the treatment reduced the tumor size, he experienced myalgia and muscle weakness with elevated serum creatine kinase and was diagnosed with rhabdomyolysis induced by dabrafenib and trametinib. After the patient recovered from rhabdomyolysis, the treatment doses of dabrafenib and trametinib were reduced, which prevented further rhabdomyolysis and maintained tumor shrinkage.. The reduction of the doses of dabrafenib and trametinib was effective in the treatment of BRAF V600E-mutant NSCLC, and also prevented the incidence of rhabdomyolysis.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Humans; Imidazoles; Lung Neoplasms; Male; Mutation; Neoplasm Staging; Off-Label Use; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Rhabdomyolysis; Treatment Outcome

Topics: Adult; Antibodies, Monoclonal, Humanized; Antigens, CD20; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Chemotherapy, Adjuvant; Glucocorticoids; Humans; Imidazoles; Interferon-beta; Male; Melanoma; Multiple Sclerosis; Neoplasm Recurrence, Local; Oximes; Polyethylene Glycols; Pyridones; Pyrimidinones; Skin Neoplasms; Treatment Outcome

Dabrafenib and trametinib combination therapy is approved for the treatment of patients with BRAF V600E positive tumors including melanoma and lung cancer. The effect of BRAF and MEK inhibitors on the immune system is not fully understood although a number of case reports indicate autoimmune side effects related to the use of these drugs. Here, we discuss a case of a patient diagnosed with granulomatosis with polyangiitis (GPA) shortly after starting treatment with dabrafenib and trametinib for BRAF V600E positive metastatic lung adenocarcinoma.. A 57 years old female patient was diagnosed with recurrent lung adenocarcinoma following initial lobectomy for early stage disease. A BRAF V600E mutation was identified at the time of recurrence and she received combination dabrafenib and trametinib therapy. Shortly after commencement of treatment, she developed persistent fevers necessitating withholding both drugs. Pyrexia continued and was followed by left vision loss and acute kidney injury. Further rheumatological workup led to the unifying diagnosis of GPA. The patient was then treated with rituximab for GPA to the present date while all antineoplastic drugs were held. Lung cancer oligoprogression was addressed with radiation therapy and has not required further systemic treatment whereas GPA has been controlled to-date with rituximab.. This case report raises awareness among clinicians treating patients with lung cancer for the possibility of triggering a flare of autoimmune diseases like GPA in patients with BRAF V600E positive lung cancer receiving treatment with BRAF directed therapy.

Topics: Adenocarcinoma of Lung; Amino Acid Substitution; Antineoplastic Combined Chemotherapy Protocols; Female; Granulomatosis with Polyangiitis; Humans; Imidazoles; Lung Neoplasms; Middle Aged; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Rituximab; Treatment Outcome

The combination of dabrafenib and trametinib is an important immunotherapy option for patients with BRAF V600 mutation-positive melanoma. This regimen has been reported to cause cutaneous eruptions. However, hair dysmorphology is not a reported side effect to these or any other medications to date. Herein, we highlight a case of pili multigemini formation in a patient with stage IV melanoma receiving treatment with dabrafenib and trametinib and the corresponding clinical findings.

Topics: Antineoplastic Combined Chemotherapy Protocols; Hair; Hair Diseases; Hair Follicle; Humans; Imidazoles; Male; Melanoma; Middle Aged; Oximes; Pigmentation Disorders; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Skin Neoplasms

We saw a 59-year-old patient who was treated with dabrafenib and trametinib because of metastatic melanoma. She had an asymptomatic, black-blue macula in the excision scar. Histopathology showed tumoral melanosis. This is an histological term for dermal aggregates of melanophages, associated with regression of melanoma.

Topics: Antineoplastic Combined Chemotherapy Protocols; Cicatrix; Female; Humans; Imidazoles; Melanoma; Melanosis; Middle Aged; Oximes; Pyridones; Pyrimidinones; Skin Diseases; Skin Neoplasms

Topics: Humans; Imidazoles; Neoadjuvant Therapy; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms

Topics: Adenocarcinoma of Lung; Aged; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Combined Modality Therapy; Humans; Imidazoles; Lung Neoplasms; MAP Kinase Kinase 1; Mutation; Oximes; Prognosis; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Radiosurgery

Previous studies have reported an acquiredBRAF V600E mutation as a potential resistance mechanism to osimertinib treatment in advanced NSCLC patients with an activating mutation in EGFR. However, the therapeutic effect of combining dabrafenib and trametinib with osimertinib remains unclear. Here we report treatment efficacy in two cases with acquired BRAF V600E mutations.. Two patients with anEGFR exon 19 deletion and a T790 M mutation, both treated with osimertinib, acquired a BRAF V600E mutation at disease progression. Following the recommendation of the molecular tumor board, a concurrent combination of dabrafenib and trametinib plus osimertinib was administered.. Because of toxicity, one patient ultimately received a reduced dose of dabrafenib and trametinib combined with a normal dose of osimertinib. Clinical response in this patient lasted for 13.4 months. Re-biopsy upon tumor progression revealed loss ofBRAF V600E and emergence of EGFR C797S. The other patient, treated with full doses of the combined therapy, had progression with metastases in lung and brain one month after starting therapy.. BRAF V600E may be a resistance mechanism induced by osimertinib in EGFR-mutated advanced NSCLC. Combined treatment using dabrafenib/trametinib concurrently with osimertinib needs to be explored for osimertinib-induced BRAF V600E mutation.

Topics: Acrylamides; Aniline Compounds; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; ErbB Receptors; Humans; Imidazoles; Lung Neoplasms; Mutation; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

BRAFG469A and V600E were reported as the mechanisms of acquired resistance to first-generation EGFR tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer patients. Here, we described a rare case of BRAF N581S after gefitinib resistance and response to BRAF inhibitor plus MEK inhibitor.. Next-generation sequencing (NGS) was performed on the tumor tissue and plasma samples of a patient with metastatic lung adenocarcinoma harboring EGFR exon 19 deletion (EGFR 19del).. EGFR 19del and MET amplification was detected after resistance to the initial gefitinib therapy. After 9 months of treatment with gefitinib plus crizotinib, the disease progressed again. NGS revealed the known EGFR 19del and a BRAF N581S missense mutation after progression. The patient obtained durable clinical benefit upon treatment with dabrafenib plus trametinib, achieving a progression-free survival (PFS) of more than 33 months.. BRAF N581S mutation could be explored as one kind of mechanism of acquired resistance to EGFR-TKIs. Combined inhibition of BRAF and MEK is a potential therapeutic strategy.

Topics: Carcinoma, Non-Small-Cell Lung; Gefitinib; Humans; Imidazoles; Lung Neoplasms; Mutation; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Azetidines; Drug Hypersensitivity Syndrome; Female; Humans; Imidazoles; Melanoma; Neoplasms, Multiple Primary; Oximes; Piperidines; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Vemurafenib

Topics: Adenoma, Oxyphilic; Antineoplastic Agents; Humans; Imidazoles; Male; Middle Aged; Molecular Targeted Therapy; Mutation; Oximes; Pituitary Neoplasms; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Thyroid Nuclear Factor 1

To investigate the safety and efficacy of dabrafenib and trametinib combination therapy for BRAF V600 mutation-positive unresectable and metastatic melanoma in over 100 Japanese patients of a real-world clinical setting.. The surveillance period of interim post-marketing surveillance (PMS) analysis was from June 2016 to November 2018, and 112 patients with unresectable and metastatic BRAF V600 melanoma who received dabrafenib and trametinib were enrolled.. The safety analysis set included 112 patients whom almost all patients had stage IV disease (n = 97, 86.61%) with an Eastern Cooperative Oncology Group performance status 0 or 1 (n = 102, 91.07%), and mean (standard deviation) lactate dehydrogenase level was 354.3 (456.4) U/L (n = 105) at baseline. Median daily dose of dabrafenib was 300.0 mg/day (118-300), and median daily dose of trametinib was 2.00 mg/day (1.0-4.0). Adverse drug reactions (ADRs) were reported in 84 patients (75%), and common ADRs (incidence ≥ 5%) were pyrexia (n = 49, 43.75%), hepatic function abnormal (n = 11, 9.82%), rash and blood creatine phosphokinase increased (n = 9 each, 8.04%), and erythema nodosum (n = 6, 5.36%). Majority of ADRs reported in this study were consistent with that reported in previous trials. In the efficacy analysis set of 110 patients, the objective response rate was 55.45% (95% confidence interval 45.67-64.93%), and median progression-free survival was 384.0 days (251.0 days-not reached).. No new safety or efficacy concerns were observed in this interim PMS analysis in Japanese patients with unresectable and metastatic melanoma with BRAF gene mutation who received dabrafenib and trametinib combination therapy.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Asian People; Female; Fever; Humans; Imidazoles; Male; Melanoma; Middle Aged; Mutation; Oximes; Pregnancy; Progression-Free Survival; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Surveys and Questionnaires; Treatment Outcome; Young Adult

Hemophagocytic lymphohistiocytosis (HLH) has been only rarely reported in patients with BRAF-mutated advanced melanoma treated with targeted therapies and never with first-line dabrafenib/trametinib combination thus far. Two patients treated with first-line dabrafenib and trametinib combination therapy for metastatic melanoma presented with sudden occurrence of fever, cytopenia, rhabdomyolysis, hepatic cytolysis, hypertriglyceridemia and very high ferritin levels after few weeks of treatment, associated with concomitant epstein-barr virus (EBV) reactivation in one patient. In both cases, drug-induced HLH was primarily considered owing to a high H-score and the absence of other etiology. Patients rapidly improved after treatment discontinuation associated with oral steroids in one patient and did not relapse after subsequent treatment resumption with a concurrent anti-BRAF/anti-MEK combination. In metastatic melanoma HLH may occur either spontaneously in the absence of any treatment as a paraneoplastic condition, related to an intercurrent infection or drug-induced mainly with various immunotherapy or with dabrafenib and trametinib following immunotherapy. However, such observations are scarce and these are the first cases of HLH occurring during first-line treatment with dabrafenib and trametinib in advanced melanoma to our knowledge. Pathomechanisms remain to be elucidated since triggering factors may encompass the treatment itself but also other significant actors including viral reactivation along with the underlying disease. The liability of treatment should be considered in cases of HLH occurring in patients with advanced melanoma successfully treated with a combined targeted therapy. A rechallenge with a concurrent anti-BRAF/anti-MEK can be proposed in this setting.

Topics: Aged; Humans; Imidazoles; Lymphohistiocytosis, Hemophagocytic; Male; Melanoma; Middle Aged; Oximes; Pyridones; Pyrimidinones; Skin Neoplasms

Topics: Antineoplastic Combined Chemotherapy Protocols; Dermatologists; Humans; Imidazoles; Male; Melanoma; Middle Aged; Molecular Targeted Therapy; Oximes; Panniculitis; Pyridones; Pyrimidinones; Skin Neoplasms

This study aimed to assess whether dabrafenib/trametinib and vemurafenib/cobimetinib treatments are associated with a change in skeletal muscle area (SMA) and total fat-free mass (FFM) assessed by computed tomography (CT), and to compare the efficacy and safety profile of these treatments in patients with metastatic melanoma. Thirty-one patients treated with B-Raf proto-oncogene, serine/threonine kinase/MAPK extracellular receptor kinase inhibitors were included between 2016 and 2019. Eighteen patients received dabrafenib/trametinib and remaining patients received vemurafenib/cobimetinib. CT scans were performed at baseline and at 4-6 months of follow-up to measure cross-sectional areas of SMA. FFM and skeletal muscle index (SMI) values were calculated. Of the patients, including 18 treated with dabrafenib/trametinib (58.1%) and 13 with vemurafenib/cobimetinib (41.9%); 58.1% were male, 41.9% were female and median age was 52 years. A significant decrease in SMA was observed after dabrafenib/trametinib and vemurafenib/cobimetinib treatments (P = 0.003 and P = 0.002, respectively). A significant decrease in FFM values was observed after dabrafenib/trametinib and vemurafenib/cobimetinib treatments (P = 0.003 and P = 0.002, respectively). Dose-limiting toxicity (DLT) was observed in 35.9% of the patients with sarcopenia. No significant difference was seen between the dabrafenib/trametinib and vemurafenib/cobimetinib groups in median progression-free survival (PFS) (11.9 vs. 7.3 months, respectively, P = 0.28) and in median overall survival (OS) (25.46 vs. 13.7 months, respectively, P = 0.41). Baseline sarcopenia was not significantly associated with PFS or OS (P = 0.172 and P = 0.326, respectively). We found a significant decrease in SMI values determined at 4-6 months compared to the values before treatment both in dabrafenib/trametinib and vemurafenib/cobimetinib groups. DLT was similar with both treatments. Baseline sarcopenia was not significantly associated with PFS or OS.

Topics: Azetidines; Female; Humans; Imidazoles; Male; Melanoma; Middle Aged; Oximes; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Mas; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Vemurafenib

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Imidazoles; Melanoma; Mutation; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

Topics: Antineoplastic Combined Chemotherapy Protocols; Humans; Imidazoles; Lung Neoplasms; Mutation; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

Mutations that lead to constitutive activation of key regulators in cellular processes are one of the most important drivers behind vigorous growth of cancer cells, and are thus prime targets in cancer treatment. BRAF V600E mutation transduces strong growth and survival signals for cancer cells, and is widely present in various types of cancers including lung cancer. A combination of BRAF inhibitor (dabrafenib) and MEK inhibitor (trametinib) has recently been approved and significantly improved the survival of patients with advanced NSCLC harboring BRAF V600E/K mutation. To improve the detection of BRAF V600E/K mutation and investigate the incidence and clinicopathological features of the mutation in lung cancer patients of southern Taiwan, a highly sensitive and specific real-time quantitative PCR (RT-qPCR) method, able to detect single-digit copies of mutant DNA, was established and compared with BRAF V600E-specific immunohistochemistry. Results showed that the BRAF V600E mutation was present at low frequency (0.65%, 2/306) in the studied patient group, and the detection sensitivity and specificity of the new RT-qPCR and V600E-specific immunohistochemistry both reached 100% and 97.6%, respectively. Screening the BRAF V600E/K mutation with the RT-qPCR and V600E-specific immunohistochemistry simultaneously could help improve detection accuracy.

Topics: Aged; Carcinoma, Non-Small-Cell Lung; Humans; Imidazoles; Immunohistochemistry; Lung Neoplasms; Male; Middle Aged; Mutation; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Real-Time Polymerase Chain Reaction; Sensitivity and Specificity; Taiwan

More effective treatments are needed for low-grade serous ovarian carcinoma (LGSOC). Our patient, who suffers from metastatic LGSOC, had received all established treatments. Sequencing analysis revealed an activating BRAF mutation. Therefore, combined treatment with BRAF and MEK inhibitors, which is the gold standard in malignant melanoma, was initiated. After eight months of therapy, the response was assessed as complete and the treatment is still, 3.5 years after initiation, of benefit. To our knowledge, no complete response on combined BRAF and MEK inhibitor treatment of low-grade serous ovarian cancer has previously been reported.

Topics: Antineoplastic Agents; Benzimidazoles; Bevacizumab; CA-125 Antigen; Carbamates; Carboplatin; Cystadenocarcinoma, Serous; Disease Progression; Everolimus; Female; High-Throughput Nucleotide Sequencing; Humans; Imidazoles; MAP Kinase Kinase 1; Medroxyprogesterone; Mutation; Neoplasm Metastasis; Neoplasm Recurrence, Local; Ovarian Neoplasms; Oximes; Paclitaxel; Progression-Free Survival; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Recurrence; Sulfonamides; Tamoxifen; Treatment Outcome; Young Adult

Topics: Antineoplastic Combined Chemotherapy Protocols; Erythema Nodosum; Humans; Imidazoles; Melanoma; Mutation; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms

Topics: Biliary Tract Neoplasms; Humans; Imidazoles; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

Topics: Biliary Tract Neoplasms; Humans; Imidazoles; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

Adjuvant treatment of operated melanoma has deeply changed in the last few years with the introduction of immune-checkpoint inhibitors and BRAF/MEK inhibitors. Sarcoidosis is a systemic inflammatory disease causing non-caseous granulomatous reactions. Sarcoid-like granulomatous reactions have been reported in patients with advanced melanoma, mostly related to immunotherapy with immune-checkpoint inhibitors. We report a case of a 38-year-old woman with stage III operated melanoma treated with adjuvant BRAF plus MEK inhibitors, who developed sarcoidosis-like syndrome with systemic involvement, resolved after discontinuation of treatment. The occurrence of immune-related toxicity with the use of MAPK inhibitors supports the hypothesis that this class of drugs may also have an immunological effect, and that the long-term efficacy of adjuvant MAPK inhibitors may be due to their immunological function.

Topics: Adrenal Cortex Hormones; Adult; Antineoplastic Combined Chemotherapy Protocols; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Imidazoles; MAP Kinase Kinase Kinases; Melanoma; Mutation; Neoplasm Staging; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Sarcoidosis; Skin Neoplasms

MEK- and BRAF-inhibitors trametinib and dabrafenib are successfully used for BRAF-mutated, metastasizing melanoma, but these compounds may induce side effects. We report a 50 years old female with BRAF-mutated metastasizing melanoma who received trametinib (2 mg/d) and dabrafenib (200 mg/d) after using interferon without benefit. Shortly after starting trametinib/dabrafenib, she experienced an inability to abduct the left eye. Eight days after starting this therapy the patient experienced loss of appetite, vomiting, diarrhea, vertigo, and fever of 40°C. Two days later she experienced visual loss, requiring permanent support for her daily activities. Two further days later myoglobinuria appeared in the absence of myalgias or muscle weakness but accompanied by marked tiredness and inactivity. She could not eat or drink during four days prior to admission. The patient suspected an adverse effect of trametinib/dabrafenib and discontinued it 2 days prior to admission. Thereafter, she experienced an almost complete remission of the deficits except for ocular muscle weakness and visual impairment.

Topics: Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Imidazoles; Middle Aged; Mutation; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Renal Insufficiency; Rhabdomyolysis; Skin Neoplasms; Vision Disorders

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Bacterial Translocation; Dysbiosis; Enterobacter cloacae; Fatal Outcome; Feces; Female; Gastrointestinal Microbiome; Humans; Imidazoles; Melanoma; Oximes; Pyridones; Pyrimidinones

There is a wide variety of pancreatic neoplasms identified, but the great majority of them are of primary origin. Metastatic disease in the pancreatic parenchyma is quite rare (2-5% of pancreatic malignancies) and most often is quite difficult to differentiate from other primary lesions. Most of the imaging studies fail to give certain discriminating features for metastatic pancreatic neoplasms, contrary to endoscopic ultrasound and tissue sampling, which can provide an accurate diagnosis. In this report, we present a case of a male middle aged man who was admitted to our hospital with painless jaundice and finally was diagnosed with a cutaneous scalp melanoma dispersedly metastasized to the pancreas and upper gastrointestinal tract (stomach and duodenum).

Topics: Adrenal Gland Neoplasms; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Cholangiopancreatography, Endoscopic Retrograde; Cranial Irradiation; Duodenal Neoplasms; Endoscopic Ultrasound-Guided Fine Needle Aspiration; Endoscopy, Digestive System; Endosonography; Humans; Imidazoles; Lung Neoplasms; Male; Melanoma; Middle Aged; Oximes; Pancreatic Neoplasms; Pyridones; Pyrimidinones; Skin Neoplasms; Stomach Neoplasms; Tomography, X-Ray Computed

Current management of locoregional and oligometastatic melanoma is typically with surgery; however, some patients are unable to undergo resection due to location/size of their tumors and/or the anticipated morbidity of the surgery. While there are currently no established guidelines for neoadjuvant therapy in melanoma, neoadjuvant BRAF-targeted therapy may make resection more feasible. A retrospective analysis was conducted of 23 patients with BRAFV600-mutant, stage III/IV melanoma treated with BRAF-targeted therapy prior to surgery, with no adjuvant treatment. Surgical specimens, preoperative imaging, and clinical outcomes were evaluated. Results: Ten of 23 patients (44%) attained a pathologic complete response (pCR), with no correlation between RECIST response based on preoperative imaging and pathologic response. After a median of 43-month follow-up, only 1 patient (10%) with a pCR recurred, while 8 of 13 (62%) patients without a pCR recurred. Patients with a pCR had significantly improved relapse-free (RFS) and overall survival (OS) compared to patients with residual tumor. Neoadjuvant BRAF-targeted therapy is associated with a high pCR rate in patients with stage III-IV melanoma, which may correlate with improved RFS and OS.

Topics: Adult; Aged; Disease-Free Survival; Female; Humans; Imidazoles; Male; Melanoma; Middle Aged; Molecular Targeted Therapy; Neoadjuvant Therapy; Neoplasm Metastasis; Neoplasm Staging; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Treatment Outcome

TRK fusions are found in a variety of cancer types, lead to oncogenic addiction, and strongly predict tumor-agnostic efficacy of TRK inhibition

Topics: Adolescent; Adult; Animals; Benzamides; Cell Proliferation; Cell-Free Nucleic Acids; Child; Clinical Trials as Topic; Drug Resistance, Neoplasm; Female; Heterografts; Humans; Imidazoles; Indazoles; Male; MAP Kinase Signaling System; Mice; Mitogen-Activated Protein Kinase Kinases; Molecular Targeted Therapy; Neoplasms; Oncogene Proteins, Fusion; Oximes; Protein Kinase Inhibitors; Pyrazoles; Pyridones; Pyrimidines; Pyrimidinones; Receptor, trkA; Young Adult

Topics: Aged; Anemia, Hemolytic, Autoimmune; Humans; Imidazoles; Leukemia, Hairy Cell; Male; Oximes; Pyridones; Pyrimidinones

Topics: Humans; Imidazoles; Melanoma; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

We have demonstrated previously that the kinase inhibitors (KIs) lapatinib, pazopanib, regorafenib and sorafenib are potent inhibitors of UGT1A1 and UGTs 1A7-1A10. The present study characterised the effects of four additional drugs in this class, dabrafenib, ibrutinib, nintedanib and trametinib, on human UGT enzyme activities in vitro. Dabrafenib, ibrutinib, nintedanib and trametinib were potent inhibitors of human liver microsomal UGT1A1; K

Topics: Adenine; Glucuronosyltransferase; Humans; Imidazoles; Indoles; Microsomes, Liver; Oximes; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyridones; Pyrimidines; Pyrimidinones

Topics: Acrylamides; Adenocarcinoma of Lung; Aged; Aniline Compounds; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Drug Resistance, Neoplasm; ErbB Receptors; Humans; Imidazoles; Lung Neoplasms; Male; Mutation; Oximes; Prognosis; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Drug Resistance, Neoplasm; Exons; Female; Humans; Imidazoles; Male; MAP Kinase Kinase Kinases; Melanoma; Middle Aged; Mutation; Neoplasm Metastasis; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Treatment Outcome

Topics: Aged; Anti-Bacterial Agents; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Drug Substitution; Drug Therapy, Combination; Dyspnea; Fever; Humans; Imidazoles; Male; Melanoma; Oximes; Pneumonia; Pyridones; Pyrimidinones; Skin Neoplasms

Although rare, NTRK gene fusions are known to be oncogenic drivers in pancreatic ductal adenocarcinoma (PDAC). We report the response of a metastatic CTRC-NTRK1 gene fusion-positive PDAC to targeted treatment with the oral tropomyosin receptor kinase (TRK) inhibitor larotrectinib and the eventual development of resistance to treatment.. A 61-year-old woman presented with a 2.5-cm mass in the body of the pancreas and a 1.2-cm liver lesion on routine follow-up for endometrial cancer that was in complete remission. Liver biopsy confirmed a primary PDAC unrelated to the endometrial cancer. The patient was treated with gemcitabine, nab-paclitaxel and ADI-PEG 20 for 12 months until disease progression and toxicity emerged [best overall response (BOR): partial response (PR)]. The patient switched to a modified regimen of folinic acid, fluorouracil, irinotecan and oxaliplatin for 4 months until neuropathy occurred. Oxaliplatin was withheld until disease progression 6 months later (BOR: stable disease). Despite recommencing oxaliplatin, the disease continued to progress. At this time, somatic profiling of the liver lesion revealed a CTRC-NTRK1 gene fusion. Treatment with larotrectinib 100 mg twice daily was commenced with BOR of PR at 2 months. The patient progressed after 6 months and was re-biopsied. Treatment was switched to the investigational next-generation TRK inhibitor selitrectinib (BAY 2731954, LOXO-195) 100 mg twice daily. After 2 months, the disease progressed and dabrafenibtrametinib combination therapy was initiated due to existence of a BRAF-V600E mutation. However, the cancer continued to progress and the patient died 2 months later.. Targeted TRK inhibition with larotrectinib in PDAC harbouring a CTRC-NTRK1 gene fusion is well tolerated and can improve quality of life for the patient. However, acquired resistance to therapy can emerge in some patients. Next-generation TRK inhibitors such as selitrectinib are currently in development to overcome this resistance (NCT02576431; NCT03215511).

Topics: Antineoplastic Combined Chemotherapy Protocols; Aza Compounds; Carcinoma, Pancreatic Ductal; Chymotrypsin; Female; Humans; Imidazoles; Middle Aged; Oncogene Proteins, Fusion; Oximes; Pancreatic Neoplasms; Protein Kinase Inhibitors; Protein Kinases; Pyrazoles; Pyridones; Pyrimidines; Pyrimidinones; Receptor, trkA

For inflammation of a tattoo occurring decades after its creation, sarcoidosis should be considered first of all. Two case of extremely delayed hypersensitivity tattoo reaction have been recently reported in patients treated with BRAF and MEK inhibitors. We report a similar new case strongly suggesting a specific effect of this drug combination.. A 58-year-old man bearing 20-year-old tattoos was treated with dabrafenib and trametinib for advanced melanoma. A painful erythematous swelling appeared on all the patient's tattoos two months later, while his general tolerance of the treatment was poor. Skin biopsy demonstrated perivascular lympho-histiocytic infiltrate without granuloma, but with prominent pigment-loaded macrophages. Inflammatory signs quickly regressed after drug discontinuation.. Great similarity exists between this new case and the first reported case, in which a female patient presented painful infiltration of old tattoos following repeated reintroduction of dabrafenib and trametinib in a setting of advanced melanoma. The immunomodulatory properties BRAF/MEK inhibition may enhance loss of tolerance to tattoo ink, accounting for the extremely long time to reaction. This third case militates in favour of a specific drug-induced reaction, of which patients with tattoos should be informed when anti-BRAF/MEK therapy is being considered.

Topics: Erythema; Humans; Hypersensitivity; Imidazoles; Male; Melanoma; Middle Aged; Oximes; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Skin Neoplasms; Tattooing

Greater understanding of molecular features of conjunctival melanoma (CM) may improve its clinical management.. To evaluate molecular features of CM and application of this information into clinical care.. In a prospective case series of CM with integrative exome and transcriptome analysis, 8 patients at an academic ocular oncology setting were evaluated. The study was conducted from November 2015 to March 2018.. Integrative exome and transcriptome analysis of CMs and clinical management of a patient's care by using this information.. Molecular characterization of CM and its potential clinical application.. In the 8 patients (4 men) included in analysis, 4 subgroups of CM were observed, including the BRAF V600E mutation in 1 tumor, NRAS Q61R mutation in 3 tumors, NF1 mutations (Q1188X, R440X, or M1215K+ S15fs) in 3 tumors, and triple-wild type (triple-WT) in 1 tumor. The triple-WT case had CCND1 amplification and mutation in the CIC gene (Q1508X). Five tumors, including the triple-WT, also harbored mutations in MAPK genes. In addition to the genes linked to mitogen-activated protein kinase and phosphoinositol 3-kinase pathways, those involved in cell cycle and/or survival, ubiquitin-mediated protein degradation, and chromatin remodeling/epigenetic regulation (ATRX being the most frequently mutated: noted in 5 tumors) may play an important role. Other frequently mutated genes included PREX2 (n = 3), APOB (n = 4), and RYR1/2 (n = 4), although their relevance remains to be determined. The mutation burden ranged from 1.1 to 15.6 mutations per megabase (Mut/Mb) and was 3.3 Mut/Mb or less in 3 tumors and more than 10 Mut/Mb in 2 tumors. A patient with a large tumor and BRAF V600E mutation was treated with combined systemic BRAF (dabrafenib) and MEK (trametinib) inhibitors. After 3 months of therapy, her CM responded substantially and the residual tumor was removed by local surgical excision.. The NRAS Q61R and NF1 mutations were more common than the BRAF V600E mutation in this series. Although small tumors (where incisional biopsy is not indicated) are treated with surgical excision regardless of mutational profile, in large tumors carrying the BRAF V600E mutation, neoadjuvant therapy with combined systemic BRAF and MEK inhibitors followed by local excision may be used as an alternative to exenteration. Integrative omics analysis of CM may be informative and guide clinical management and treatment in selected cases.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Conjunctival Neoplasms; DNA Mutational Analysis; Exome; Female; Gene Expression Profiling; GTP Phosphohydrolases; Humans; Imidazoles; Male; Melanoma; Membrane Proteins; Neurofibromin 1; Oximes; Precision Medicine; Prospective Studies; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

Before the approval of dabrafenib and trametinib in combination, there were no approved therapies in the adjuvant setting that target the RAS/RAF/MEK/ERK pathway.. To evaluate the budget impact of dabrafenib and trametinib in combination for adjuvant treatment of patients with BRAF V600 mutation-positive resected Stage IIIA, IIIB, or IIIC melanoma from a U.S. commercial payer perspective using data from the COMBI-AD trial, as well as other sources.. The budget impact of dabrafenib and trametinib in combination for patients with BRAF V600E/K mutation-positive, resected Stage IIIA, IIIB, or IIIC melanoma was evaluated from the perspective of a hypothetical population of 1 million members with demographic characteristics consistent with those of a commercially insured U.S. insurance plan (i.e., adults aged less than 65 years) using an economic model developed in Microsoft Excel. The model compared melanoma-related health care costs over a 3-year projection period under 2 scenarios: (1) a reference scenario in which dabrafenib and trametinib are assumed to be unavailable for adjuvant therapy and (2) a new scenario in which the combination is assumed to be available. Treatments potentially displaced by dabrafenib and trametinib were assumed to include observation, high-dose interferon alpha-2b, ipilimumab, and nivolumab. Costs considered in the model include those of adjuvant therapies and treatment of locoregional and distant recurrences. The numbers of patients eligible for treatment with dabrafenib and trametinib were based on data from cancer registries, published sources, and assumptions. Treatment mixes under the reference and new scenarios were based on market research data, clinical expert opinion, and assumptions. Probabilities of recurrence and death were based on data from the COMBI-AD trial and an indirect treatment comparison. Medication costs were based on wholesale acquisition cost prices. Costs of distant recurrence were from a health insurance claims study.. In a hypothetical population of 1 million commercially insured members, 48 patients were estimated to become eligible for treatment with dabrafenib and trametinib in combination over the 3-year projection period; in the new scenario, 10 patients were projected to receive such treatment. Cumulative costs of melanoma-related care were estimated to be $6.3 million in the reference scenario and $6.9 million in the new scenario. The budget impact of dabrafenib and trametinib in combination was an increase of $549 thousand overall and 1.5 cents per member per month.. For a hypothetical U.S. commercial health plan of 1 million members, the budget impact of dabrafenib and trametinib in combination as adjuvant treatment for melanoma is likely to be relatively modest and within the range of published estimates for oncology therapies. These results may assist payers in making coverage decisions regarding the use of adjuvant dabrafenib and trametinib in melanoma.. Funding for this research was provided to Policy Analysis Inc. (PAI) by Novartis Pharmaceuticals. Stellato, Moynahan, and Delea are employed by PAI. Ndife, Koruth, Mishra, and Gunda are employed by Novartis. Ghate was employed by Novartis at the time of this study and is shareholder in Novartis, Provectus Biopharmaceuticals, and Mannkind Corporation. Gerbasi was employed by PAI at the time of this study and is currently an employee, and stockholder, of Sage Therapeutics. Delea reports grant funding from Merck and research funding from Amgen, Novartis, Sanofi, Seattle Genetics, Takeda, Jazz, EMD Serono, and 21st Century Oncology, unrelated to this work.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Budgets; Chemotherapy, Adjuvant; Clinical Trials, Phase III as Topic; Decision Making; Disease-Free Survival; Drug Costs; For-Profit Insurance Plans; Humans; Imidazoles; Male; Melanoma; Middle Aged; Models, Economic; Mutation; Oximes; Progression-Free Survival; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms

Topics: Cell Line, Tumor; Drug Resistance, Neoplasm; Humans; Imidazoles; MAP Kinase Signaling System; Melanoma; Mitogen-Activated Protein Kinase Kinases; Mutation; Oximes; Phosphorylation; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Ribosomal Protein S6; TOR Serine-Threonine Kinases

Acute encephalopathy secondary to targeted therapy with BRAF inhibitors is uncommon. There are few case reports in patients with metastatic melanoma who received treatment with dabrafenib and trametinib, and developed acute confusion. The encephalopathy appears to resolve after the discontinuation of offending drug, with patient returning to their baseline mentation and functional ability. The mechanism of the encephalopathy has been unclear. Unlike posterior reversible encephalopathy syndrome, which has been reported with vemurafenib and cobimetinib combination in melanoma patients, there are generally no acute imaging abnormalities observed (e.g. on computed tomography and magnetic resonance imaging brain scans). We report a case of acute encephalopathy in a patient with BRAF mutated metastatic lung cancer due to dabrafenib and trametinib treatment. With the increasing use of targeted therapies in lung cancer treatments, it is important for clinicians to be aware of potentially toxic effects of novel treatments.

Topics: Adenocarcinoma of Lung; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Brain Diseases; Humans; Imidazoles; Male; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

To determine the role of BRAF

Topics: Aged; Animals; Antineoplastic Agents; Apoptosis; Carcinoma, Neuroendocrine; Cell Line, Tumor; Colorectal Neoplasms; Exons; Female; Follow-Up Studies; G1 Phase Cell Cycle Checkpoints; Humans; Imidazoles; Intestinal Neoplasms; Male; MAP Kinase Signaling System; Mice; Mice, Inbred NOD; Middle Aged; Mitogen-Activated Protein Kinase Kinases; Mutation; Neuroendocrine Tumors; Oximes; Pancreatic Neoplasms; Phosphorylation; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Stomach Neoplasms; Survival Analysis; Tissue Array Analysis; Vemurafenib; Xenograft Model Antitumor Assays

A survival benefit was demonstrated by dabrafenib + trametinib for metastatic BRAF-mutated melanoma patients. Best response is a strong prognostic marker for survival.. The specific features associated with complete response (CR) were evaluated.. A total of 15/66 patients achieved CR. Median size of lesions was 3 cm (range: 0.5-10). Using that value as cut-off, the CR rate was 39.3% in patients with smaller lesions and 10.5% in patients with bigger size (p = 0.006). The clinical features associated with CR were the number of metastatic sites and the largest diameter of the biggest metastatic site.. The number of the metastases and the diameter of the largest metastatic site are associated with a higher CR rate.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Azetidines; Female; Humans; Imidazoles; Male; MAP Kinase Kinase 1; Melanoma; Middle Aged; Mutation; Oximes; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Retrospective Studies; Skin Neoplasms; Treatment Outcome; Vemurafenib

Topics: Aged; Animals; Antineoplastic Combined Chemotherapy Protocols; Humans; Imidazoles; Male; Melanoma; Mice; Mutation; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin; Skin Neoplasms; Treatment Outcome; Xenograft Model Antitumor Assays

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Astrocytoma; Bevacizumab; Brain Neoplasms; Female; Humans; Imidazoles; Meningeal Carcinomatosis; Mutation; Oximes; Prognosis; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

BRAF and MEK kinase inhibitors can be highly effective in treating BRAF-mutant melanomas, but their safety and activity in patients with active/symptomatic brain metastases are unclear. We sought to shed light on this open clinical question. We conducted a multicenter retrospective study on real-life patients with melanoma and active brain metastases treated with combination BRAF/MEK inhibitors. A total of 65 patients were included (38 men and 27 women; median age: 49 years). Of them, 53 patients received dabrafenib/trametinib, 10 received vemurafenib/cobimetinib, one received encorafenib/binimetinib, and one received vemurafenib/trametinib. We did not observe any unexpected treatment-related safety signals in our cohort. Overall, 17 patients continued on therapy through the cutoff date. After initiation of therapy, steroid dose could be decreased in 22 of 33 patients (11 tapered off entirely), anticonvulsants were stopped in four of 21, and narcotics were stopped in four of 12. Median progression-free survival from the start of therapy was 5.3 months (95% confidence interval: 3.6-6.1), and median overall survival was 9.5 months (95% confidence interval: 7.7-13.5). A total of 20 patients were surviving at the cutoff date. Univariate analysis of age, sex, ulceration status, thickness, stage, location, or lactate dehydrogenase did not reveal significant predictors of progression-free survival or overall survival within our cohort, but multivariate analysis suggested that older age, lower risk location of original lesion, and nodular melanoma are poor prognostic indicators. Combination therapy with BRAF/MEK inhibitors is a viable treatment option for patients with BRAF-mutant melanoma and brain metastases, but further studies should help to define the optimal treatment approach in this population.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Brain Neoplasms; Female; Follow-Up Studies; Humans; Imidazoles; Male; MAP Kinase Kinase 1; Melanoma; Middle Aged; Oximes; Prognosis; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Retrospective Studies; Survival Rate; Young Adult

Advances in single-cell biology have enabled measurements of >40 protein features on millions of immune cells within clinical samples. However, the data analysis steps following cell population identification are susceptible to bias, time-consuming, and challenging to compare across studies. Here, an ensemble of unsupervised tools was developed to evaluate four essential types of immune cell information, incorporate changes over time, and address diverse immune monitoring challenges. The four complementary properties characterized were (i) systemic plasticity, (ii) change in population abundance, (iii) change in signature population features, and (iv) novelty of cellular phenotype. Three systems immune monitoring studies were selected to challenge this ensemble approach. In serial biopsies of melanoma tumors undergoing targeted therapy, the ensemble approach revealed enrichment of double-negative (DN) T cells. Melanoma tumor-resident DN T cells were abnormal and phenotypically distinct from those found in nonmalignant lymphoid tissues, but similar to those found in glioblastoma and renal cell carcinoma. Overall, ensemble systems immune monitoring provided a robust, quantitative view of changes in both the system and cell subsets, allowed for transparent review by human experts, and revealed abnormal immune cells present across multiple human tumor types.

Topics: Adenoids; Adult; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Immunological; Female; Humans; Imidazoles; Male; MAP Kinase Kinase Kinases; Middle Aged; Monitoring, Immunologic; Neoplasms; Oximes; Palatine Tonsil; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; T-Lymphocytes

Topics: Adult; Amphetamine-Related Disorders; Antineoplastic Combined Chemotherapy Protocols; Hepatitis C; Humans; Imidazoles; Male; Melanoma; Molecular Targeted Therapy; Neoplasm Metastasis; Oximes; Pyridones; Pyrimidinones; Skin Neoplasms

Combined BRAF and MEK inhibition (BRAF-MEK) is a standard therapy for patients with BRAF V600-mutant melanoma, but to the authors' knowledge, the tolerance, adverse event (AE) profile, and efficacy have not been well defined in the post-programmed cell death protein 1 (PD-1) setting.. Patients with BRAF V600-mutant melanoma who received combined BRAF-MEK after prior PD-1-based therapy were assembled from 4 tertiary care centers in the United States and Australia. Dose modification was defined as a treatment break, dose reduction, or intermittent dosing. Rates of hospitalization and discontinuation due to AEs were collected, and overall survival (OS) was calculated using Kaplan-Meier methods from the time of the initiation of BRAF-MEK therapy.. A total of 78 patients were identified as having received a BRAF-MEK regimen at a median of 34 days after the last dose of PD-1-based therapy. The majority of patients (86%) received the combination of dabrafenib and trametinib. Approximately 80% of patients had American Joint Committee on Cancer M1c or M1d disease. Sixty-five regimens (83%) had ≥1 dose modification. The median time to the first dose modification was 14 days; 86% occurred within 90 days and 71% involved pyrexia. Dose modifications were more common in patients receiving BRAF-MEK <90 days after the last dose of PD-1 and who were not receiving steroids. Of the dose modifications, 25 (31%) led to an AE-related hospitalization. Among 55 BRAF-naive patients, the median time receiving BRAF-MEK therapy was 5.8 months and the median OS was 15.6 months.. The majority of patients receiving BRAF-MEK inhibition after PD-1 therapy require dose interruptions, and a significant minority require hospitalization for AEs. In this higher risk population, the median time receiving therapy and OS may be inferior to those presented in published phase 3 trials.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Australia; Female; Humans; Imidazoles; Male; Melanoma; Middle Aged; Oximes; Programmed Cell Death 1 Receptor; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Survival Analysis; Tertiary Care Centers; Treatment Outcome; United States

Therapies for advanced non-small cell lung cancer (NSCLC) continue to become more sophisticated. Chemotherapeutics are giving way to newer approaches such as immune checkpoint inhibitors and targeted therapies for greater efficacy and improved outcomes. Dabrafenib plus trametinib combination therapy was first approved for the treatment of metastatic melanoma harboring the

Topics: Adenocarcinoma of Lung; Adrenal Cortex Hormones; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Cohort Studies; Disease Management; Drug-Related Side Effects and Adverse Reactions; Female; Follow-Up Studies; Humans; Imidazoles; Lung Neoplasms; Male; Middle Aged; Mutation; Oximes; Prognosis; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Survival Rate

Between 2010 and 2015, pivotal trials with strict enrolment criteria led to the approval of several new treatments for metastatic melanoma (MM). We sought to determine the impact of these treatments in the 'real world'. We took advantage of the Danish MM database (DAMMED), which contains data on the entire, unselected population diagnosed with MM within Denmark. All MM cases (excluding ocular MM, n = 837) diagnosed in three non-consecutive years marked by major changes in the first-line treatments (2012: interleukin-2 and BRAF inhibitors; 2014: anti-CTLA-4: Cytotoxic T-Lymphocyte Antigen 4 and 2016: anti-PD-1: programmed cell death protein 1 and MEK inhibitors) were retrieved. Patients were grouped into 'trial-like' and 'trial-excluded' based on the common trial eligibility criteria. In the 'trial-like' population (39% of all MM), the median overall survival (OS) was not reached in 2016 versus 18.8 months in 2014 (hazard ratio [HR] 0.52, 95% confidence interval [CI] 0.35-0.75; p = 0.0005) and 16.5 months in 2012 (HR 0.41, 95% CI 0.27-0.63; p < 0.0001). In the 'trial-excluded' population (61% of all MM), 75% had brain metastases and/or (performance status) PS ≥ 2. Here, the median OS improved to 6.9 months in 2016 versus 5.2 months in 2014 (HR 0.66, 95% CI 0.52-0.84; p = 0.0008) and 4.2 months in 2012 (HR 0.66, 95% CI 0.52-0.84; p = 0.0007). Subgroup analysis of the BRAF wild-type population showed an improved 1-year survival rate in 2016 versus 2014 (35.9% vs 18.8%, p = 0.0153). In conclusion, the introduction of modern treatments has led to an improved survival of real-world patients with MM, regardless of their eligibility to clinical trials and the BRAF status. These data support the application of modern treatments to patient populations which are not represented in pivotal trials.

Topics: Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Alkylating; Antineoplastic Agents, Immunological; Denmark; Female; Humans; Imidazoles; Ipilimumab; Male; Melanoma; Nivolumab; Oximes; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Skin Neoplasms; Survival Rate; Temozolomide

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Chemokine CXCL5; Humans; Imidazoles; Male; Melanoma; Middle Aged; Oximes; Prognosis; Pyridones; Pyrimidinones; Rhabdomyolysis; Severity of Illness Index; Skin Neoplasms

The combination therapy of dabrafenib and trametinib revolutionized the treatment for BRAF V600-mutated melanoma. Various adverse events have been reported for this treatment, most notably fever. Herein, we report two cases of novel an adverse event, namely sudden and significant elevation of plasma D-dimer level induced by this therapy. In the first case, the remarkable elevation of plasma D-dimer level up to 87.4 mg/dL was noted on day 11, and in the second case, the plasma D-dimer level reached 125.5 mg/dL on day 25. In both cases, D-dimer levels gradually decreased after the cessation of this therapy. Although the exact cause is not clear, we assume two possible hypotheses: the first is that the combination therapy may induce disseminated intravascular coagulation, and the second is that the therapy induced pathological condition of secondary thrombotic microangiopathies. Our cases suggest that this thrombotic adverse event should not be overlooked, and coagulation parameters need to be monitored during the course of this treatment.

Topics: Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Diarrhea; Fatigue; Female; Fever; Fibrin Fibrinogen Degradation Products; Humans; Imidazoles; Melanoma; Middle Aged; Mutation; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Treatment Outcome; Vomiting

Topics: Antineoplastic Agents; Female; Humans; Imidazoles; Melanoma; Middle Aged; Oximes; Pyridones; Pyrimidinones; Skin Neoplasms; Sweet Syndrome

The most common adverse event (AE) of dabrafenib and trametinib (DT) is pyrexia, which has been reported to occur in up to 71% of patients. Pyrexia resulted in therapy discontinuation in up to 26% of patients that otherwise were benefiting from the treatment. Little is known about the pathogenesis and optimal management of this common AE. We hypothesized that the etiology of pyrexia in patients treated with DT could be extrapolated from DT-related cutaneous adverse effects in which a paradoxical MAPK pathway activation has been identified. Based on preliminary data by our group suggesting an upregulation of the mitogen-activated protein kinases (MAPKs) in human lymphocytes exposed to dabrafenib and trametinib, specifically elevated expression of phosphorylated JNK (p-JNK), p38 MAPK (p-p38 MAPK), and ERK5 (p-ERK5), we hypothesized that the mechanism of MAPK pathway activation with DT therapy is similar to that reported in patients with familial Mediterranean fever (FMF), a rare, inherited condition characterized by episodes of fever and rash that responds exceedingly well to colchicine-based therapy in which the MAPK pathway is hyper-activated. Based on this association, our group explored the use of oral colchicine for the treatment of DT-associated pyrexia in five patients with metastatic melanoma.

Topics: Antineoplastic Combined Chemotherapy Protocols; Colchicine; Enzyme Activation; Fever; Humans; Imidazoles; Male; Melanoma; Middle Aged; Mitogen-Activated Protein Kinases; Mutation; Oximes; Pyridones; Pyrimidinones

Topics: Aged; Antineoplastic Agents; Azetidines; Female; Humans; Imidazoles; Male; Melanoma; Middle Aged; Molecular Targeted Therapy; Oximes; Piperidines; Polyneuropathies; Pyridones; Pyrimidinones; Skin Neoplasms; Vemurafenib

MAPK (RAS-RAF-MEK-ERK-MAP) and mTOR inhibitors are novel treatments for pediatric central nervous system (CNS) tumors. The literature on common cutaneous adverse reactions to these therapies is sparse in the pediatric population. The aim of this study was to describe common cutaneous adverse reactions to BRAF, MEK, and mTOR inhibitors in children with CNS tumors.. In this cross-sectional study, patients younger than 21 years of age receiving BRAF, MEK, and mTOR inhibitor monotherapy for a CNS tumor were enrolled over a one-year period. Full body skin examination, photographs of dermatologic findings, and initial treatment recommendations were included at the initial visit, and follow-up skin examinations were recommended every three months.. Twenty-two patients were enrolled in the study. Fifty percent (11/22) received trametinib, a MEK inhibitor, 27.3% (6/22) received dabrafenib, a BRAF inhibitor, and 22.7% (5/22) received everolimus, an mTOR inhibitor. Median age at visit was 11 years (range, 3-19). Median time from treatment initiation to skin examination was 4.5 months (range, 0-43). Ninety-six percent (21/22) of all patients had at least one skin reaction. The most common reactions across treatment groups included follicular/acneiform eruptions and xerosis. Two patients on MEK inhibitors and one patient on a BRAF inhibitor required therapy cessation due to severe cutaneous reactions.. Cutaneous reactions to targeted anticancer therapy in children are common, treatable, and rarely require drug dose reduction or discontinuation. Routine surveillance and early intervention may improve quality of life and facilitate continuation of life-saving therapy.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Central Nervous System Neoplasms; Child; Child, Preschool; Cross-Sectional Studies; Drug Eruptions; Female; Follow-Up Studies; Humans; Imidazoles; Male; Molecular Targeted Therapy; Oximes; Prognosis; Pyridones; Pyrimidinones; Skin Diseases; Young Adult

Topics: Antineoplastic Combined Chemotherapy Protocols; Cell Differentiation; Female; Humans; Imidazoles; Middle Aged; Mutation; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Thyroid Neoplasms

Melanoma of the skin is the sixth most common type of cancer in Europe and accounts for 3.4% of all diagnosed cancers. More alarming is the degree of recurrence that occurs with approximately 20% of patients lethally relapsing following treatment. Malignant melanoma is a highly aggressive skin cancer and metastases rapidly extend to the regional lymph nodes (stage 3) and to distal organs (stage 4). Targeted oncotherapy is one of the standard treatment for progressive stage 4 melanoma, and BRAF inhibitors (e.g. vemurafenib, dabrafenib) combined with MEK inhibitor (e.g. trametinib) can effectively counter BRAFV600E-mutated melanomas. Compared to conventional chemotherapy, targeted BRAFV600E inhibition achieves a significantly higher response rate. After a period of cancer control, however, most responsive patients develop resistance to the therapy and lethal progression. The many underlying factors potentially causing resistance to BRAF inhibitors have been extensively studied. Nevertheless, the remaining unsolved clinical questions necessitate alternative research approaches to address the molecular mechanisms underlying metastatic and treatment-resistant melanoma. In broader terms, proteomics can address clinical questions far beyond the reach of genomics, by measuring, i.e. the relative abundance of protein products, post-translational modifications (PTMs), protein localisation, turnover, protein interactions and protein function. More specifically, proteomic analysis of body fluids and tissues in a given medical and clinical setting can aid in the identification of cancer biomarkers and novel therapeutic targets. Achieving this goal requires the development of a robust and reproducible clinical proteomic platform that encompasses automated biobanking of patient samples, tissue sectioning and histological examination, efficient protein extraction, enzymatic digestion, mass spectrometry-based quantitative protein analysis by label-free or labelling technologies and/or enrichment of peptides with specific PTMs. By combining data from, e.g. phosphoproteomics and acetylomics, the protein expression profiles of different melanoma stages can provide a solid framework for understanding the biology and progression of the disease. When complemented by proteogenomics, customised protein sequence databases generated from patient-specific genomic and transcriptomic data aid in interpreting clinical proteomic biomarker data to provide a deeper and more comprehensive

Topics: Biological Specimen Banks; Biomarkers, Tumor; Drug Resistance, Neoplasm; Humans; Imidazoles; Melanoma; Melanoma, Cutaneous Malignant; Neoplasm Staging; Oximes; Protein Kinase Inhibitors; Proteomics; Pyridones; Pyrimidinones; Skin Neoplasms; Translational Research, Biomedical

Topics: Adenocarcinoma of Lung; Aged; Antineoplastic Combined Chemotherapy Protocols; High-Throughput Nucleotide Sequencing; Humans; Imidazoles; Lung Neoplasms; Male; Mutation; Neoplasm Metastasis; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Remission Induction; Treatment Outcome

Topics: Humans; Imidazoles; Melanoma; Mutation; Oximes; Patient Reported Outcome Measures; Pyridones; Pyrimidinones; Quality of Life

Topics: Follow-Up Studies; Humans; Imidazoles; Melanoma; Neoplasm Recurrence, Local; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

Topics: Follow-Up Studies; Humans; Imidazoles; Melanoma; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms

Topics: Follow-Up Studies; Humans; Imidazoles; Melanoma; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms

Panniculitis and vitiligo-like lesions have been recently identified as rare cutaneous side effects of the combination of BRAF and MEK inhibitors, a standard of care in metastatic and locally advanced BRAF V600 mutated melanoma. An immune-mediated mechanism has been advocated in the pathogenesis of these skin lesions. Herein we retrospectively reviewed our institutional experience with the aim to explore the association between the occurrence of panniculitis and vitiligo-like lesions during combination therapy with dabrafenib (D) and trametinib (T) and outcome of advanced melanoma patients. Among 52 consecutive BRAF V600 mutated melanoma patients submitted to DT in our center, 12 (23%) developed immune related skin lesions (IRSLs): 8 panniculitis and 4 vitiligo. Patients with IRSLs diagnosis obtained a better disease response (83% versus 25%) (p = 0.001) than their counterpart and had a longer progression free survival and overall survival. The association of IRSLs and lower risk of disease progression (HR 0.19; CI 95% 0.04-0.90; p = 0.043) was confirmed after adjusting for major prognostic factors in multivariate analysis. IRSLs might represent an easy predictive surrogate marker for treatment response and favourable outcome in melanoma patients submitted to DT combination therapy.

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Imidazoles; Kaplan-Meier Estimate; Male; MAP Kinase Signaling System; Melanoma; Middle Aged; Mutation; Oximes; Panniculitis; Progression-Free Survival; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Retrospective Studies; Skin Neoplasms; Treatment Outcome; Vitiligo

Topics: Humans; Imidazoles; Melanoma; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms

Topics: Antineoplastic Combined Chemotherapy Protocols; Asian People; Dermoscopy; Female; Humans; Imidazoles; Lymph Node Excision; Lymph Nodes; Margins of Excision; Melanoma; Middle Aged; Mutation; Neoplasm Staging; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Treatment Outcome; Warts

Topics: Adenocarcinoma of Lung; Aged; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Humans; Imidazoles; Lung Neoplasms; Male; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

Real-life comparative data on BRAF inhibitors (BRAFi) and BRAFi + MEK inhibitors (MEKi) combination in BRAF-mutant (BRAFm) non-small-cell lung cancer (NSCLC) is lacking.. Consecutive BRAFm advanced NSCLC patients (n = 58) treated in 9 Israeli centers in 2009-2018 were identified. These were divided according to mutation subtype and treatment into groups A1 (V600E, BRAFi; n = 5), A2 (V600E, BRAFi + MEKi; n = 15), A3 (V600E, no BRAFi; n = 7), B1 (non-V600E, BRAFi ± MEKi; n = 7), and B2 (non-V600E, no BRAFi; n = 23); one patient received both BRAFi and BRAFi + MEKi. Safety, objective response rate, progression-free survival with BRAFi ± MEKi, and overall survival were assessed.. Objective response rate was 40%, 67%, and 33% in groups A1, A2, and B1, respectively (P = .5 for comparison between groups A1 and A2). In group B1, G469A and L597R mutations were associated with response to BRAFi + MEKi. Median progression-free survival was 1.2 months (95% confidence interval [CI], 0.5-5.3), 5.5 months (95% CI, 0.7-9.3), and 3.6 months (95% CI, 1.5-6.7) for groups A1, A2, and B1, respectively (log-rank for comparison between groups A1 and A2, P = .04). Median overall survival with BRAFi ± MEKi was 1.7 months (95% CI, 0.5-NR), 9.5 months (95% CI, 0.2-14.9), and 7.1 months (95% CI, 1.8-NR) in groups A1, A2, and B1, respectively (log-rank for comparison between groups A1 and A2, P = .6). Safety profiles differed slightly, and similar treatment discontinuation rates were observed with BRAFi and BRAFi + MEKi.. In the real-life setting, activity and safety of BRAFi + MEKi in V600E BRAFm NSCLC are comparable to those observed in prospective clinical trials; the combination of BRAFi + MEKi is superior to monotherapy with a BRAFi. Further research should be done to explore the impact of BRAFi + MEKi treatment on the natural history of BRAFm NSCLC.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Cohort Studies; Female; Humans; Imidazoles; Lung Neoplasms; Male; MAP Kinase Kinase Kinases; Middle Aged; Mutation; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Survival Analysis; Vemurafenib

Although the treatment of metastatic melanoma has been significantly improved by both anti-BRAF/MEK and checkpoint immunotherapies, resistance to these treatment modalities remains a substantial clinical problem. Multiple clinical studies are addressing the optimal sequencing of these agents in larger patient cohorts, but successful long-term individualized treatment will likely require the elucidation of resistance mechanisms from post-progression samples. Here, we describe a patient with BRAF-V600E-positive metastatic melanoma who was sequentially treated with BRAF/MEK inhibitors (dabrafenib/trametinib) and checkpoint inhibitor immunotherapy (nivolumab, followed by pembrolizumab). After the emergence of resistance, whole exome sequencing was performed, implicating MAP2K2 and B2M mutations in loss of response to anti-BRAF/MEK and anti-PD1 therapies, respectively.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; beta 2-Microglobulin; Humans; Imidazoles; Male; MAP Kinase Kinase 2; MAP Kinase Kinase Kinases; Melanoma; Middle Aged; Mutation; Nivolumab; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Treatment Failure

Topics: Antineoplastic Agents; Gallbladder Neoplasms; Humans; Imidazoles; Male; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Melanoma; Middle Aged; Neoplasm Staging; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Time Factors; Treatment Outcome

To estimate the incremental cost-utility ratio (ICUR) of isolated and combined targeted therapy regimens compared to dacarbazine for first-line treatment of advanced and metastatic melanoma with BRAF V600 mutation.. A Markov model with three health states (no progression, progression and death), monthly duration cycle and 10-year time horizon was constructed to compare targeted therapy regimens (vemurafenib, dabrafenib, vemurafenib/cobimetinib and dabrafenib/trametinib) with dacarbazine chemotherapy under the Brazilian public health perspective. One-way and probabilistic sensitivity analyses were performed.. Mean cost was R$5662.50 ($1490.13) for dacarbazine, R$175 937.18 (46 299.26) for vemurafenib, R$167 461.70 ($44 068.87) for dabrafenib, R$425 901 ($112 079.21) for vemurafenib/cobimetinib and R$411 799.81 ($108 368.37) for dabrafenib/trametinib, whereas QALY was 0.91 for dacarbazine, 1.08 for vemurafenib, 1.12 for dabrafenib, 1.64 for vemurafenib/cobimetinib and 1.56 for dabrafenib/trametinib. The ICUR was estimated from R$572 165.76 ($150 569.94) to R$1 012 524.56 ($266 453.83) per patient, and the most impactful parameters were risk of progression and death, and treatment cost.. The incorporation of targeted therapies in the Brazilian public health system would produce an additional expenditure of at least 19 times the national GDP per capita to increase in one year the quality-adjusted survival of each patient with advanced/metastatic BRAF-mutant melanoma.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Azetidines; Brazil; Cost-Benefit Analysis; Dacarbazine; Drug Costs; Health Care Costs; Humans; Imidazoles; Melanoma; Oximes; Piperidines; Pyridones; Pyrimidinones; Vemurafenib

Pyrexia is the most common adverse event in patients with melanoma or other solid organ malignancies that are treated with the combination of dabrafenib and trametinib (combi-DT). Given the expanded indication for combi-DT, management of pyrexia is a high priority. No previous case series has revealed which blood markers reflect the course of pyrexia and there is no consensus on the management strategy for pyrexia. The current case series study describes the utility of neutrophil count (NC), neutrophil ratio (NR) and C-reactive protein (CRP) in 11 patients with metastatic melanoma and BRAF V600 mutations who experienced pyrexia during combi-DT in our department. We also described the clinical course of pyrexia episodes that were managed with the concomitant use of oral prednisolone and immediate withdrawal of combi-DT. Consequently, the analysis of 37 pyrexia episodes in 11 patients showed that the differences in NC, NR and CRP at the onset of pyrexia were significantly different from those at pyretolysis (P = 0.01, 0.006 and 0.03, respectively). Additionally, in the 24 pyrexia episodes treated with the concomitant use of oral prednisolone and the immediate withdrawal of combi-DT, the mean duration of pyrexia and the mean time to restart combi-DT were 3 and 6 days, respectively. Therefore, the blood markers that reflect the course of pyrexia during combi-DT may be helpful for the appropriate management of pyrexia; also, our management strategy for pyrexia successfully reduced the duration of pyrexia and did not require a long-term drug holiday. Further large-scale studies are required to verify our results.

Topics: Administration, Oral; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biomarkers; C-Reactive Protein; Feasibility Studies; Female; Fever; Humans; Imidazoles; Leukocyte Count; Male; Melanoma; Middle Aged; Neutrophils; Oximes; Prednisolone; Pyridones; Pyrimidinones; Retrospective Studies; Skin Neoplasms; Time Factors; Treatment Outcome; Young Adult

BRAF and MEK inhibitors are highly active in the setting of

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Humans; Imidazoles; Male; MAP Kinase Kinase 1; Melanoma; Molecular Targeted Therapy; Neoplasm Metastasis; Oximes; Prognosis; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

Dabrafenib plus trametinib is US Food and Drug Administration approved combination therapy for use in patients with BRAF V600E-mutant non-small cell lung cancer, but information on use outside of clinical trials is limited. We report the case of a 70-year-old Asian woman (never smoker) who was diagnosed with lung adenocarcinoma in May 2014. Testing at diagnosis was negative for programmed death ligand 1 or EGFR, ALK, and ROS1 alterations. She was started on carboplatin-pemetrexed-bevacizumab and maintenance bevacizumab but progressed in September 2015. Subsequently, she progressed on second-line nivolumab and third-line docetaxel. In March 2016, pleural fluid obtained at diagnosis tested positive for the BRAF V600E mutation and she received dabrafenib plus trametinib. She experienced rapid tumor shrinkage and symptom improvement and became able to participate in regular daily activities with no notable adverse events. In December 2016, she died from a hemorrhagic stroke considered unrelated to treatment. In this heavily pretreated patient with non-small cell lung cancer, dabrafenib plus trametinib elicited an excellent response.

Topics: Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Female; Humans; Imidazoles; Lung Neoplasms; Mutation; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

Topics: Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Chemoradiotherapy, Adjuvant; Disease-Free Survival; Female; Humans; Imidazoles; Male; Middle Aged; Mutation; Neck Dissection; Neoadjuvant Therapy; Neoplasm Recurrence, Local; Neoplasm Staging; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Survival; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms; Thyroidectomy

Small molecule inhibitors of BRAF and MEK have proven effective at inhibiting tumor growth in melanoma patients, however this efficacy is limited due to the almost universal development of drug resistance. To provide advanced insight into the signaling responses that occur following kinase inhibition we have performed quantitative (phospho)-proteomics of human melanoma cells treated with either dabrafenib, a BRAF inhibitor; trametinib, a MEK inhibitor or SCH772984, an ERK inhibitor. Over nine experiments we identified 7827 class I phosphorylation sites on 4960 proteins. This included 54 phosphorylation sites that were significantly down-modulated after exposure to all three inhibitors, 34 of which have not been previously reported. Functional analysis of these novel ERK targets identified roles for them in GTPase activity and regulation, apoptosis and cell-cell adhesion. Comparison of the results presented here with previously reported phosphorylation sites downstream of ERK showed a limited degree of overlap suggesting that ERK signaling responses may be highly cell line and cue specific. In addition we identified 26 phosphorylation sites that were only responsive to dabrafenib. We provide further orthogonal experimental evidence for 3 of these sites in human embryonic kidney cells over-expressing BRAF as well as further computational insights using KinomeXplorer. The validated phosphorylation sites were found to be involved in actin regulation, which has been proposed as a novel mechanism for inhibiting resistance development. These results would suggest that the linearity of the BRAF-MEK-ERK module is at least context dependent.

Topics: Apoptosis; Cell Line, Tumor; Drug Resistance, Neoplasm; Extracellular Signal-Regulated MAP Kinases; Humans; Imidazoles; Indazoles; MAP Kinase Signaling System; Melanoma; Mitogen-Activated Protein Kinase Kinases; Oximes; Phosphorylation; Piperazines; Proteome; Proteomics; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms

For the treatment of stage III/IV malignant melanoma (MM), a network meta-analysis (NMA) was conducted to compare the short and long-term efficacy of targeted therapy with single or double-drug regimens. All conducted randomized controlled trials (RCTs) searched from PubMed and Cochrane Library were included in the study for direct and indirect comparison for MM. The odds ratio (OR) and surface under the cumulative ranking curves (SUCRA) value of the targeted therapy with single or double-drug regimens for treatment of stage III/IV MM were also analyzed. To group the treatments according to their similarity with regards to both outcomes, cluster analyses were performed. Ultimately, 16 RCTs were incorporated for this NMA. The NMA revealed that the overall response rate (ORR) values of single-drug regimens (Vemurafenib [Vem], Dabrafenib [Dab], and Nivolumab [Niv]) were higher than those of Dacarbazine (Dac). Also the ORR values of double-drug regimens (Dab + Trametinib [Dab + Tra], Niv + Ipilimumab [Niv + Ipi], and Vem + Cobimetinib [Vem + Cob]) were moderately higher than those of Dac. The results of the SUCRA showed that short-term efficacy of single-drug regimens (Vem and Dab) were better, while the short-term efficacy of double-drug regimens (Dab + Tra and Vem + Cob) were relatively better. It was determined that Vem, Dab, and Niv might be the best choice in evaluating the treatment of stage III/IV MM among different single-drug targeted therapy regimens, while Dab + Tra, Niv + Ipi, and Vem + Cob might have better short-term efficacy among different double-drug targeted therapy regimens. J. Cell. Biochem. 119: 640-649, 2018. © 2017 Wiley Periodicals, Inc.

Topics: Antibodies, Monoclonal; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Azetidines; Dacarbazine; Humans; Imidazoles; Indoles; Ipilimumab; Melanoma; Molecular Targeted Therapy; Neoplasm Staging; Network Meta-Analysis; Nivolumab; Odds Ratio; Oximes; Piperidines; Pyridones; Pyrimidinones; Randomized Controlled Trials as Topic; Sulfonamides; Survival Analysis; Treatment Outcome; Vemurafenib

Topics: Acute Disease; Adult; Antineoplastic Agents; Granuloma; Heart Failure; Humans; Imidazoles; Lymphatic Metastasis; Male; Melanoma; Myocarditis; Oximes; Pyridones; Pyrimidinones; Skin Neoplasms

Topics: Acanthoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Imidazoles; Melanoma; Oximes; Pyridones; Pyrimidinones; Skin Neoplasms

Topics: Administration, Oral; Adult; Antineoplastic Combined Chemotherapy Protocols; Biopsy; Drug Eruptions; Erythema Multiforme; Female; Glucocorticoids; Humans; Imidazoles; Melanoma; Neoplasm Staging; Nivolumab; Oximes; Pyridones; Pyrimidinones; Severity of Illness Index; Skin; Skin Neoplasms

Patients with anaplastic thyroid cancer (ATC) have a dismal prognosis, despite systemic cytotoxic chemotherapy. The objective of this study was to investigate the efficacy and safety of targeted therapy in ATC patients when used outside of a clinical trial.. This is a retrospective review from April 2015 to May 2016 at a single academic institution where 16 ATC patients receiving targeted therapy outside of a clinical trial were studied. Ten patients (eight BRAF wild type and two BRAF. The majority of patients (63%) were men, and all had distant metastases or radiation-resistant primary disease at the time of treatment. In the entire cohort, 6/16 (38%) had a partial response, 6/16 (38%) had stable disease, and 2/16 (12%) had progressive disease. Two (12%) patients died before restaging. Median follow-up time was 11.8 months. Median progression-free survival was 3.7 months [confidence interval 1.8-7.6] in the entire cohort, 2.7 months for lenvatinib, and 5.2 months for dabrafenib plus trametinib. Median OS was 6.3 months [confidence interval 1.8-7.6] for the entire cohort, 3.9 months for lenvatinib, and 9.3 months for dabrafenib plus trametinib. Adverse events were as expected and manageable.. Targeted therapies, lenvatinib, and dabrafenib plus trametinib (for BRAF

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Imidazoles; Male; Middle Aged; Mutation; Oximes; Phenylurea Compounds; Prognosis; Progression-Free Survival; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Quinolines; Retrospective Studies; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms; Treatment Outcome

BRAF and MEK inhibitors have improved clinical outcomes in advanced, BRAF

Topics: Adult; Amino Acid Substitution; Base Sequence; Drug Resistance, Neoplasm; Female; Humans; Imidazoles; MAP Kinase Signaling System; Melanoma; Mutation, Missense; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Sequence Deletion

Topics: Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cardiac Conduction System Disease; Electrocardiography; Female; Heart Conduction System; Heart Ventricles; Humans; Imidazoles; Melanoma; Oximes; Pyridones; Pyrimidinones; Skin Neoplasms

Pleomorphic xanthoastrocytoma is a rare brain tumor with unique high frequency of BRAF V600E mutation which is plausible for targeted therapy. The anaplastic variant has generally worse prognosis. We present an adolescent patient with a disseminated relapse of anaplastic pleomorphic xanthoastrocytoma following surgery, radiotherapy, and chemotherapy. She had a dramatic and prolonged response to a BRAF inhibitor (Dabrafinib) and later to addition of a MEK inhibitor (Trametinib) on tumor progression. With minimal side effects and a good quality of life, the patient is alive more than 2 years after initiation of targeted therapy. This experience confirms the potential role of targeted treatments in high-grade BRAF-mutated brain tumors.

Topics: Adolescent; Amino Acid Substitution; Astrocytoma; Brain Neoplasms; Female; Humans; Imidazoles; Mutation, Missense; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Biopsy; Child; Child, Preschool; Female; Glioma; Humans; Imidazoles; Infant; Magnetic Resonance Imaging; Male; Molecular Targeted Therapy; Mutation; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Radiography; Treatment Outcome

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Chemical and Drug Induced Liver Injury; Female; Humans; Imidazoles; Liver Function Tests; Melanoma; Oximes; Pyridones; Pyrimidinones; Severity of Illness Index; Skin Neoplasms; Vemurafenib

Patients with brain metastases (BM) from melanoma have an overall survival (OS) of 2-6 months after whole-brain radiotherapy. Targeted therapy (TT) is an effective treatment for BRAF-mutated metastatic melanoma. Moreover, recent studies indicate intracranial responses of TT in patients with BM. We analyzed 146 patients with BM from BRAF-mutated melanoma treated with vemurafenib, dabrafenib, or dabrafenib+trametinib between 2010 and 2016. We determined clinical and radiological response, progression-free survival (PFS), and OS. Median OS of patients treated with dabrafenib+trametinib was 11.2 months [n=30; 95% confidence interval (CI): 6.8-15.7], 8.8 months for dabrafenib alone (n=31; 95% CI: 3.9-13.7), and 5.7 months for vemurafenib (n=85; 95% CI: 4.6-6.8). A significantly longer OS was observed in the dabrafenib+trametinib group than in the vemurafenib group (hazard ratio for death, 0.52; 95% CI: 0.30-0.89; P=0.02). Median intracranial PFS of all patients was 4.1 months. Median intracranial PFS for patients treated with dabrafenib+trametinib was 5.8 months (95% CI: 3.2-8.5), 5.7 months (95% CI: 3.0-8.4) for dabrafenib, and 3.6 months (95% CI: 3.5-3.8) for vemurafenib (P=0.54). A total of 63 (43%) patients had symptomatic BM. Intracranial disease control rate at 8 weeks in these patients was 65 versus 70% extracranially. Neurological symptoms improved in 46% of patients with symptomatic BM, whereas in 21%, they remained stable. Median OS in patients with BM from BRAF-mutated melanoma treated with dabrafenib+trametinib was significantly longer than for vemurafenib. Improvement of neurological symptoms was seen in almost half of the patients with symptomatic BM treated with TT.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Humans; Imidazoles; Male; MAP Kinase Kinase Kinases; Melanoma; Middle Aged; Mutation; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Retrospective Studies; Skin Neoplasms; Treatment Outcome; Vemurafenib; Young Adult

The mitogen-activated protein kinase pathway regulates cell growth and differentiation and is activated by BRAF mutations. BRAF mutations are present in about 40-50% of cutaneous melanomas. More than 90% of BRAF mutations are the V600E type. BRAF inhibitor (dabrafenib or vemurafenib) and MEK inhibitor (trametinib or cobimetinib) combination therapies are effective for BRAF-mutant advanced melanomas. A variety of side effects have been observed with combination therapy including pyrexia, fatigue, nausea, and vomiting. Rhabdomyolysis is one of the most severe adverse events, but it is very rare. Only two cases of rhabdomyolysis have been reported in clinical trials. A 41-year-old Japanese woman with cutaneous melanoma was started on a combination of dabrafenib and trametinib therapy after failure of immune checkpoint therapy. One month later, she complained of myalgia and fatigue and was shifted to our hospital. She was diagnosed with trametinib-induced rhabdomyolysis and showed improvement only with a high volume of fluid infusion. We stopped combination therapy, but there were no useful treatment options for her. After resuming dabrafenib, followed by trametinib, she did not have any problems. This is the first case of a patient with metastatic cutaneous melanoma who could recommence combination therapy after trametinib-associated rhabdomyolysis. We assume that not all patients experience recurrence of rhabdomyolysis in trametinib-induced rhabdomyolysis. As few cases have been reported, more information is needed. We have to evaluate safety carefully if rechallenging combination therapy.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Imidazoles; Melanoma; Oximes; Pyridones; Pyrimidinones; Rhabdomyolysis; Skin Neoplasms

Topics: Humans; Imidazoles; Melanoma; Neoadjuvant Therapy; Oximes; Pyridones; Pyrimidinones; Standard of Care

Topics: Aged; Anti-Bacterial Agents; Antineoplastic Combined Chemotherapy Protocols; Humans; Imidazoles; Male; Melanoma; Methicillin-Resistant Staphylococcus aureus; Oximes; Protein Kinase Inhibitors; Pyoderma Gangrenosum; Pyridones; Pyrimidinones; Risk Factors; Skin Neoplasms; Staphylococcal Infections; Treatment Outcome

Efficacy of BRAF V600E targeted therapies in brain tumors harboring the mutation has been shown in several case reports and is currently being studied in larger clinical trials. Monotherapy with vemurafenib has been associated with significant side effects, including rashes, papillomas, and squamous cell carcinomas. Here we describe an adolescent female with anaplastic ganglioglioma and significant skin reaction to vemurafenib with subsequent tumor response and tolerance to the BRAF/MEK inhibitor combination of dabrafenib and trametinib without recurrence of previous reaction.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Drug Resistance, Neoplasm; Female; Ganglioglioma; Humans; Imidazoles; MAP Kinase Kinase 1; Mutation; Oximes; Prognosis; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Vemurafenib

Topics: Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Biopsy; Chemotherapy, Adjuvant; Female; Fibrinolytic Agents; Humans; Imidazoles; Leg; Lymph Node Excision; Lymphatic Metastasis; Melanoma; Oximes; Pyridones; Pyrimidinones; Sentinel Lymph Node; Skin Neoplasms; Ultrasonography; Venous Thrombosis

On June 22, 2017, the Food and Drug Administration expanded indications for dabrafenib and trametinib to include treatment of patients with metastatic non-small cell lung cancer (NSCLC) harboring BRAF V600E mutations. Approval was based on results from an international, multicenter, multicohort, noncomparative, open-label trial, study BRF113928, which sequentially enrolled 93 patients who had received previous systemic treatment for advanced NSCLC (Cohort B,. The approvals of dabrafenib and trametinib, administered concurrently, provide a new regimen for the treatment of a rare subset of non-small cell lung cancer (NSCLC) and demonstrate how drugs active for treatment of

Topics: Adult; Aged; Aged, 80 and over; Carcinoma, Non-Small-Cell Lung; Female; Humans; Imidazoles; Lung Neoplasms; Male; Middle Aged; Mutation; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Treatment Outcome

Although uveitis is reported as a rare adverse event (AE) associated with dabrafenib/trametinib therapy or nivolumab, the occurrence of severe uveitis is extremely rare. We describe two cases of Vogt-Koyanagi-Harada (VKH)-like uveitis developing after the sequential administration of nivolumab and dabrafenib/trametinib therapy. Interestingly, both cases had HLA-DRB1*04:05, which is strongly associated with VKH disease, and achieved biologically complete remission after the treatment for uveitis. Our cases suggest a possible correlation between VKH-like uveitis as an AE and the clinical outcomes of sequential administration of nivolumab and dabrafenib/trametinib therapy for the treatment of advanced melanoma.

Topics: Adult; Aged; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Choroid; Female; Glucocorticoids; HLA-DRB1 Chains; Humans; Imidazoles; Magnetic Resonance Imaging; Male; Melanoma; Nivolumab; Oximes; Pyridones; Pyrimidinones; Skin Neoplasms; Treatment Outcome; Uveomeningoencephalitic Syndrome; Visual Acuity

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; DNA Mutational Analysis; Humans; Imidazoles; Lymphatic Metastasis; Male; Melanoma; Mutation; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Treatment Outcome

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Father-Child Relations; Fathers; Female; Fertility; Humans; Imidazoles; Infant, Newborn; Male; Melanoma; Mutation; Neoplasm Metastasis; Oximes; Pregnancy; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Semen Analysis; Skin Neoplasms

A sensitive and selective method of high performance liquid chromatography (HPLC) coupled to tandem mass spectrometry (MS/MS) has been developed for the simultaneous quantification of six anticancer protein kinase inhibitors (PKIs), dabrafenib, trametinib, vemurafenib, cobimetinib, pazopanib, regorafenib, and two active metabolites (regorafenib-M2 and regorafenib-M5) in human plasma. Plasma protein precipitation with methanol enables the sample extraction of 100 μL aliquot of plasma. Analytes are detected by electrospray triple-stage quadrupole mass spectrometry and quantified using the calibration curves with stable isotope-labeled internal standards. The method was validated based on FDA recommendations, including assessment of extraction yield (74-104%), matrix effects, analytical recovery (94-104%) with low variability (<15%). The method is sensitive (lower limits of quantification within 1 to 200 ng/mL), accurate (intra- and inter-assay bias: -0.3% to +12.7%, and -3.2% to +6.3%, respectively) and precise (intra- and inter-assay CVs within 0.7-7.3% and 2.5-8.0%, respectively) over the clinically relevant concentration range (upper limits of quantification 500 to 100,000 ng/mL). This method is applied in our laboratory for both clinical research programs and routine therapeutic drug monitoring service of PKIs.

Topics: Administration, Oral; Antineoplastic Agents; Azetidines; Child; Chromatography, High Pressure Liquid; Humans; Imidazoles; Indazoles; Indoles; Limit of Detection; Linear Models; Oximes; Phenylurea Compounds; Piperidines; Pyridines; Pyridones; Pyrimidines; Pyrimidinones; Reproducibility of Results; Sulfonamides; Tandem Mass Spectrometry; Vemurafenib

Topics: Administration, Oral; Antineoplastic Agents; Humans; Imidazoles; Melanoma; Neoplasm Metastasis; Neoplasm Staging; Oximes; Pyridones; Pyrimidinones; Survival Rate

Topics: Aged, 80 and over; Antineoplastic Agents; Dermatomyositis; Drug Resistance; Drug Therapy, Combination; Female; Glucocorticoids; Humans; Imidazoles; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

Topics: Adenocarcinoma of Lung; Drug Resistance, Neoplasm; Female; Humans; Imidazoles; Lung Neoplasms; Middle Aged; Mutation; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

Topics: Amino Acid Substitution; Antineoplastic Agents; Drug Therapy, Combination; Humans; Imidazoles; Lung Neoplasms; Mutation; Oximes; Precision Medicine; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Fatal Outcome; Granulocyte Colony-Stimulating Factor; Head and Neck Neoplasms; Humans; Imidazoles; Male; Melanoma; Oximes; Pyridones; Pyrimidinones; Scalp; Skin Neoplasms

Real-time monitoring of cancer cells' phenotypic evolution during therapy can provide vital tumour biology information for treatment management. Circulating tumour cell (CTC) analysis has emerged as a useful monitoring tool, but its routine usage is restricted by either limited multiplexing capability or sensitivity. Here, we demonstrate the use of antibody-conjugated and Raman reporter-coated gold nanoparticles for simultaneous labelling and monitoring of multiple CTC surface markers (named as "cell signature"), without the need for isolating individual CTCs. We observe cell heterogeneity and phenotypic changes of melanoma cell lines during molecular targeted treatment. Furthermore, we follow the CTC signature changes of 10 stage-IV melanoma patients receiving immunological or molecular targeted therapies. Our technique maps the phenotypic evolution of patient CTCs sensitively and rapidly, and shows drug-resistant clones having different CTC signatures of potential clinical value. We believe our proposed method is of general interest in the CTC relevant research and translation fields.

Topics: Antibodies, Neoplasm; Antineoplastic Agents; Biomarkers, Tumor; CD146 Antigen; Cell Line, Tumor; Cell Tracking; Gene Expression; Gold; Humans; Imidazoles; Immunoconjugates; Immunophenotyping; Melanoma; Metal Nanoparticles; Mitochondrial Proteins; Molecular Targeted Therapy; Neoplastic Cells, Circulating; Nerve Tissue Proteins; Oximes; Phenotype; Primary Cell Culture; Pyridones; Pyrimidinones; Receptor, ErbB-3; Receptors, Nerve Growth Factor; Skin Neoplasms; Spectrum Analysis, Raman; Staining and Labeling

Topics: Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Imidazoles; MAP Kinase Kinase Kinases; Melanoma; Middle Aged; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Sweet Syndrome

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Imidazoles; Lung Neoplasms; Lymphohistiocytosis, Hemophagocytic; Melanoma; Middle Aged; Oximes; Prognosis; Pyridones; Pyrimidinones

Topics: Antibodies, Neoplasm; Cell Line, Tumor; Humans; Imidazoles; Melanoma; Mitogen-Activated Protein Kinase Kinases; Nestin; Oximes; Phenotype; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

Febrile illnesses are common in the management of metastatic solid organ malignancies. Traditionally they occur in the setting of immunosuppression and neutropenia owing to cytotoxic therapy necessitating consideration of systemic infections. Systemic markers of inflammation, such as C-reactive protein and procalcitonin (PCT), may be used to assist in determining the aetiology of a fever in such patients. Newer anticancer therapies may cause significant noninfectious fevers and may result in a rise in inflammatory markers, despite the absence of an infection. We present a case of a critically unwell febrile patient being treated with dabrafenib and trametinib for advanced melanoma. The patient had an extreme elevation in PCT in the absence of infection. We discuss the presentation of fevers related to dabrafenib and trametinib therapy in the management of advanced melanoma, and the utility of PCT in the management of fevers in advanced solid organ malignancies.

Topics: Anti-Bacterial Agents; Antineoplastic Combined Chemotherapy Protocols; Fever; Humans; Imidazoles; Male; Melanoma; Middle Aged; Oximes; Pyridones; Pyrimidinones; Sepsis; Skin Neoplasms

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Chemotherapy, Adjuvant; Combined Modality Therapy; Gene Expression Regulation, Neoplastic; Humans; Imidazoles; Immunotherapy; Interferon alpha-2; Interferon-alpha; Ipilimumab; MAP Kinase Kinase 1; Melanoma; Nivolumab; Oximes; Prognosis; Programmed Cell Death 1 Receptor; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Randomized Controlled Trials as Topic; Recombinant Proteins; Recurrence; Skin Neoplasms; Survival Analysis

Although therapies for advanced melanoma have been greatly improved by the development of immune checkpoint inhibitors and BRAF/mitogen-activated protein kinase kinase inhibitors, there are still many concerns about the administration of these novel drugs. Therefore, to combine these therapies sequentially at appropriate time points of the disease is important. In this report, we report two cases in which dabrafenib and trametinib therapy for advanced melanoma failed but were successfully controlled by nivolumab monotherapy, and investigated the sera sCD163, CCL22 and CXCL10 as biomarkers for tumor progression. Interestingly, the sera levels of sCD163, CXCL10 and CCL22, both of which are produced by activated tumor-associated macrophages, were increased in parallel with the tumor progression in each case. Because this report presents only two cases, further data will need to be accumulated to provide more fundamental insights into the usefulness of these biomarkers for predicting disease progression in melanoma.

Topics: Adult; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Bile Duct Neoplasms; Disease Progression; Female; Humans; Imidazoles; Lymphatic Metastasis; Male; Melanoma; Middle Aged; Nivolumab; Oximes; Pancreatic Neoplasms; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Skin Neoplasms; Treatment Outcome

Mounting evidence suggests that RAF-mediated MEK activation plays a crucial role in paradox MAPK (re)activation, leading to resistance and therapeutic failure with agents hitting a single step along the MAPK cascade.. We examined the molecular and functional effects of single and combined BRAF (dabrafenib), pan-RAF (RAF265), MEK (trametinib) and EGFR/HER2 (lapatinib) inhibition, using Western Blot and conservative isobologram analysis to assess functional synergism, and explored genetic determinants of synergistic interactions. Immunoprecipitation based assays were used to detect the interaction between BRAF and CRAF. The Mann-Whitney U test was used for comparing quantitative variables.. Here we demonstrated that a combination of MEK and BRAF inhibitors overcomes paradoxical MAPK activation (induced by BRAF inhibitors) in BRAF-wt/RAS-mut NSCLC and PDAC in vitro. This results in growth inhibitory synergism, both in vitro and in vivo, in the majority (65%) of the cellular models analyzed, encompassing cell lines and patient-derived cancer stem cells and organoids. However, RAS mutational status is not the sole determinant of functional synergism between RAF and MEK inhibitors, as demonstrated in KRAS isogenic tumor cell line models. Moreover, in EGFR-driven contexts, paradoxical MAPK (re)activation in response to selective BRAF inhibition was dependent on EGFR family signaling and could be offset by simultaneous EGFR/HER-2 blockade.. Overall, our data indicate that RAF inhibition-induced paradoxical MAPK activation could be exploited for therapeutic purposes by simultaneously targeting both RAF and MEK (and potentially EGFR family members) in appropriate molecular contexts. KRAS mutation per se does not effectively predict therapeutic synergism and other biomarkers need to be developed to identify patients potentially deriving benefit from combined BRAF/MEK targeting.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Disease Models, Animal; Humans; Imidazoles; MAP Kinase Signaling System; Mice; Mitogen-Activated Protein Kinase Kinases; Mutation; Neoplastic Stem Cells; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins p21(ras); Pyridones; Pyrimidinones; Xenograft Model Antitumor Assays

To compare healthcare resource utilization (HRU) between patients with metastatic melanoma (MM) initiated on first-line (1L) combination therapy with the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib (D + T; oral) and those initiated on 1 L monotherapy with the anti-PD1 monoclonal antibodies nivolumab or pembrolizumab (N/P; intravenous).. Patients with melanoma initiated on D + T or N/P from Q1/2014 to Q2/2016 (defined as 1 L treatment for MM) were identified in the Truven MarketScan database. Entropy balancing was used to reweight the N/P cohort in order to make it comparable to the D + T cohort with respect to the mean and variance of baseline covariates. HRU outcomes during 1 L therapy, reported per patient-year (PPY), were described and compared between the two cohorts post-weighting (i.e. independently of baseline covariates).. Of the 445 patients included, 202 and 243 were initiated on D + T and N/P, respectively. After weighting, patients initiated on N/P had more outpatient visits for drug administration during 1 L therapy than those initiated on D + T (difference = 18.6 visits PPY [95% CI = 16.0-21.1]). Patients initiated on N/P also had more outpatient office visits for reasons other than drug administration (difference = 8.1 visits PPY [95% CI = 1.9-13.7]). No significant differences were observed for other HRU parameters (i.e. inpatient admissions, inpatient days, and emergency department visits during 1 L therapy).. HRU during 1 L therapy was generally similar between patients initiated on D + T and N/P. Nonetheless, patients initiated on N/P had more outpatient visits, including more outpatient visits for reasons unrelated to drug administration.

Topics: Adult; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Cohort Studies; Female; Humans; Imidazoles; Male; Melanoma; Middle Aged; Nivolumab; Oximes; Patient Acceptance of Health Care; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Retrospective Studies

We report the results of serial F-FDG PET/CT investigations in a 49-year-old woman presenting with an advanced cecal high-grade neuroendocrine carcinoma harboring a somatic BRAF mutation. Patient was refractory to standard chemotherapy regimen showing life-threatening hyperlactatemia. Early after the beginning of BRAF-MEK therapy (dabrafenib and trametinib), impressive improvement in PET/CT imaging was achieved. The pathological F-FDG uptake in cecal primary tumor as well as in nodal, hepatic, and bone metastases drastically decreased. Moreover, the reduction of total lesion glycolysis on PET/CT images was strictly related to extraordinary patient clinical response and lactic acid level normalization.

Topics: Acidosis, Lactic; Carcinoma, Neuroendocrine; Combined Modality Therapy; Female; Humans; Imidazoles; Middle Aged; Mitogen-Activated Protein Kinase Kinases; Molecular Targeted Therapy; Mutation; Oximes; Positron Emission Tomography Computed Tomography; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Treatment Outcome

This observational study investigates the effectiveness and safety of dabrafenib/trametinib combination in patients with metastatic melanoma.. Seventy-six patients treated with dabrafenib/trametinib (150 mg twice daily/2 mg once daily) were included.. Median progression-free survival was 9 months (95% CI: 7-11) and median overall survival was 14 months (11-16); disease control rate was 72%. Nine patients (12%) experienced a complete response. Of these, seven presented one metastatic site, none had lung or CNS metastasis, and none had elevated baseline lactate dehydrogenase (LDH) levels. Overall, subgroup analysis for patients with adverse prognostic features led to similar results. No new safety signals were reported.. Dabrafenib/trametinib combination can be effective and well-tolerated also in a heterogeneous 'real life' population comprising patients with adverse prognostic features.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Female; Follow-Up Studies; Humans; Imidazoles; Italy; Kaplan-Meier Estimate; Male; Melanoma; Middle Aged; Mutation; Neoplasm Metastasis; Neoplasm Staging; Neoplasms; Oximes; Prognosis; Pyridones; Pyrimidinones; Treatment Outcome; Young Adult

BRAF inhibitors (BRAFi) and MEK inhibitors (MEKi) are among the cornerstones of metastatic melanoma therapy demonstrating excellent response rates with duration of 7-12 m. Long-term benefit from these agents was reported in patients with normal lactate dehydrogenase (LDH) and less than three disease sites. However, a treatment-dependent marker for long-term efficacy is lacking. Data suggest that immune-related adverse events (irAEs) are associated with clinical benefit in patients treated with immunotherapy and that response to BRAF/MEK therapy may have an underlying immune mechanism. We hypothesised that AEs with an underlying immune mechanism may be associated with a durable response to targeted therapy. We retrospectively identified a cohort of 78 BRAF V600-mutant metastatic melanoma patients treated with BRAFi or BRAFi + MEKi between November 2010 and November 2013. Four treatment-related AEs including vitiligo, uveitis, erythema nodosum and keratitis sicca were defined as irAEs of interest. Retrospective analysis of AEs in relationship to progression-free survival (PFS), disease burden and LDH levels was performed. Median PFS (mPFS) for all patients was 7.5 months with responses ongoing in eight patients as of April 2017. Ten patients were identified with the AEs defined previously. Cox regression analysis revealed a very strong association between those AEs and PFS; mPFS was 42.8 m in patients with at least one AE versus 6.1 m in those without an AE (hazard ratio [HR] 0.22, p = 0.002). This association was independent of LDH levels and disease burden (HR 0.24, p = 0.035). This analysis demonstrates a strong association between immune AEs and durable response to targeted therapy and may provide a treatment-related biomarker to estimate the outcome of therapy.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Arthralgia; Azetidines; Female; Humans; Imidazoles; Kaplan-Meier Estimate; Male; MAP Kinase Kinase 1; Melanoma; Middle Aged; Mutation; Neoplasm Metastasis; Oximes; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Retrospective Studies; Skin Diseases; Skin Neoplasms; Vemurafenib; Young Adult

Topics: Adult; Female; Humans; Imidazoles; Melanoma; Oximes; Pyridones; Pyrimidinones; Tattooing

The use of molecularly targeted therapy is becoming widespread in oncology. These agents cause tumour-specific genetic alterations in signal transduction pathways, hence less generalised toxicity. Dabrafenib, a BRAF inhibitor and Trametinib, a MEK inhibitor are two molecularly targeted agents recently approved for treatment of advanced, unresectable melanomas. MEK retinopathy is a recently introduced term describing retinal toxicity secondary to MEK inhibitors.. A 71-year-old man presented with 'circular, green patches' in his central vision for 2 weeks. He had multiple relapsed stage IV BRAF gene mutant malignant melanoma. He was on treatment with Dabrafenib (Tafinlar) for 7 months and Trametinib (Mekinist) for 4 months respectively. The fundus looked normal. The OCT scan showed bilateral symmetrical cystoid macular edema, intraretinal and subretinal fluid, thickening of elliposoid zone and subretinal granular deposits. The symptoms resolved with temporary cessation of chemotherapy but OCT signs persisted.. This case report identifies two new remarkable features of MEK retinopathy as thickening of ellipsoid zone and 'starry sky' pattern of distribution of subretinal granular deposits. These changes signify photoreceptors/ RPE toxicity and dysfunction. The subretinal granular deposits showed increased autofluorescence suggested abnormal lipofuscin clearance due to RPE dysfunction. The molecularly targeted therapy has revolutionized the cancer treatment and increased the survival rate. These agents are relatively new and recently approved for clinical use and most of them are associated with ocular toxicities. Awareness of ocular symptoms, side-effect profile of drugs, monitoring regime and liaison between oncologist and eye care professional with ocular imaging is key to early diagnosis and management of ocular adverse events.

Topics: Aged; Humans; Imidazoles; Macular Edema; Male; Mitogen-Activated Protein Kinase Kinases; Molecular Targeted Therapy; Oximes; Paraneoplastic Syndromes, Ocular; Photoreceptor Cells, Vertebrate; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Retinal Diseases; Retinal Pigment Epithelium; Skin Neoplasms; Subretinal Fluid; Tomography, Optical Coherence

BRAF and MEK inhibitors (BRAF/MEKi) are targeted therapy for proto-oncogene BRAF mutated metastatic unresectable melanoma. Compared to monotherapy, an increased cardiovascular toxicity is reported with the combination of Dabrafenib and Trametinib. This case report documents Grade 4 cardiac treatment emergent adverse effect of pericardial effusion and cardiac tamponade induced by this combination therapy.. A 52 year old man presented with clinical stage II unresectable melanoma with BRAF mutation, was initiated on treatement with Dabrafenib and Trametinib. He complained of generalised edema and increased his weight by 27 kg. This progressed to shortness of breath and he underwent echocardiogram which revealed cardiac tamponade.. Emergent pericardiocentesis was performed. No definited pathology was demonstrated in laboratory analysis of pericardial fluid. Re- initiating treatment resulted in cardiac tamponade and pericardiotomy was performed by video-assisted thoracic surgical (VATS). Pericardial biopsy revealed nonspecific chronic inflammation.. Discontinuation of treatment with Dabrafenib and Trametinib and diuretics resolved peripheral edema. Cardiac function normalized after pericardiocentesis and pericardiotomy.. Treatment with Dabrafenib and Trametinib caused significant peripheral edema and pericardial effusion resulting in cardiac tamponade. Naranjo score suggests probable association of treatment induced pericardial effusion and cardiac tamponade.. This is the first documented report of pericardial effusion and cardiac tamponade induced by Dabrafenib and Trametinib. Cardiac toxicity of BRAF/MEK inhibitors is rare but clinicans must monitor for treatment emergent adverse effects.

Topics: Antineoplastic Combined Chemotherapy Protocols; Cardiac Tamponade; Humans; Imidazoles; Male; Melanoma; Melanoma, Cutaneous Malignant; Middle Aged; Oximes; Pericardiectomy; Proto-Oncogene Mas; Pyridones; Pyrimidinones; Skin Neoplasms; Thoracic Surgery, Video-Assisted

Topical treatment using photodynamic therapy (PDT) for many types of skin cancers has largely been limited by the inability of existing photosensitizers to penetrate into the deep skin tissue. To overcome these problems, we developed a mesoporous nanovehicle with dual loading of photosensitizers and clinically relevant drugs for combination therapy, while utilizing microneedle technology to facilitate their penetration into deep skin tissue. Sub-50 nm photodynamically active mesoporous organosilica nanoparticles were synthesized with photosensitizers covalently bonded to the silica matrix, which dramatically increased the quantum yield and photostability of these photosensitizers. The mesopores of the nanoparticles were further loaded with small-molecule inhibitors, i. e., dabrafenib and trametinib, that target the hyperactive mitogen-activated protein kinase (MAPK) pathway for melanoma treatment. As-prepared empty nanovehicle was cytocompatible with normal skin cells in the dark, while NIR-irradiated drug-loaded nanovehicle showed a synergistic killing effect on skin cancer cells mainly through reactive oxygen species and caspase-activated apoptosis. The nanovehicle could significantly inhibit the proliferation of tumor cells in a 3D spheroid model in vitro. Porcine skin fluorescence imaging demonstrated that microneedles could facilitate the penetration of nanovehicle across the epidermis layer of skin to reach deep-seated melanoma sites. Tumor regression studies in a xenografted melanoma mouse model confirmed superior therapeutic efficacy of the nanovehicle through combinational PDT and targeted therapy.

Topics: Administration, Topical; Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Combined Modality Therapy; Drug Delivery Systems; Female; Heterografts; Humans; Imidazoles; Indoles; Isoindoles; Melanoma; Mice, Nude; Nanostructures; Needles; Oxidative Stress; Oximes; Photochemotherapy; Photosensitizing Agents; Pyridones; Pyrimidinones; Silicon Dioxide; Skin Neoplasms

To report the diagnosis of acute VKH-like syndrome as a complication from dabrafenib (a serine/threonine inhibitor of BRAF V600) and trametinib (a MEK inhibitor). In combination, these targeted agents have been shown to prolong overall survival and progression free survival in BRAF mutant metastatic melanoma.. Retrospective medical chart review including radiologic and ophthalmologic investigations.. A patient with metastatic melanoma being treated with dabrafenib and trametinib for 2 months presented with 1 week of visual blurring. He had developed bilateral optic disc swelling and uveitis that responded to pulsed steroid therapy.. VKH-like syndrome is a rare but serious complication of targeted therapy that should be considered when evaluating a patient with visual disturbances on dabrafenib and trametinib therapy.

Topics: Antineoplastic Agents; Disease-Free Survival; Drug Therapy, Combination; Humans; Imidazoles; Male; Melanoma; Middle Aged; Optic Disk; Oximes; Papilledema; Pyridones; Pyrimidinones; Skin Neoplasms; Tomography, Optical Coherence; Uveitis

Topics: Antineoplastic Agents; Drug Therapy, Combination; Female; Fluorescein Angiography; Fundus Oculi; Humans; Imidazoles; Ischemia; MAP Kinase Kinase 1; Melanoma; Melanoma, Cutaneous Malignant; Middle Aged; Neoplasm Metastasis; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Retinal Vasculitis; Retinal Vessels; Skin Neoplasms

Topics: Antineoplastic Combined Chemotherapy Protocols; Brugada Syndrome; Humans; Imidazoles; Male; Melanoma; Middle Aged; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms

Targeted therapies for cancers are fast-growing therapies. For instance kinase inhibitors such as BRAF inhibitors (BRAFi) and MEK inhibitors (MEKi) are increasingly used to treat malignant melanoma. The metabolic profile of these drugs can result in great interindividual variability, justifying therapeutic drug monitoring (TDM). We describe a rapid and specific method for quantification of 2 BRAFi (vemurafenib, dabrafenib) and 3 MEKi (cobimetinib, trametinib and binimetinib). Chromatography was performed on a Waters Acquity-UPLC system with CORTECS C18+ column, under a gradient of 10% acetic acid in water/acetonitrile. An Acquity-TQD® with electrospray ionization was used for detection. Samples were prepared by solid phase extraction (Oasis® MCX microElution) before injection in the system. Calibration curves ranges from 0.4 to 100μg/ml for vemurafenib, from 1 to 1000ng/ml for dabrafenib, from 0.5 to 500ng/ml for cobimetinib and binimetinib, and from 0.75 to 250ng/ml for trametinib. At all concentrations the bias was within ±15% of the nominal concentrations and precision was ≤15%. All results were within the acceptance criteria of the EMA guidelines on method validation. This rapid, sensitive and specific UPLC-MS/MS method can perform simultaneous quantification of targeted therapies used in malignant melanoma and is usable for routine TDM.

Topics: Azetidines; Benzimidazoles; Chromatography, High Pressure Liquid; Humans; Imidazoles; Indoles; Limit of Detection; Linear Models; Melanoma; Mitogen-Activated Protein Kinase Kinases; Oximes; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Sulfonamides; Tandem Mass Spectrometry; Vemurafenib

The activation of oncogenic Wnt/β-catenin pathway in melanoma contributes to a lack of T-cell infiltration. Whether baseline β-catenin expression in the context of tumour-infiltrating lymphocytes (TILs) and programmed death ligand-1 (PD-L1) overexpression correlates with prognosis of metastatic melanoma patients (MMPs) treated with mitogen-activated protein kinase, MAPK inhibitor (MAPKi) monotherapy, however, has not been fully clarified.. Sixty-four pre-treatment formalin-fixed and paraffin embedded melanoma samples from MMP treated with a BRAF inhibitor (n = 39) or BRAF and MEK inhibitors (n = 25) were assessed for presence of β-catenin, PD-L1, cluster of differentiation (CD)8, CD103 and forkhead box protein P3 (FOXP3) expression by immunohistochemistry, and results were correlated with clinical outcome. Quantitative assessment of mRNA transcripts associated with Wnt/β-catenin pathway and immune response was performed in 51 patients.. We found an inverse correlation between tumoural β-catenin expression and the level of CD8, CD103 or forkhead box protein P3 (FOXP3) positivity in the tumour microenvironment (TME). By multivariate analysis, PD-L1 <5% (odds ratio, OR 0.12, 95% confidence interval, CI 0.03-0.53, p = 0.005) and the presence of CD8+ T cells (OR 18.27, 95%CI 2.54-131.52, p = 0.004) were significantly associated with a higher probability of response to MAPKi monotherapy. Responding patients showed a significantly increased expression of mRNA transcripts associated with adaptive immunity and antigen presentation. By multivariate analysis, progression-free survival (PFS) (hazards ratio (HR) = 0.25 95%CI 0.10-0.61, p = 0.002) and overall survival (OS) (HR = 0.24 95%CI 0.09-0.67, p = 0.006) were longer in patients with high density of CD8+ T cells and β-catenin <10% than those without CD8+ T cells infiltration and β-catenin ≥10%.. Our findings provide evidence that in the context of MAPKi monotherapy, immune subsets in the (TME) and gene signature predict prognosis in MMPs.

Topics: Adult; Aged; Aged, 80 and over; Antigens, CD; beta Catenin; CD8 Antigens; Female; Forkhead Transcription Factors; Humans; Imidazoles; Indoles; Integrin alpha Chains; Lymphocytes, Tumor-Infiltrating; Male; Melanoma; Middle Aged; Mitogen-Activated Protein Kinase Kinases; Oximes; Prognosis; Programmed Cell Death 1 Receptor; Prospective Studies; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Sulfonamides; Treatment Outcome; Vemurafenib; Young Adult

We present a patient with BRAF-V600E mutant papillary craniopharyngioma successfully treated with combination BRAF (dabrafenib 150 mg twice daily) and MEK (trametinib 2 mg daily) inhibitors after her unresectable tumor proved refractory to radiation. Serial brain MRIs and PET revealed marked tumor reduction with gradual neurological improvement and permanent panhypopituitarism.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Craniopharyngioma; Female; Humans; Imidazoles; Middle Aged; Mutation; Oximes; Pituitary Neoplasms; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Humans; Imidazoles; Male; Melanoma; Mitogen-Activated Protein Kinase Kinases; Neoplasm Metastasis; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Remission Induction; Skin Neoplasms; Treatment Outcome

Topics: Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Cytokines; Female; Humans; Imidazoles; Indoles; Macrophage Activation; Male; Melanoma; Middle Aged; Nivolumab; Oximes; Programmed Cell Death 1 Receptor; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Sulfonamides; Vemurafenib

Increasing evidence exists for the role of immunosuppressive adenosine in promoting tumor growth and spread in a number of cancer types, resulting in poor clinical outcomes. In this study, we assessed whether the CD73-adenosinergic pathway is active in melanoma patients and whether adenosine restricts the efficacy of clinically approved targeted therapies for commonly mutated BRAF

Topics: 5'-Nucleotidase; Adenosine; Animals; Drug Therapy, Combination; GPI-Linked Proteins; Humans; Imidazoles; Lung Neoplasms; MAP Kinase Kinase 1; Melanoma; Mice; Mice, Inbred C57BL; Mice, Knockout; Molecular Targeted Therapy; Mutation; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Receptor, Adenosine A2A; Skin Neoplasms

Various cutaneous side-effects have been reported with anti-melanoma systemic therapies. This study investigated the changes in melanocytic lesion pigmentation in patients on four different therapies.. We analysed the serial dermatoscopic photographs of atypical melanocytic lesions taken from patients with advanced metastatic melanoma on four different systemic therapies (selective BRAF-inhibitor monotherapy, dabrafenib combined with trametinib [D&T], anti-programmed cell death protein 1 [anti-PD1] therapies, and anti-PD1 combined with ipilimumab) seen from February 2013 to May 2016. We compared these changes with the melanocytic lesions of 10 control patients.. In the control group, 19% of naevi lightened, 64% did not change and 17% darkened. Only the BRAF inhibitor group showed more darkened lesions than controls (37%, P < 0.001). Meanwhile, there were more lightened naevi in the D&T therapy group (86%, P < 0.001) as well as the anti-PD1 and ipilimumab groups (59%, P < 0.001) than controls. Patients on anti-PD1 monotherapy had more lightened (49%) and fewer darkened naevi (9%) than controls, but differences were not significant.. Our study showed that different anti-melanoma systemic therapies have different effects on the pigmentation of melanocytic lesions. BRAF inhibitor may have the propensity to cause darkening while D&T therapy and anti-PD1 caused lightening compared with controls. The findings emphasise the importance of regular dermatological monitoring in specialised clinics for patients on anti-melanoma systemic therapy. Clinicians should expect changes in the global pigmentation of melanocytic lesions but be suspicious of lesions with structural changes.

Topics: Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Dermoscopy; Female; Humans; Imidazoles; Ipilimumab; Male; Melanoma; Middle Aged; Molecular Targeted Therapy; Nivolumab; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Skin Pigmentation

To describe a case of bilateral choroidal neovascularization (CNV) in multifocal choroiditis (MFC) associated with dabrafenib and trametinib chemotherapy for metastatic melanoma.. We present a case of a 57-year-old man with MFC who underwent combination therapy with dabrafenib plus trametinib for metastatic melanoma. The patient presented to our ophthalmology department complaining of bilateral vision loss of 2 days' duration. He underwent multimodal imaging showing a MFC reactivation complicated by bilateral CNV. The patient underwent 3 ranibizumab injections in the right eye and 7 ranibizumab injections in the left eye. Anatomical and functional improvement has been observed.. This report emphasizes the importance of strict ophthalmologic follow-up in patients with metastatic melanoma treated with dabrafenib plus trametinib since rare severe ocular toxicities can occur, especially in patients with a history of uveitis.

Topics: Antineoplastic Combined Chemotherapy Protocols; Choroidal Neovascularization; Choroiditis; Fluorescein Angiography; Humans; Imidazoles; Male; Melanoma; Middle Aged; Multifocal Choroiditis; Multimodal Imaging; Oximes; Pyridones; Pyrimidinones; Skin Neoplasms; Tomography, Optical Coherence

A multi-institutional, randomized phase II trial of continuous dosing of dabrafenib with or without trametinib is ongoing in metastatic thyroid cancer. Preclinical evidence and emerging clinical experience in other cancers support evaluating intermittent dosing of these two agents to achieve more durable response, while being better tolerated and more cost effective.. Two consecutive patients with symptomatic, metastatic radioactive iodine-resistant BRAF. Both patients showed rapid clinical improvement upon starting the regimen. They also noted improved tolerance of treatment upon transitioning to the intermittent dosing schedule. They continue to show evidence of antitumor activity 27 and 18 months respectively from the start of treatment and 15 and 13 months respectively from the start of the first break using intermittent dosing.. Achieving durable palliation in these consecutive patients supports evaluating the intermittent dosing schedule of dabrafenib and trametinib in BRAF

Topics: Aged, 80 and over; Amino Acid Substitution; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Papillary; Drug Administration Schedule; Drug Monitoring; Female; Humans; Imidazoles; Middle Aged; Mutation; Oximes; Palliative Care; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Thyroid Cancer, Papillary; Thyroid Neoplasms; Treatment Outcome

To report a case of uveitis and neuroretinal detachment in a patient treated with Trametinib and Dabrafenib due to metastatic cutaneous melanoma stage IV.. We evaluated slit lamp examination, fundoscopy, optical coherence tomography, fluorescein and indocyanine green angiography in a 66 years old man suffering visual loss. Fundoscopy showed serous neuroretinal detachment of the fovea accompanied with white spots surrounding the fovea in both eyes. Although therapy with Trametinib and Dabrafenib was stopped uveitis anterior was seen 2 weeks later. After a year, the therapy was started again and the serous neuroretinal detachment appeared once more, however without inflammatory reaction of the anterior chamber.. Patients treated with Trametinib and Dabrafenib should undergo consecutive eye examinations from the beginning of the therapy.

Topics: Aged; Antineoplastic Agents; Humans; Imidazoles; Male; Oximes; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Retinal Detachment; Uveitis

Donor-derived malignancy, particularly melanoma, is a rare but known complication of organ transplantation. Here we describe a case of metastatic melanoma in a deceased-donor kidney transplant recipient. After diagnosis, the patient was successfully treated with cessation of immunosuppression, explantation of the renal allograft, and novel melanoma therapies, including the mutation-targeted agents dabrafenib and trametinib and the immune checkpoint inhibitor nivolumab. These 2 new classes of melanoma therapy have revolutionized the course of metastatic melanoma, altering it from one of nearly certain mortality to one of potential cure. This case reviews the mechanisms of action of these therapies and reports our experience with them in the rare setting of donor-derived melanoma in a dialysis-dependent patient.

Topics: Allografts; Antibodies, Monoclonal; Antineoplastic Agents; Checkpoint Kinase 1; Checkpoint Kinase 2; Humans; Imidazoles; Kidney; Kidney Neoplasms; Kidney Transplantation; Liver Neoplasms; Lung Neoplasms; Male; Melanoma; Middle Aged; Nivolumab; Oximes; Pyridones; Pyrimidinones; Tissue Donors

Craniopharyngiomas are histologically benign but locally aggressive tumors in the sellar region that may cause devastating neurological and endocrine deficits. They tend to recur following surgery with high morbidity; hence, postoperative radiotherapy is recommended following sub-total resection. BRAFV600E mutation is the principal oncogenic driver in the papillary variant of craniopharyngiomas. Recently, a dramatic tumor reduction has been reported in a patient with BRAFV600E mutated, multiply recurrent papillary craniopharyngioma using a combination therapy of BRAF inhibitor dabrafenib and MEK inhibitor trametinib. Here, we report on near-radical reduction of a growing residual BRAFV600E craniopharyngioma using the same neoadjuvant therapy.

Topics: Aged; Craniopharyngioma; Humans; Imidazoles; Male; Molecular Targeted Therapy; Mutation; Neoadjuvant Therapy; Neoplasm Recurrence, Local; Oximes; Pituitary Neoplasms; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Sella Turcica

Malignant melanomas presenting with unknown primaries are uncommon. In the majority of cases metastases of occult melanoma were detected in skin or in lymph nodes. Melanoma can rarely occur as a primary or metastatic intramammary tumor.. We report the case of a 58-year-old Caucasian woman who came to our department with a voluminous mass in her right breast. Histopathological examination found metastasis of epithelioid melanoma with unknown primary lesion. Our patient underwent a radical enlarged mastectomy, but due to the extension a radical removal was not possible.. In 2.2% of cases, melanoma may present with a metastasis without an identifiable primary lesion; this case should be considered a stage IV melanoma (Tx; N1; M1) due to the extension of the lesion and the infiltration of adjacent structures.. In literature, the presence of a breast metastasis of melanoma with unknown primary origin was reported just in one case. The execution of histopathological analysis is mandatory for a correct differential diagnosis with primary carcinoma of the breast. Palliative metastasectomy should be discussed with multidisciplinary melanoma board.. Breast metastases, Metastatic melanoma, Unknown primary site.. Il melanoma maligno, nel 2.2% dei casi, si presenta in forma metastatica con localizzazione primaria non identificabile, si parla in questi casi di metastasi da melanoma primitivo occulto. Le metastasi di melanoma sono localizzate più frequentemente a livello cutaneo e linfonodale, mentre la presenza di metastasi mammarie è poco frequente. In letteratura è riportato un solo caso di metastasi intramammarie da melanoma primitivo occulto, in questo lavoro ne presentiamo un nuovo caso. Si tratta di una donna caucasica di 58 anni che è giunta alla nostra attenzione per una voluminosa massa a livello della mammella destra. L’esame istologico della lesione ha diagnosticato la presenza di metastasi mammaria da melanoma cutaneo. La paziente è stata quindi sottoposta ad un accurato esame dermatologico, oftalmologico, pneumologico e gastroenterologico ma non è stata identificata la lesione primitiva. Si tratta di un caso molto particolare e di difficile gestione ed inquadramento terapeutico per le dimensioni della massa e l’estesa infiltrazione alla parete toracica anteriore. La paziente è stata sottoposta a mastectomia radicale allargata, ma a causa dell’estensione della lesione non è stata possibile un’escissione radicale. Sebbene la stadiazione del melanoma occulto sia difficile a causa dell’impossibilità di determinare se si tratti di metastasi regionali o a distanza, questo caso dovrebbe essere considerato uno stadio IV (Tx; N1; M1) per l’estensione e l’infiltrazione delle strutture adiacenti. Nei casi di metastasi intramammarie l’esame istopatologico è dirimente per una corretta diagnosi differenziale con il carcinoma mammario primitivo. La mastectomia palliativa dovrebbe essere attentamente valutata con un team multidisciplinare per la cura del melanoma.

Topics: Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Carcinoma, Ductal, Breast; Combined Modality Therapy; Diagnosis, Differential; Female; Humans; Imidazoles; Mastectomy; Melanoma; Middle Aged; Neoplasm Invasiveness; Neoplasm Staging; Neoplasms, Unknown Primary; Oximes; Palliative Care; Pyridones; Pyrimidinones

The spectacular outcomes of the phase III trials regarding nivolumab versus ipilimumab in fully resected stage IIIB/C-IV and of the combination of dabrafenib (D) plus trametinib (T) in BRAF-mutant stage III patients demonstrate that effective treatments in advanced melanoma are also highly effective in the adjuvant setting. In 2016, an overall survival benefit with adjuvant high-dose ipilimumab was demonstrated, and the European Organisation for Research and Treatment of Cancer trial 1325 comparing pembrolizumab versus placebo will complete the picture in the early 2018. Toxicity profiles are in line with the experience in advanced melanoma, i.e. favourable for the anti-PD1 agents and for D + T and problematic for ipilimumab. The 2017 outcomes are practice changing and put an end to the use of interferon (IFN) and ipilimumab. In countries with only access to IFN, its use can be restricted to patients with ulcerated melanoma, based on the individual patient data meta-analysis recently published. Because of the results of the Melanoma Sentinel Lymph node Trial-2 (MSLT-2) trial, completion lymph node dissection (CLND) will decrease sharply, leading to a lack of optimal prognostic information. Prognosis in sentinel node-positive stage IIIA/B patients is extremely heterogeneous with 5-year survival rates varying from 90% to 40% and depends mostly on the number of positive nodes identified by CLND. This information is crucial for clinical decision-making. How to guarantee optimal staging information needs to be discussed urgently. Further improvements of adjuvant therapies will have to address all these questions as well as the exploration of neoadjuvant use of active drugs and combination approaches. Important paradigm shifts in the management of high-risk melanoma patients are upon us.

Topics: Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Clinical Decision-Making; Evidence-Based Medicine; Humans; Imidazoles; Interferons; Ipilimumab; Melanoma; Neoadjuvant Therapy; Neoplasm Staging; Oximes; Patient Selection; Practice Patterns, Physicians'; Predictive Value of Tests; Pyridones; Pyrimidinones; Randomized Controlled Trials as Topic; Risk Factors; Skin Neoplasms; Time Factors; Treatment Outcome

BRAFV600E mutations have been identified in a number of glioma subtypes, most frequently in pleomorphic xanthoastrocytoma, ganglioglioma, pilocytic astrocytoma, and epithelioid glioblastoma. Although the development of BRAF inhibitors has dramatically improved the clinical outcome for patients with BRAFV600E mutant tumors, resistance develops in a majority of patients due to reactivation of the MAPK pathway. Addition of MEK inhibition to BRAF inhibition improves survival. Here we report successful treatment of two patients with BRAFV600E mutant pleomorphic xanthoastrocytoma using the BRAF inhibitor dabrafenib in combination with the MEK inhibitor trametinib.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Female; Glioma; Humans; Imidazoles; Middle Aged; Mutation; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

Patients with advanced melanoma have a poor prognosis. Since the discovery of BRAF mutations in cutaneous melanoma, new pharmacological agents have been developed to inhibit this target. Although the survival of patients with advanced melanoma has improved with BRAF inhibitors, the emergence of drug resistance and the high incidence of cutaneous side effects represent important limitations. The aim of our study was to compare the incidence of cutaneous side effects between BRAF inhibitor monotherapy and BRAF and MEK inhibitor combination therapy in our cohort of patients. This study was a longitudinal prospective observational study. The study population comprised 83 patients with advanced cutaneous melanoma presenting with BRAF V600 mutation. The inclusion criteria included: age above 18 years, metastatic cutaneous melanoma or melanoma with high risk of metastasis, the presence of BRAF V600 mutation, and treatment with BRAF inhibitors or a combination of BRAF and MEK inhibitors. The majority of patients developed skin toxicity during treatment. The most common cutaneous side effects were localized hyperkeratosis and verrucous keratosis. Other cutaneous side effects observed were photosensitivity, squamous cell carcinoma, and keratoacanthoma. Our results indicate that cutaneous side effects are generally observed during BRAF inhibitor monotherapy and are significantly different from those observed in patients treated with combination therapy.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Carbamates; Humans; Imidazoles; Indoles; MAP Kinase Kinase Kinases; Melanoma; Melanoma, Cutaneous Malignant; Mutation; Oximes; Prospective Studies; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Diseases; Skin Neoplasms; Sulfonamides; Vemurafenib

Topics: Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Humans; Imidazoles; Male; Melanoma; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Remission Induction; Skin Neoplasms

Diverse pathways drive resistance to BRAF/MEK inhibitors in BRAF-mutant melanoma, suggesting that durable control of resistance will be a challenge. By combining statistical modeling of genomic data from matched pre-treatment and post-relapse patient tumors with functional interrogation of >20 in vitro and in vivo resistance models, we discovered that major pathways of resistance converge to activate the transcription factor, c-MYC (MYC). MYC expression and pathway gene signatures were suppressed following drug treatment, and then rebounded during progression. Critically, MYC activation was necessary and sufficient for resistance, and suppression of MYC activity using genetic approaches or BET bromodomain inhibition was sufficient to resensitize cells and delay BRAFi resistance. Finally, MYC-driven, BRAFi-resistant cells are hypersensitive to the inhibition of MYC synthetic lethal partners, including SRC family and c-KIT tyrosine kinases, as well as glucose, glutamine, and serine metabolic pathways. These insights enable the design of combination therapies that select against resistance evolution.

Topics: Antineoplastic Agents, Hormonal; Benzimidazoles; Cell Line, Tumor; Estradiol; Evolution, Molecular; Female; Fulvestrant; Humans; Imidazoles; Indoles; Male; Melanoma; Oximes; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins c-myc; Pyridones; Pyrimidinones; Quinolines; Signal Transduction; Sulfonamides

The main objective of the study was to evaluate the efficacy and safety of dabrafenib alone or combined with trametinib for compassionate use in patients with metastatic melanoma.This retrospective, observational study involved 135 patients with unresectable stage IIIC or stage IV melanoma from an expanded-access program at 30 Spanish centers.Forty-eight patients received dabrafenib monotherapy and 87 received combination dabrafenib and trametinib; 4.4% and 95.6% of the patients had stage IIIC and IV melanoma, respectively. All patients showed BRAF mutations in their primary or metastatic lesions; 3 were positive for V600K while the remainder had V600E or V600+. A positive response to treatment was reported in 89.3% of the patients. Overall survival rates at 12 and 24 months were 59.6% (95% confidence interval [CI], 52.5-68.9%) and 36.4% (95% CI, 27.8-45%), respectively. Progression-free survival rates at 12 and 24 months were 39.3% (95% CI, 31.1-47.5%) and 21.6% (95% CI, 14.5-28.7%), respectively. Fifty-seven patients (42.2%) reported cutaneous toxicity of any type, mainly hyperkeratosis (14.8%) and rash (11.9%). The most frequent adverse events were pyrexia (27.4%), asthenia (19.3%), arthralgia (16.9%), and diarrhoea (13.2%).Our results suggest that both dabrafenib alone or in combination with trametinib are effective for compassionate use in terms of response and/or survival rates. However, differences in patients' prognostic features ought to be considered. No new findings were revealed regarding the safety profiles of either regimen. This is the first study to evaluate the efficacy of these 2 selective BRAF and mitogen-activated extracellular signal-regulated kinase inhibitors in a real-world setting in Spain.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Compassionate Use Trials; Female; Humans; Imidazoles; Male; Melanoma; Middle Aged; Neoplasm Metastasis; Oximes; Pyridones; Pyrimidinones; Retrospective Studies; Spain; Survival Analysis

Biomarkers have improved the clinical application of numerous targeted agents used to treat solid tumors. In melanoma, the finding that approximately 60% of tumor cells harbor specific Val600 mutations of BRAF has increased the likelihood of response to certain agents aimed at inhibiting the mutant kinase. While dabrafenib is an effective anti-tumor agent with acceptable tolerability in patients with BRAF-mutated melanoma, we report the development (and outcome) of a previously unpublished acute toxic reaction observed in a patient receiving the drug.

Topics: Acute Disease; Aged; Antineoplastic Combined Chemotherapy Protocols; Brain Diseases; Female; Humans; Imidazoles; Melanoma; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Drug Eruptions; Female; Humans; Imidazoles; Indoles; Keratoacanthoma; Keratoderma, Palmoplantar; Keratosis, Actinic; Keratosis, Seborrheic; Male; Melanoma; Middle Aged; Mitogen-Activated Protein Kinase Kinases; Oximes; Photosensitivity Disorders; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Sulfonamides; Vemurafenib

Metastatic melanoma is a highly aggressive skin cancer with a poor prognosis. It is the leading cause of skin cancer deaths with a median overall survival for advanced-stage metastatic disease of <6 months. Despite advances in the field with conventional and targeted therapies, the heterogeneity of melanoma poses the greatest ongoing challenge, ultimately leading to relapse and progression to a more drug-resistant tumor in most patients. Particularly noteworthy are recent findings, indicating that these therapies exert selective pressure on tumors resulting in the activation of pathways associated with cancer stem cells that are unresponsive to current therapy. Our previous studies have shown how Nodal, an embryonic morphogen of the transforming growth factor-beta superfamily, is one of these critical factors that is reactivated in aggressive melanoma and resistant to conventional chemotherapy, such as dacarbazine. In the current study, we sought to determine whether BRAF inhibitor (BRAFi) therapy targeted Nodal-expressing tumor cells in uniquely matched unresectable stage III and IV melanoma patient samples before and after therapy that preceded their eventual death due to disease. The results demonstrate that BRAFi treatment failed to affect Nodal levels in melanoma tissues. Accompanying experiments in soft agar and in nude mice showed the advantage of using combinatorial treatment with BRAFi plus anti-Nodal monoclonal antibody to suppress tumor growth and metastasis. These data provide a promising new approach using front-line therapy combined with targeting a cancer stem cell-associated molecule-producing a more efficacious response than monotherapy.

Topics: Animals; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Blotting, Western; Cell Line, Tumor; Female; Humans; Imidazoles; Immunohistochemistry; Lung Neoplasms; Melanoma; Mice, Nude; Molecular Targeted Therapy; Mutation; Nodal Protein; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Treatment Outcome; Xenograft Model Antitumor Assays

We present a 35-year-old woman with left axillary mass. Histopathological analysis revealed metastatic infiltration for BRAF-mutant melanoma. F-FDG PET/CT showed bilateral axillary lymphadenopathy as well as bone and subcutaneous metastases. Dabrafenib (a BRAF inhibitor) and trametinib (a MEK inhibitor) combined therapy was started with a complete metabolic response established by 2 consecutive PET/CT scans. A follow-up PET/CT showed FDG uptake in several subcutaneous nodules in both distal legs, suggesting metastases. Painless cutaneous lesions were observed on physical examination, and biopsy revealed erythema nodosum-like panniculitis.

Topics: Adult; Antineoplastic Agents; Erythema Nodosum; False Positive Reactions; Female; Fluorodeoxyglucose F18; Humans; Imidazoles; Melanoma; Oximes; Panniculitis; Positron Emission Tomography Computed Tomography; Pyridones; Pyrimidinones; Radiopharmaceuticals

The combination of dabrafenib and trametinib is a standard of care for the management of BRAF mutant metastatic melanoma. Clinical trials excluded patients with end-stage kidney disease (ESKD), and as such, no data are available regarding the safety, efficacy and pharmacokinetics of these drugs in such patients. Here, we present the case of a 78-yr-old male patient with ESKD managed with haemodialysis (HD), treated with dabrafenib and trametinib at reduced doses. The patient has had a partial response, and this response continues at 9 months since our last follow-up without any dose escalation. Treatment was complicated by the development of diarrhoea, attributed to trametinib, necessitating temporary cessation of trametinib. Pharmacokinetic profiling of dabrafenib was undertaken, and its metabolites were similar pre- and post-dialysis and comparable to those in patients with normal renal function. Moreover, HD did not lower the plasma concentration of dabrafenib or trametinib. It is feasible to administer dabrafenib, in combination with trametinib, to patients with ESKD undergoing HD.

Topics: Aged; Antineoplastic Agents; Humans; Imidazoles; Kidney Failure, Chronic; Male; Melanoma; Oximes; Pyridones; Pyrimidinones; Renal Dialysis; Tissue Distribution; Treatment Outcome

Topics: Drug Resistance; Erdheim-Chester Disease; Female; Humans; Imidazoles; Middle Aged; Mitogen-Activated Protein Kinase Kinases; Oximes; Point Mutation; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins p21(ras); Pyridones; Pyrimidinones

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; DNA Mutational Analysis; Female; Humans; Imidazoles; Lung Neoplasms; MAP Kinase Kinase Kinases; Middle Aged; Molecular Targeted Therapy; Mutation; Neoplasm Staging; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Remission Induction

Metastatic melanoma is an aggressive form of skin cancer with a high mortality rate and the fastest growing global incidence rate of all malignancies. The introduction of BRAF/MEK inhibitor combinations has yielded significant increases in PFS and OS for melanoma. However, at present, no direct comparisons between different BRAF/MEK combinations have been conducted. In light of this, an indirect treatment comparison was performed between two BRAF/MEK inhibitor combination therapies for metastatic melanoma, dabrafenib plus trametinib and vemurafenib plus cobimetinib, in order to understand the relative efficacy and toxicity profiles of these therapies.. A systematic literature search identified two randomized trials as suitable for indirect comparison: the coBRIM trial of vemurafenib plus cobimetinib versus vemurafenib and the COMBI-v trial of dabrafenib plus trametinib versus vemurafenib. The comparison followed the method of Bucher et al. and analyzed both efficacy (overall survival [OS], progression-free survival [PFS], and overall response rate [ORR]) and safety outcomes (adverse events [AEs]).. The indirect comparison revealed similar efficacy outcomes between both therapies, with no statistically significant difference between therapies for OS (hazard ratio [HR] 0.94, 95% confidence interval [CI] 0.68 - 1.30), PFS (HR 1.05, 95% CI 0.79 - 1.40), or ORR (risk ratio [RR] 0.90, 95% CI 0.74 - 1.10). Dabrafenib plus trametinib differed significantly from vemurafenib plus cobimetinib with regard to the incidence of treatment-related AE (RR 0.92, 95% CI 0.87 - 0.97), any AE grade ≥3 (RR 0.71, 95% CI 0.60 - 0.85) or dose interruption/modification (RR 0.77, 95% CI 0.60 - 0.99). Several categories of AEs occurred significantly more frequently with vemurafenib plus cobimetinib, while some occurred significantly more frequently with dabrafenib plus trametinib. For severe AEs (grade 3 or above), four occurred significantly more frequently with vemurafenib plus cobimetinib and no severe AE occurred significantly more frequently with dabrafenib plus trametinib.. This indirect treatment comparison suggested that dabrafenib plus trametinib had comparable efficacy to vemurafenib plus cobimetinib but was associated with reduced adverse events.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Azetidines; Female; Humans; Imidazoles; Indoles; Male; Melanoma; Middle Aged; Neoplasm Metastasis; Oximes; Piperidines; Pyridones; Pyrimidinones; Randomized Controlled Trials as Topic; Sulfonamides; Treatment Outcome; Vemurafenib; Young Adult

A phase I/II clinical trial suggests that dabrafenib shrinks or stabilizes low-grade gliomas in children with the BRAF V600E mutation. Objective, durable responses occurred in 38% of patients, and the side effects were less severe than with chemotherapy. The researchers have started a second trial for patients with glioma and other BRAF-mutant tumor types, this time evaluating dabrafenib combined with trametinib.

Topics: Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Child; Clinical Trials as Topic; Disease-Free Survival; Female; Glioma; Humans; Imidazoles; Male; Mutation; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Survival Analysis; Treatment Outcome

Studies focused on the killing of activated B-RAF melanoma cells by the histone deacetylase (HDAC) inhibitor AR42. Compared to other tumor cell lines, PDX melanoma isolates were significantly more sensitive to AR42-induced killing. AR42 and the multi-kinase inhibitor pazopanib interacted to activate: an eIF2α-Beclin1 pathway causing autophagosome formation; an eIF2α-DR4/DR5/CD95 pathway; and an eIF2α-dependent reduction in the expression of c-FLIP-s, MCL-1 and BCL-XL. AR42 did not alter basal chaperone activity but increased the ability of pazopanib to inhibit HSP90, HSP70 and GRP78. AR42 and pazopanib caused HSP90/HSP70 dissociation from RAF-1 and B-RAF that resulted in reduced 'RAF' expression. The drug combination activated a DNA-damage-ATM-AMPK pathway that was associated with: NFκB activation; reduced mTOR S2448 and ULK-1 S757 phosphorylation; and increased ULK-1 S317 and ATG13 S318 phosphorylation. Knock down of PERK, eIF2α, Beclin1, ATG5 or AMPKα, or expression of IκB S32A S36A, ca-mTOR or TRX, reduced cell killing. AR42, via lysosomal degradation, reduced the protein expression of HDACs 2/5/6/10/11. In vivo, a 3-day exposure of dabrafenib/trametinib resistant melanoma cells to the AR42 pazopanib combination reduced tumor growth and enhanced survival from ~25 to ~40 days. Tumor cells that had adapted through therapy exhibited elevated HGF expression and the c-MET inhibitor crizotinib enhanced AR42 pazopanib lethality in this evolved drug-resistant population.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Combined Chemotherapy Protocols; Autophagosomes; Blotting, Western; Cell Line, Tumor; Cell Survival; Drug Resistance, Neoplasm; Drug Synergism; Endoplasmic Reticulum Chaperone BiP; Eukaryotic Initiation Factor-2; Histone Deacetylase 6; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Imidazoles; Indazoles; Kaplan-Meier Estimate; Male; Melanoma; Mice, Nude; Microscopy, Fluorescence; Oximes; Phenylbutyrates; Pyridones; Pyrimidines; Pyrimidinones; RNA Interference; Signal Transduction; Sulfonamides; Xenograft Model Antitumor Assays

Many patients with histiocytic disorders such as Langerhans cell histiocytosis (LCH) or Erdheim-Chester disease (ECD) have treatment-refractory disease or suffer recurrences. Recent findings of gene mutations in histiocytoses have generated options for targeted therapies. We sought to determine the utility of prospective sequencing of select genes to further characterize mutations and identify targeted therapies for patients with histiocytoses. Biopsies of 72 patients with a variety of histiocytoses underwent comprehensive genomic profiling with targeted DNA and RNA sequencing. Fifteen patients (21%) carried the known

Topics: 3T3 Cells; Adult; Anaplastic Lymphoma Kinase; Animals; Drug Resistance, Neoplasm; Female; Histiocytosis; Humans; Imidazoles; Infant; Male; MAP Kinase Kinase 1; Mice; Mutation; Oximes; Prospective Studies; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Sequence Analysis, DNA; Sequence Analysis, RNA; Treatment Outcome; Young Adult

Topics: Adult; Antineoplastic Agents; Dermatitis, Allergic Contact; Female; Humans; Imidazoles; MAP Kinase Kinase 1; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Recurrence; Tattooing

Dabrafenib and trametinib, BRAF and MEK inhibitors, respectively, are effective targeted metastatic melanoma therapies, but little is known about their nephrotoxicity. Although tubulointerstitial injury has been the most widely reported renal side effect of targeted melanoma therapy, nephrotic syndrome has not been reported before. We report on a patient with metastatic melanoma who developed nephrotic syndrome during dabrafenib and trametinib treatment. Kidney biopsy showed diffuse loss of podocyte cytoarchitecture, extensive foot-process effacement, and glomerular endothelial injury. Kidney function and glomerular ultrastructural changes recovered fully after drug withdrawal. In vitro, BRAF inhibition decreased PLCε1 expression in podocytes, accompanied by a reduction in nephrin expression and an increase in permeability to albumin. Additionally, these drugs inhibited the podocyte-vascular endothelial growth factor (VEGF) system. In addition to implications for nephrotic syndrome pathophysiology, we suggest that patients given dabrafenib and trametinib be monitored closely for potential glomerular damage.

Topics: Aged; Antineoplastic Agents; Female; Humans; Imidazoles; Melanoma; Nephrotic Syndrome; Oximes; Podocytes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Signal Transduction; Skin Neoplasms

In unresectable or metastatic melanoma with a BRAF V600 mutation, combined BRAF/MEK targeted therapy improves clinical outcomes. Yet, disease progression because of acquired resistance occurs in the majority of patients. There is emerging evidence that resistance to BRAF-inhibitor-based targeted therapy can be reversible in some cases. We retrospectively analyzed four patients with BRAF-mutant stage IV cutaneous melanoma who were treated with dabrafenib plus trametinib and rechallenged with the same combination after previously experiencing progression. At initial treatment with dabrafenib plus trametinib, three patients achieved a partial response and one patient achieved a complete response. Progression-free survival varied from 9.9 to 24.3 (median 19.8) months. The targeted therapy-free interval ranged from 2.3 to 11.7 (median 8.8) months. At rechallenge, all four patients had a partial response, with progression-free survival ranging from 3.6 to 6.8 (median 5.2) months. Clinical benefit and a second radiological response can be obtained upon readministration of dabrafenib plus trametinib after previously acquiring resistance to this combination. A better understanding of the biological underpinnings of genomic and nongenomic mechanisms of resistance to BRAF-inhibitor-based targeted therapy is needed to identify patients who may benefit from this rechallenge approach.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Disease Progression; Disease-Free Survival; Female; Humans; Imidazoles; Male; Melanoma; Middle Aged; Oximes; Pyridones; Pyrimidinones; Response Evaluation Criteria in Solid Tumors; Retreatment; Retrospective Studies; Skin Neoplasms

Patients with BRAF. In this open-label, single arm, dual-centre, phase 2 academic study in Belgium, patients aged 18 years or older with BRAF. Between April 5, 2014, and Feb 2, 2016, 25 patients were enrolled and initiated treatment in our study. A partial response was documented in eight (32%) of 25 patients (95% CI 15-54; six patients had progressed on previous treatment with dabrafenib plus trametinib and two patients had progressed on previous BRAF inhibitor monotherapy). Stable disease was noted in ten patients (40%; 95% CI 21-61). Rechallenge with dabrafenib plus trametinib was well tolerated. There were no unexpected or grade 4 or 5 treatment-related adverse events. Grade 3 adverse events occurred in two patients (8%; panniculitis [n=1] and pyrexia [n=1]). Serious adverse events which occurred on study were one patient with an Addison crisis triggered by grade 2 pyrexia symptoms that resolved after discontinuation of dabrafenib and trametinib. No patients died as a result of study treatment.. Rechallenge with dabrafenib plus trametinib showed anti-tumour activity in patients who had previously progressed on BRAF inhibitors and as such, rechallenge represents a potential new treatment option for these patients.. Vlaamse Liga Tegen Kanker, Novartis.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Disease Progression; Female; Follow-Up Studies; Humans; Imidazoles; Lymphatic Metastasis; Male; MAP Kinase Kinase 1; Melanoma; Middle Aged; Mutation; Neoplasm Staging; Oximes; Prognosis; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Survival Rate

Topics: Adult; Antineoplastic Agents; Arrhythmias, Cardiac; Defibrillators, Implantable; Heart Neoplasms; Humans; Imidazoles; Male; Melanoma; Molecular Targeted Therapy; Oximes; Positron Emission Tomography Computed Tomography; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Skin Neoplasms

Topics: Aged; Antineoplastic Agents; Female; Humans; Imidazoles; Melanoma; Mutation; Neoplasm Metastasis; Oximes; Pyridones; Pyrimidinones

Vemurafenib is a newly licensed target-directed medication. It has been proven to improve the survival of patients with metastatic melanoma and the BRAF(V600E) mutation; however, adverse cutaneous reactions are frequent. Few cases of life-threatening severe cutaneous adverse reactions (SCARs) induced by vemurafenib have been reported. Dabrafenib, another selective BRAF inhibitor, has been licensed recently as an alternative drug with the same indications. From a molecular point of view, both vemurafenib and dabrafenib contain a sulfonamide group; cross-reactivity to sulfonamide compounds has been reported in allergic patients. We report on a patient with vemurafenib-induced toxic epidermal necrolysis (TEN). In vitro analysis of lymphocyte reactivity to vemurafenib showed positive results, confirming drug causality. In addition, lymphocytes from the patient reacted to dabrafenib and to the antibiotic sulfonamide drug sulfamethoxazole. Moreover, lymphocytes from two patients with cutaneous adverse reactions to sulfamethoxazole also reacted to vemurafenib and dabrafenib in vitro. These data strongly suggest that there might be clinical cross-reactivity between BRAF inhibitors and sulfonamides in some patients. Thus, precautions should be taken to avoid sulfonamide drugs as much as possible in patients showing serious hypersensitivity reactions to vemurafenib and vice versa.

Topics: Aged; Antineoplastic Agents; Drug Interactions; Drug Therapy, Combination; Humans; Imidazoles; Indoles; Male; Melanoma; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Stevens-Johnson Syndrome; Sulfonamides; Vemurafenib

We recently reported that BRAF V600E is the principal oncogenic driver of papillary craniopharyngioma, a highly morbid intracranial tumor commonly refractory to treatment. Here, we describe our treatment of a man age 39 years with multiply recurrent BRAF V600E craniopharyngioma using dabrafenib (150mg, orally twice daily) and trametinib (2mg, orally twice daily). After 35 days of treatment, tumor volume was reduced by 85%. Mutations that commonly mediate resistance to MAPK pathway inhibition were not detected in a post-treatment sample by whole exome sequencing. A blood-based BRAF V600E assay detected circulating BRAF V600E in the patient's blood. Re-evaluation of the existing management paradigms for craniopharyngioma is warranted, as patient morbidity might be reduced by noninvasive mutation testing and neoadjuvant-targeted treatment.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Craniopharyngioma; Craniotomy; Cytoreduction Surgical Procedures; Drug Administration Schedule; Glutamic Acid; Humans; Imidazoles; Magnetic Resonance Imaging; Male; Molecular Targeted Therapy; Mutation; Neoplasm Recurrence, Local; Neoplasm, Residual; Oximes; Pituitary Neoplasms; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Treatment Outcome; Valine

Selective BRAF inhibitors (BRAFi) yield objective responses in 50% of patients with metastatic BRAF V600E mutant melanoma. Adding an MEK inhibitor increases this response rate to 70%. Limited data are available on the outcomes of unresectable stage III patients, and it remains unclear whether BRAF-targeted therapy can be utilized as a neoadjuvant strategy. Data on patients with advanced locoregional BRAF V600E mutant melanoma treated with BRAF-targeted therapy at Moffitt Cancer Center were analyzed to determine response rates, subsequent resection rates after tumor downsizing, pathologic responses, and patient survival. Fifteen patients with locoregional disease treated with BRAF-targeted therapy, either BRAFi alone (vemurafenib; 11 patients) or a combination of BRAFi and an MEK inhibitor (dabrafenib plus trametinib or placebo; four patients), were identified. The median age was 50 years; the median follow-up was 25.4 months. The median BRAF-targeted therapy treatment duration was 6.0 months (range 1.2-29.4 months). Response Evaluation Criteria In Solid Tumors-based evaluation demonstrated objective response in 11 patients (73.3%). Six patients underwent resection of the remaining disease after therapy. Pathological analysis showed complete pathologic response (n=2), partial pathologic response (n=2), or no pathologic response (n=2). Four of six patients undergoing surgery have been alive for more than 2 years, including three patients currently free from active disease. No complications attributable to BRAF-targeted therapy were observed in the perioperative period. Dose reduction or discontinuation because of toxicities occurred in 10/15 patients. Neoadjuvant BRAF-targeted therapy may be effective in advanced locoregional BRAF V600E mutant melanoma patients in increasing resectability, yielding pathological responses, and achieving prolonged survival.

Topics: Amino Acid Substitution; Antineoplastic Combined Chemotherapy Protocols; Disease Progression; Female; Follow-Up Studies; Glutamic Acid; Humans; Imidazoles; Indoles; Male; Melanoma; Middle Aged; Molecular Targeted Therapy; Mutation, Missense; Neoadjuvant Therapy; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Retrospective Studies; Skin Neoplasms; Sulfonamides; Treatment Outcome; Valine; Vemurafenib

The purpose of this study is to report our institutional experience using radiotherapy in the treatment of ameloblastoma and ameloblastic carcinoma. Three patients with ameloblastoma and 3 patients with ameloblastic carcinoma were treated with radiotherapy alone (2 patients) or surgery and postoperative radiotherapy (4 patients) at the University of Florida between 1973 and 2007. Follow-up ranged from 4.0 to 13.1 years with a median of 7.8 years. Radiotherapy complications were scored using the Common Terminology Criteria for Adverse Events, version 4.0. Local control was achieved in 4 of the 6 patients. One patient treated with RT alone for an unresectable ameloblastoma developed a local recurrence and metastases in both the cervical lymph nodes and lungs, but had excellent response to dual BRAF/MEK inhibition with dabrafenib and trametinib. Another patient treated with surgery and postoperative radiotherapy for an ameloblastic carcinoma recurred locally without metastasis, but was not salvaged. No significant treatment-related complications were observed. For patients with local recurrence or inadequate margins after surgery, adjuvant radiotherapy provides the potential for disease control. In the setting of metastatic disease, targeted therapies may provide an additional opportunity for salvage.

Topics: Adult; Aged; Ameloblastoma; Antineoplastic Agents; Carcinoma, Squamous Cell; Combined Modality Therapy; Female; Head and Neck Neoplasms; Humans; Imidazoles; Long Term Adverse Effects; Male; Middle Aged; Neck Dissection; Neoplasm Recurrence, Local; Outcome and Process Assessment, Health Care; Oximes; Pyridones; Pyrimidinones; Radiotherapy, Adjuvant

The combined use of the BRAF inhibitor dabrafenib and MEK inhibitor trametinib has been found to improve survival over dabrafenib alone. The management of melanoma brain metastases continues to present challenges. In this study, we report our initial experience in the management of melanoma brain metastases with stereotactic radiosurgery (SRS) with the use of BRAF and MEK inhibitors. We identified six patients treated with SRS for 17 brain metastases within 3 months of BRAF and MEK inhibitor administration. The median planning target volume was 0.42 cm (range: 0.078-2.08 cm). The median treatment dose was 21 Gy (range 18-24 Gy). The median follow-up of all lesions from SRS was 10.6 months (range 5.8-28.5 months). One lesion was found to undergo local failure 21.7 months following SRS treatment. The median overall survival was 20.0 months (range 6.1-31.8 months) from the time of SRS treatment and 23.1 months (range: 12.1-30.9 months) from the date of BRAFi and MEKi administration. There was no evidence of increased nor unexpected toxicity with the two modalities combined. In this initial experience of melanoma brain metastases treated with BRAF and MEK inhibition with SRS, we find the two modalities can be combined safely. These outcomes should be assessed further in prospective evaluations.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Chemoradiotherapy; Female; Humans; Imidazoles; Male; MAP Kinase Kinase 1; Melanoma; Middle Aged; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Radiosurgery; Skin Neoplasms

Dabrafenib (Tafinlar(®)) and trametinib (Mekinist(®)) are registered for the treatment of patients with BRAF V600 mutation positive unresectable or metastatic melanoma. To support therapeutic drug monitoring (TDM) and clinical pharmacological trials, an assay to simultaneously quantify dabrafenib and trametinib in human plasma using liquid chromatography tandem mass spectrometry was developed and validated. Human plasma samples were collected on an outpatient base and stored at nominally -20°C. Analytes and internal standards (stable isotope labeled compounds) were extracted with TBME. After snap freezing the samples in a dry ice-ethanol bath, the organic layer was transferred to a clean tube and evaporated under a gentle stream of nitrogen gas. The dry extract was then reconstituted with 100μL acetonitrile and 5μL of the final extract was injected and separated on a C18 column with gradient elution, and analyzed with triple quadrupole mass spectrometry in positive-ion mode. The validated assay ranges from 50 to 5000ng/mL for dabrafenib and 0.5-50ng/mL for trametinib were linear, and correlation coefficient (r(2)) of 0.996 or better. At all concentrations of both analytes the biases were within ±15% of the nominal concentrations and precisions were ≤15%. All results were within the acceptance criteria of the latest US FDA guidance and EMA guidelines on method validation. Dabrafenib was found to degrade under the influence of light in different organic solvents and at least seven degradation products were detected. In conclusion, the described method to simultaneously quantify dabrafenib and trametinib in human plasma was successfully validated and applied for therapeutic drug monitoring in cancer patients treated with dabrafenib and trametinib.

Topics: Calibration; Chromatography, High Pressure Liquid; Humans; Imidazoles; Limit of Detection; Oximes; Pyridones; Pyrimidinones; Reproducibility of Results; Tandem Mass Spectrometry

Metastatic malignant melanoma belongs to a group of cancers with high mortality. In recent years, advances in our knowledge of the pathogenesis of melanoma and the discovery of new drugs has resulted in significant progress in the treatment of metastatic malignant melanoma patients. The development of resistance to these drugs, however, remains a challenge. One way how to avoid resistance, or at least delay it, is to administer combination therapy.. This case study demonstrates that combination therapy with a BRAF and a MEK inhibitor can be used to successfully treat metastatic malignant melanoma patients and suggests they should be employed in therapeutic algorithms for patients with metastatic malignant melanoma and BRAF gene mutations.

Topics: Antineoplastic Combined Chemotherapy Protocols; Humans; Imidazoles; Melanoma; Mitogen-Activated Protein Kinase Kinases; Neoplasm Metastasis; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

BRAF V600 mutant circulating cell-free tumor DNA (BRAF V600mut ctDNA) could serve as a specific biomarker in patients with BRAF V600 mutant melanoma. We analyzed the value of BRAF V600mut ctDNA from plasma as a monitoring tool for advanced melanoma patients treated with BRAF/MEK inhibitors.. Allele-specific quantitative PCR analysis for BRAF V600 E/E2/D/K/R/M mutations was performed on DNA extracted from plasma of patients with known BRAF V600 mutant melanoma who were treated with dabrafenib and trametinib.. 245 plasma samples from 36 patients were analyzed. In 16 patients the first plasma sample was obtained before the first dosing of dabrafenib/trametinib. At baseline, BRAF V600mut ctDNA was detected in 75 % of patients (n = 12/16). BRAF V600mut ctDNA decreased rapidly upon initiation of targeted therapy (p < 0.001) and became undetectable in 60 % of patients (n = 7/12) after 6 weeks of treatment. During treatment, disease progression (PD) was diagnosed in 27 of 36 patients. An increase of the BRAF V600mut ctDNA copy number and fraction, identified PD with a sensitivity of 70 % (n = 19/27) and a specificity of 100 %. An increase in the BRAF V600mut ctDNA fraction was detected prior to clinical PD in 44 % of cases (n = 12/27) and simultaneously with PD in 26 % of patients (n = 7/27).. Quantitative analysis of BRAF V600mut ctDNA in plasma has unique features as a monitoring tool during treatment with BRAF/MEK inhibitors. Its potential as an early predictor of acquired resistance deserves further evaluation.

Topics: Cell-Free System; Disease Progression; DNA, Neoplasm; Drug Monitoring; Female; Humans; Imidazoles; Kaplan-Meier Estimate; Male; Melanoma; Middle Aged; Mutation; Neoplastic Cells, Circulating; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

Results from a phase II trial show that the BRAF inhibitor dabrafenib has significant single-agent activity in patients with advanced non-small cell lung cancer harboring the BRAF V600E mutation. However, data from another arm of the study suggest that combining dabrafenib with a MEK inhibitor may be a more effective treatment strategy for these patients.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Clinical Trials, Phase II as Topic; Disease-Free Survival; Humans; Imidazoles; Lung Neoplasms; Mutation; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Treatment Outcome

Novel systemic therapies with anti-tumor activity in the brain including small molecules targeting BRAF and MEK, and immune checkpoint inhibition, offer the possibility of improved control of intracranial disease. A number of prospective trials support the judicious use of modern systemic therapies in patients with melanoma and limited brain metastases .The intracranial clinical course of patients who progress extracranially on BRAF/MEK inhibition remains poorly described in the literature. In this report, we highlight a series of clinical cases, with rapid progression of intracranial disease following discontinuation of dabrafenib/trametinib for extracranial disease progression or toxicity, a previously unreported finding in the medical literature with significant implications for patient care.

Topics: Adult; Brain Neoplasms; Humans; Imidazoles; Magnetic Resonance Imaging; Male; MAP Kinase Kinase Kinases; Melanoma; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

Approximately 50% of metastatic melanoma patients harbor BRAF mutations. Several treatment options including the combination of BRAF and MEK inhibitors (BRAF/MEKi) and immunotherapy (mainly anti CTLA-4 and anti PD-1 antibodies), have been shown to improve survival in these patients. Although preclinical data support the synergistic effect of both modalities in combination, data confirming the activity and tolerability of these combinations are not yet available in the clinical setting. Herein, we report the case of a melanoma patient treated with sequential BRAF/MEKi (dabrafenib plus trametinib) followed by the anti CTLA-4 antibody ipilimumab who achieved a pathological complete response. Unfortunately, the patient died due to fatal gastrointestinal (GI) toxicity. Analysis of the BRAFV600E mutation in circulating tumoral DNA (ctDNA) from peripheral blood samples and serial tumor tissue biopsies throughout treatment demonstrated a good correlation with clinical evolution.

Topics: Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Biopsy; Bone Neoplasms; DNA, Neoplasm; Fatal Outcome; Gastrointestinal Tract; Humans; Imidazoles; Ipilimumab; Male; MAP Kinase Kinase Kinases; Melanoma; Middle Aged; Mutation; Neoplastic Cells, Circulating; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Treatment Outcome

Combination therapy with dabrafenib and trametinib is safer and more effective than BRAF inhibitor-based monotherapy for metastatic melanoma.. We retrospectively analyzed BRAF-mutated metastatic melanoma patients treated at our institution with daily oral dabrafenib 300 mg and trametinib 2 mg from November 2013 to April 2016. This clinical record included both untreated and previously treated stage IV melanomas. Physical examination and laboratory examinations were performed monthly and disease re-evaluations were performed every 3 months.. A total of 48 patients (24 male, 24 female) with BRAF-mutated metastatic melanoma received dabrafenib and trametinib; median age was 48 years (range 23-75). Median follow-up was 362.5 days (range 72-879). Best overall response rate consisted of 6.2% (3 patients) complete response, 64.6% (31) partial response, and 25% (12) stable disease; median time to best response was 11 weeks (range 5.7-125.5). Progression of disease was seen in 19 patients (39.6%), with median time to progression (TTP) of 26 weeks (range 8-54). A total of 15 patients (31.2%) died due to progression of disease. Median progression-free survival and median overall survival were not reached. To date, 30 patients (62.5%) are still under treatment. A total of 27 (56.2%) patients had at least one adverse event (AE); grade 3-4 AEs were seen in 4 cases (8.3%). The main toxicities were fever (25%), skin rash (14.6%), arthralgias (10.4%), and aspartate aminotransferase/alanine aminotransferase increase (8.3%). Treatment dose was reduced in 7 subjects (14.6%), with only one case of discontinuation due to AE.. Our data, using combined targeted therapy, are in line with the scientific literature in terms of both safety and effectiveness in a real-life setting.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Female; Follow-Up Studies; Humans; Imidazoles; Male; Melanoma; Middle Aged; Molecular Targeted Therapy; Mutation; Neoplasm Metastasis; Neoplasm Staging; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Retrospective Studies; Treatment Outcome; Young Adult

The standard management of a single brain metastasis is usually maximal resection when feasible followed by radiotherapy. In case of multiple lesions, several options have to be considered depending on the natural behavior of the primary tumor, the localization of brain lesions, their functional impact and related symptoms. In case of life-threatening brain metastasis, debulking surgery is often proposed first, with the risk of major bleeding and postponing the initiation of other treatments. This approach is now challenged by the rapid tumor shrinkage that could be observed with novel targeted therapies. Here we report the case of a patient suffering from a melanoma with multiple brain metastasis, treated with BRAF and MEK double blockade, with impressive and rapid response.

Topics: Brain; Brain Neoplasms; Humans; Imidazoles; Lymph Node Excision; Lymph Nodes; Magnetic Resonance Imaging; Melanoma; Middle Aged; Mutation; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

Topics: Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Dermoscopy; Disease Progression; Drug Substitution; Epidermis; Fibrosis; Humans; Imidazoles; Indoles; Male; Melanoma; Melanoma, Cutaneous Malignant; Melanosis; Mutation, Missense; Neoplasm Proteins; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Remission Induction; Skin Neoplasms; Substrate Specificity; Sulfonamides; Vemurafenib

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Immunological; Azetidines; Chemotherapy, Adjuvant; Drug Discovery; Drug Therapy, Combination; Humans; Imidazoles; Indoles; Ipilimumab; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Melanoma; Molecular Targeted Therapy; Neoplasm Metastasis; Nivolumab; Oximes; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Sulfonamides; Vemurafenib

Anaplastic thyroid cancer (ATC) is a rare malignancy that progresses extremely aggressively and often results in dismal prognosis. We investigated the efficacy of inhibiting the activated RAS/RAF/MEK pathway in ATC cells aiming to clarify the mechanism of effect and resistance. Four human ATC cell lines (ACT-1, OCUT-2, OCUT-4 and OCUT-6) were used. OCUT-4 had a BRAF mutation. OCUT-2 had both BRAF and PI3KCA mutations. ACT-1 and OCUT-6 had wild-type BRAF and NRAS mutations. The effects of dabrafenib, a selective inhibitor of the BRAFV600E kinase, and trametinib, a reversible inhibitor of MEK activity, were investigated. Dabrafenib strongly inhibited the viability in BRAF mutated cells by demonstrating G0/G1-arrest via the downregulation of MEK/ERK phosphorylation. Upregulated phosphorylation of MEK was observed in RAS mutated cells after dabrafenib treatment and caused VEGF upregulation, but was not related to the cellular proliferation. Trametinib inhibited the cellular viability to variable degrees in every cell by downregulating ERK phosphorylation. Dual blockade by both inhibitors demonstrated clear cytostatic effect in all the cells. OCUT-4 showed the weakest sensitivity to trametinib, no additional effect of either inhibitor in combination with the other, and an increase of SNAI1 mRNA expression after treatment with inhibitors, suggesting a mechanism for resistance. Our findings demonstrated the efficacy of a mutation-selective BRAF inhibitor and a MEK inhibitor in human ATC cells in a genetic alteration-specific manner.

Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Survival; G1 Phase Cell Cycle Checkpoints; GTP Phosphohydrolases; Humans; Imidazoles; MAP Kinase Kinase 1; Membrane Proteins; Nuclear Proteins; Oximes; Phosphorylation; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; RNA, Messenger; Snail Family Transcription Factors; Thyroid Carcinoma, Anaplastic; Transcription Factors; Vascular Endothelial Growth Factor A

Findings from a phase I/II study indicate a higher response rate among patients with BRAF-mutant metastatic colorectal cancer treated with an EGFR inhibitor alongside dual, as opposed to single-level, MAPK blockade. Panitumumab combined with trametinib and dabrafenib only modestly increased median progression-free survival, however; a short-lived decrease in responders' BRAF V600E mutant allele fraction and the emergence of RAS mutations may have been contributing factors.

Topics: Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Disease-Free Survival; Humans; Imidazoles; MAP Kinase Signaling System; Mutation; Oximes; Panitumumab; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Treatment Outcome

Dabrafenib plus trametinib treatment provides significant benefits over BRAF-inhibitor monotherapy in patients with BRAF. We did a retrospective individual data analysis based on all published randomised trials that included treatment-naive patients with BRAF. 617 patients were included in this analysis with a median follow-up of 20·0 months (range 0-48·0, IQR 10·1-24·8); 396 patients had progression events (ie, disease progression or death) and 290 patients had died. Median progression-free survival (11·1 months [95% CI 9·7-12·9]), median overall survival (25·6 months [23·1-34·3]), 1-year progression-free survival (48% [44-52]) and overall survival (74% [71-78]), and 2-year progression-free survival (30% [26-34]) and overall survival (53% [49-57]) were consistent with those in the individual trials. Patients with normal lactate dehydrogenase (LDH) concentration and fewer than three organ sites containing metastases (n=237) had the longest 1-year progression-free survival (68% [95% CI 62-74]) and overall survival (90% [87-94]) and 2-year progression-free survival (46% [40-54]) and overall survival (75% [70-81]), whereas patients with LDH concentration at least two times the upper limit of normal (n=70) had the shortest 1-year progression-free survival (8% [3-19]) and overall survival (40% [29-55]) and 2-year progression-free survival (2% [0-13]) and overall survival (7% [3-19]). Of patients with disease progression (n=379), survival after progression was longest in those with progression in baseline or new non-CNS lesions (n=205; median 10·0 months [95% CI 7·9-12·0]) and shortest in those with new CNS lesions or concurrent progression in baseline and new lesions (n=171; median 4·0 months [3·5-4·9]).. Several patient and clinical characteristics at and after baseline are associated with outcomes with dabrafenib plus trametinib, and durable benefit is possible with targeted treatment in defined patient subsets.. Novartis.

Topics: Antineoplastic Combined Chemotherapy Protocols; Disease Progression; Female; Humans; Imidazoles; Male; Melanoma; Mutation; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Randomized Controlled Trials as Topic; Retrospective Studies

BRAF mutations occur commonly in metastatic melanomas and inhibition of mutant BRAF and the downstream kinase MEK results in rapid tumor regression and prolonged survival in patients. Combined therapy with BRAF and MEK inhibition improves response rate, progression free survival and overall survival compared with single agent BRAF inhibition, and reduces the skin toxicity that is seen with BRAF inhibitor monotherapy. However, this combination is associated with an increase in other toxicities, particularly drug-related pyrexia, which affects approximately 50% of patients treated with dabrafenib and trametinib (CombiDT). We provide guidance on managing adverse events likely to arise during treatment with combination BRAF and MEK inhibition with CombiDT: pyrexia, skin conditions, fatigue; and discuss management of CombiDT during surgery and radiotherapy. By improving tolerability and in particular preventing unnecessary treatment cessations or reduction in drug exposure, best outcomes can be achieved for patients undergoing CombiDT therapy.

Topics: Antineoplastic Combined Chemotherapy Protocols; Australia; Drug Eruptions; Exanthema; Fever; Humans; Imidazoles; MAP Kinase Kinase Kinases; Medical Oncology; Melanoma; Melanoma, Cutaneous Malignant; Mutation; Oximes; Practice Guidelines as Topic; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms

Although activating BRAF/NRAS mutations are frequently seen in melanomas, they are not sufficient to drive malignant transformation and require additional events. Frequent co-occurrence of mutations in the promoter for telomerase reverse transcriptase (TERT), along with BRAF alterations, has recently been noted and correlated with poorer prognosis, implicating a functional link between BRAF signaling and telomerase reactivation in melanomas. Here, we report that RAS-ERK signaling in BRAF mutant melanomas is critical for regulating active chromatin state and recruitment of RNA polymerase II at mutant TERT promoters. Our study provides evidence that the mutant TERT promoter is a key substrate downstream of the RAS-ERK pathway. Reactivating TERT and hence reconstituting telomerase is an important step in melanoma progression from nonmalignant nevi with BRAF mutations. Hence, combined targeting of RAS-ERK and TERT promoter remodeling is a promising avenue to limit long-term survival of a majority of melanomas that harbor these two mutations.

Topics: Cell Line, Tumor; Disease Progression; Humans; Imidazoles; MAP Kinase Signaling System; Melanoma; Models, Biological; Mutation; Oximes; Promoter Regions, Genetic; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; ras Proteins; RNA Polymerase II; Skin Neoplasms; Telomerase

With the emergence of new oral therapies for metastatic melanoma to the market, as well as ongoing pre-marketing trials and special access schemes, it is important to keep up to date with the side effect profiles of these medications. A common side effect associated with the BRAF inhibitor dabrafenib is severe fever symptoms such as pyrexia and rigors/chills; however, treatment options are limited. We report a patient who was debilitated by severe pyrexia and rigors caused by dabrafenib used in combination with trametinib to treat metastatic melanoma, who was treated with low-dose steroids. To our knowledge, the use of prednisolone for the treatment and prevention of further dabrafenib-associated pyrexia is not published; however, it is a low risk and low cost option that was very effective in this case.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Cefepime; Cephalosporins; Drug Delivery Systems; Female; Fever; Humans; Imidazoles; Melanoma; Oximes; Pyridones; Pyrimidinones; Severity of Illness Index

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Biopsy; DNA Mutational Analysis; Humans; Imidazoles; Immunohistochemistry; Male; MAP Kinase Kinase Kinases; Melanoma; Middle Aged; Molecular Targeted Therapy; Mutation; Oximes; Pancreatic Neoplasms; Positron-Emission Tomography; Predictive Value of Tests; Protein Kinase Inhibitors; Proto-Oncogene Proteins; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins p21(ras); Pyridones; Pyrimidinones; ras Proteins; Risk Factors; Skin Neoplasms; Time Factors; Tomography, X-Ray Computed; Treatment Outcome

The management of metastatic melanoma has changed significantly in the past decade with the development of immunotherapies and targeted molecular therapies. Trials of targeted therapies have focused mainly on patients with the most common BRAF V600 mutations, namely V600E/K substitutions, with very little information available on the benefit of targeted therapies on less commonly occurring mutations such as V600R/D and M.. We present a 54-year-old man with metastatic melanoma harbouring a rare BRAF V600M mutation, who experienced clinical and radiological response to combined therapy with the BRAF inhibitor dabrafenib and MEK inhibitor trametinib.. As our understanding of these therapies evolves and an increasing number of patients have mutational testing performed, there is a clear imperative--as highlighted by this case--to test for rarer mutations and facilitate their inclusion both in everyday practice and in future clinical trials.

Topics: Abdominal Neoplasms; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Humans; Imidazoles; Intestinal Neoplasms; Lymphatic Metastasis; Male; Melanoma; Middle Aged; Molecular Targeted Therapy; Mutation; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Treatment Outcome

Cancer immunotherapy has long been used in the treatment of metastatic melanoma, and an anti-CTLA-4 monoclonal antibody treatment has recently been approved by the US Food and Drug Administration. Targeted therapies such as small molecule kinase inhibitors targeting deregulated mitogen-activated protein kinase (MAPK) signaling have markedly improved melanoma control in up to 50% of metastatic disease patients and have likewise been recently approved. Combination therapies for melanoma have been proposed as a way to exploit the high-level but short-term responses associated with kinase inhibitor therapies and the low-level but longer-term responses associated with immunotherapy. Cancer immunotherapy now includes adoptive transfer of autologous tumor-specific chimeric antigen receptor (CAR) T cells and this mode of therapy is a candidate for combination with small molecule drugs. This paper describes CART cells that target GD2-expressing melanoma cells and investigates the effects of approved MAPK pathway-targeted therapies for melanoma [vemurafenib (Vem), dabrafenib (Dab), and trametinib (Tram)] on the viability, activation, proliferation, and cytotoxic T lymphocyte activity of these CAR T cells, as well as on normal peripheral blood mononuclear cells. We report that, although all these drugs lead to inhibition of stimulated T cells at high concentrations in vitro, only Vem inhibited T cells at concentrations equivalent to reported plasma concentrations in treated patients. Although the combination of Dab and Tram also resulted in inhibition of T-cell effector functions at some therapeutic concentrations, Dab itself had little adverse effect on CAR T-cell function. These findings may have implications for novel therapeutic combinations of adoptive CAR T-cell immunotherapy and MAPK pathway inhibitors.

Topics: Antineoplastic Agents; Cell Line; Cell Survival; Flow Cytometry; Humans; Imidazoles; Immunotherapy; In Vitro Techniques; Indoles; Leukocytes, Mononuclear; Lymphocyte Activation; MAP Kinase Signaling System; Melanoma; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Receptors, Antigen, T-Cell; Sulfonamides; T-Lymphocytes, Cytotoxic; Transfection; Vemurafenib

Topics: Adult; Ameloblastoma; Antineoplastic Combined Chemotherapy Protocols; Black or African American; Compassionate Use Trials; Glutamic Acid; Humans; Imidazoles; Lung Neoplasms; Male; Mandibular Neoplasms; Molecular Targeted Therapy; Mutation; Neoplasm Recurrence, Local; Neoplasm Staging; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Radiography; Treatment Outcome; Valine

To assess the immunologic effects of dabrafenib and trametinib in vitro and to test whether trametinib potentiates or antagonizes the activity of immunomodulatory antibodies in vivo.. Immune effects of dabrafenib and trametinib were evaluated in human CD4(+) and CD8(+) T cells from healthy volunteers, a panel of human tumor cell lines, and in vivo using a CT26 mouse model.. Dabrafenib enhanced pERK expression levels and did not suppress human CD4(+) or CD8(+) T-cell function. Trametinib reduced pERK levels, and resulted in partial/transient inhibition of T-cell proliferation/expression of a cytokine and immunomodulatory gene subset, which is context dependent. Trametinib effects were partially offset by adding dabrafenib. Dabrafenib and trametinib in BRAF V600E/K, and trametinib in BRAF wild-type tumor cells induced apoptosis markers, upregulated HLA molecule expression, and downregulated certain immunosuppressive factors such as PD-L1, IL1, IL8, NT5E, and VEGFA. PD-L1 expression in tumor cells was upregulated after acquiring resistance to BRAF inhibition in vitro. Combinations of trametinib with immunomodulators targeting PD-1, PD-L1, or CTLA-4 in a CT26 model were more efficacious than any single agent. The combination of trametinib with anti-PD-1 increased tumor-infiltrating CD8(+) T cells in CT26 tumors. Concurrent or phased sequential treatment, defined as trametinib lead-in followed by trametinib plus anti-PD-1 antibody, demonstrated superior efficacy compared with anti-PD-1 antibody followed by anti-PD-1 plus trametinib.. These findings support the potential for synergy between targeted therapies dabrafenib and trametinib and immunomodulatory antibodies. Clinical exploration of such combination regimens is under way.

Topics: Animals; Antineoplastic Agents; B7-H1 Antigen; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cell Line, Tumor; Cell Proliferation; CTLA-4 Antigen; Drug Synergism; Female; Humans; Imidazoles; Immunologic Factors; MAP Kinase Kinase Kinases; Mice; Mice, Inbred BALB C; Oximes; Programmed Cell Death 1 Receptor; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Xenograft Model Antitumor Assays

To evaluate the expression of tumor PD-L1 and changes in tumor-infiltrating lymphocyte (TIL) populations in patients with metastatic melanoma treated with targeted MAPK inhibitors.. Ninety-three tumors were analyzed from 40 patients treated with a BRAF inhibitor alone (BRAFi; n = 28) or combination of BRAF and MEK inhibitors (Combi; n = 12). Tumors were excised before treatment (PRE), early during treatment (EDT), and at progression (PROG). Immunohistochemical staining was performed for CD4, CD8, CD68, FOXP3, LAG3, PD-1, and PD-L1 and correlated with clinical outcome.. Patients' tumors that were PD-L1 positive at baseline showed a significant decrease in PD-L1 expression at PROG (P = 0.028), whereas patients' tumors that were PD-L1 negative at baseline showed a significant increase in PD-L1 expression at PROG (P = 0.008) irrespective of treatment with BRAFi or Combi. Overall PD-L1 expression highly correlated with TIL immune markers. BRAFi-treated patients showed significant increases in CD4(+), CD8(+), and PD-1(+) lymphocytes from PRE to EDT (P = 0.001, P = 0.001, P = 0.017, respectively), and Combi-treated patients showed similar increases in CD4(+) and CD8(+) lymphocytes from PRE to EDT (P = 0.017, P = 0.021).. The addition of MEKi to BRAFi did not result in significant reduction in immune infiltration in EDT biopsies. This provides support for conducting trials that combine MAPKi with immune checkpoint inhibitors in the hope of improving complete and durable response rates. PD-L1 expression at PROG on MAPK inhibitors varied according to baseline expression suggesting that combining MAPKi with immunotherapies concurrently may be more effective in patients with PD-L1 expression and TILs in baseline melanoma samples.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; B7-H1 Antigen; Female; Humans; Imidazoles; Immunohistochemistry; Indoles; Kaplan-Meier Estimate; Lymphocytes, Tumor-Infiltrating; Male; MAP Kinase Kinase Kinases; Melanoma; Middle Aged; Oximes; Proportional Hazards Models; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Sulfonamides; Vemurafenib; Young Adult

The treatment of locally advanced metastasized melanoma is challenging because there is no level 1 evidence to guide clinical decision-making. Moreover, the treatment options available fail to improve overall survival and are associated with considerable morbidity. Here, we show that systemic treatment with BRAF inhibitor vemurafenib substituted by dual BRAF/MEK inhibition (dabrafenib and trametinib) before surgery can offer the potential to cure the initially difficult or inoperable melanoma. A 62-year-old woman was diagnosed with an AJCC stage IIIB melanoma harboring the BRAF V600E mutation after a complete initial evaluation. Clinically, the patient presented a large primary lesion that was surrounded by ∼25 secondary epidermotropic lesions both satellite and 'in transit' with a diameter between 1 and 6 mm. Following multidisciplinary consultation, the patient was started on 960 mg twice-daily vemurafenib, which was stopped and resumed at 720 mg twice daily, and finally substituted with the combination dabrafenib and trametinib to reduce the persistent side effects. Successive clinical examinations had shown a progressive reduction in the thickness of the melanoma lesions. After about 5 months of therapy, surgery was performed and the histopathological analysis showed an almost complete regression of tumor cells. The treatment with dabrafenib/trametinib was continued only 3 months after surgery and stopped at the patient's request. The patient currently remains in complete remission at 8 months after surgery. The case presented here supports the use of neoadjuvant treatment with BRAF inhibitors in advanced 'in transit' melanoma.

Topics: Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Drug Substitution; Female; Genetic Predisposition to Disease; Humans; Imidazoles; Indoles; Melanoma; Middle Aged; Molecular Targeted Therapy; Mutation; Neoadjuvant Therapy; Oximes; Phenotype; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Sulfonamides; Time Factors; Treatment Outcome; Vemurafenib

In this issue of Blood, Pettirossi et al, including Drs Tiacci and Falini, who led the effort in 2011 defining the BRAF-V600E driving mutation in hairy cell leukemia (HCL),provide extensive laboratory studies showing that inhibitors of BRAF-V600E and/or mitogen-activated protein kinase kinase (MEK) reach their targets and cause HCL cell death

Topics: Antineoplastic Agents; Humans; Imidazoles; Indoles; Leukemia, Hairy Cell; Oximes; Pyridones; Pyrimidinones; Sulfonamides; Transcriptome; Vemurafenib

Combining immunotherapy and BRAF targeted therapy may result in improved antitumor activity with the high response rates of targeted therapy and the durability of responses with immunotherapy. However, the first clinical trial testing the combination of the BRAF inhibitor vemurafenib and the CTLA4 antibody ipilimumab was terminated early because of substantial liver toxicities. MEK [MAPK (mitogen-activated protein kinase) kinase] inhibitors can potentiate the MAPK inhibition in BRAF mutant cells while potentially alleviating the unwanted paradoxical MAPK activation in BRAF wild-type cells that lead to side effects when using BRAF inhibitors alone. However, there is the concern of MEK inhibitors being detrimental to T cell functionality. Using a mouse model of syngeneic BRAF(V600E)-driven melanoma, SM1, we tested whether addition of the MEK inhibitor trametinib would enhance the antitumor activity of combined immunotherapy with the BRAF inhibitor dabrafenib. Combination of dabrafenib and trametinib with pmel-1 adoptive cell transfer (ACT) showed complete tumor regression, increased T cell infiltration into tumors, and improved in vivo cytotoxicity. Single-agent dabrafenib increased tumor-associated macrophages and T regulatory cells (Tregs) in tumors, which decreased with the addition of trametinib. The triple combination therapy resulted in increased melanosomal antigen and major histocompatibility complex (MHC) expression and global immune-related gene up-regulation. Given the up-regulation of PD-L1 seen with dabrafenib and/or trametinib combined with antigen-specific ACT, we tested the combination of dabrafenib, trametinib, and anti-PD1 therapy in SM1 tumors, and observed superior antitumor effect. Our findings support the testing of triple combination therapy of BRAF and MEK inhibitors with immunotherapy in patients with BRAF(V600E) mutant metastatic melanoma.

Topics: Animals; Antigens, Neoplasm; Antineoplastic Agents; Cell Line, Tumor; Cell Survival; CTLA-4 Antigen; Humans; Imidazoles; Immunotherapy; Major Histocompatibility Complex; MAP Kinase Kinase Kinases; Melanoma; Mice; Mice, Inbred C57BL; Mice, Transgenic; Oximes; Programmed Cell Death 1 Receptor; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms

Treatment with selective BRAF or MEK inhibitors is frequently associated with cutaneous toxicities, including squamous cell carcinoma (SCC), papillomas and rash. These cutaneous adverse effects are typically observed at a lower incidence during combined BRAF and MEK inhibitor therapy.. Two male patients with stage IV metastatic BRAF-mutated melanoma were treated with a combination of a selective BRAF inhibitor and a selective MEK inhibitor (dabrafenib and trametinib, or encorafenib (LGX818) and binimetinib (MEK162)) within two different clinical trials. Ten and 150 days after treatment start respectively, the patients developed painful nodules on the legs. In addition, one patient developed symmetrical articulation pain and intermittent fever episodes.. Based on the clinical and histological presentation, erythema nodosum-like panniculitis was diagnosed in both cases. No other aetiology could be found. After receiving topical or oral steroid treatment and anti-inflammatory analgesics, the painful nodular lesions disappeared several weeks later. In one case, a rebound of the painful nodules was observed when the combination treatment (dabrafenib and trametinib) was resumed after a 1-week unscheduled treatment interruption.. Panniculitis has previously been described in association with BRAF inhibitor treatment, but not MEK inhibitor treatment. Combination treatment is usually associated with a lower incidence of cutaneous adverse events (AEs), as compared to monotherapy. Panniculitis was observed in two patients during combined BRAF and MEK inhibitor treatment. These cases illustrate the need for further research in a larger patient population to identify a possible link between combined BRAF and MEK inhibitor treatment and the incidence of panniculitis.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Carbamates; Humans; Imidazoles; Male; Melanoma; Mitogen-Activated Protein Kinases; Oximes; Panniculitis; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Sulfonamides

Topics: Female; Humans; Imidazoles; Male; Melanoma; Mitogen-Activated Protein Kinases; Mutation; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms

Topics: Antineoplastic Agents; Drug Therapy, Combination; Humans; Imidazoles; Indoles; MAP Kinase Signaling System; Melanoma; Oximes; Pyridones; Pyrimidinones; Sulfonamides; Vemurafenib

Topics: Aged; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Colitis; Colon; Female; Humans; Imidazoles; Immunotherapy; Ipilimumab; Melanoma; Middle Aged; Oximes; Pyridones; Pyrimidinones; Skin Neoplasms

The aim of combination drug treatment in cancer therapy is to improve response rate and to decrease the probability of the development of drug resistance. Preferably, drug combinations are synergistic rather than additive, and, ideally, drug combinations work synergistically only in cancer cells and not in non-malignant cells. We have developed a workflow to identify such targeted synergies, and applied this approach to selectively inhibit the proliferation of cell lines with mutations in genes that are difficult to modulate with small molecules. The approach is based on curve shift analysis, which we demonstrate is a more robust method of determining synergy than combination matrix screening with Bliss-scoring. We show that the MEK inhibitor trametinib is more synergistic in combination with the BRAF inhibitor dabrafenib than with vemurafenib, another BRAF inhibitor. In addition, we show that the combination of MEK and BRAF inhibitors is synergistic in BRAF-mutant melanoma cells, and additive or antagonistic in, respectively, BRAF-wild type melanoma cells and non-malignant fibroblasts. This combination exemplifies that synergistic action of drugs can depend on cancer genotype. Next, we used curve shift analysis to identify new drug combinations that specifically inhibit cancer cell proliferation driven by difficult-to-drug cancer genes. Combination studies were performed with compounds that as single agents showed preference for inhibition of cancer cells with mutations in either the CTNNB1 gene (coding for β-catenin), KRAS, or cancer cells expressing increased copy numbers of MYC. We demonstrate that the Wnt-pathway inhibitor ICG-001 and trametinib acted synergistically in Wnt-pathway-mutant cell lines. The ERBB2 inhibitor TAK-165 was synergistic with trametinib in KRAS-mutant cell lines. The EGFR/ERBB2 inhibitor neratinib acted synergistically with the spindle poison docetaxel and with the Aurora kinase inhibitor GSK-1070916 in cell lines with MYC amplification. Our approach can therefore efficiently discover novel drug combinations that selectively target cancer genes.

Topics: Antineoplastic Combined Chemotherapy Protocols; Aza Compounds; Benzimidazoles; beta Catenin; Cell Line, Tumor; Cell Proliferation; Humans; Imidazoles; Indazoles; Indoles; Melanoma; Molecular Targeted Therapy; Mutation; Oxazoles; Oximes; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins c-myc; Proto-Oncogene Proteins p21(ras); Pyridones; Pyrimidinones; Quinolines; Sulfonamides; Triazoles; Vemurafenib

Topics: beta Catenin; Cell Line, Tumor; Cell Proliferation; Drug Synergism; Humans; Imidazoles; Indoles; Mutation; Oximes; Proto-Oncogene Proteins c-myb; Proto-Oncogene Proteins p21(ras); Pyridones; Pyrimidinones; Sulfonamides; Vemurafenib

The cutaneous adverse effects of the BRAF inhibitors vemurafenib and dabrafenib mesylate in the treatment of metastatic melanoma have been well reported. The addition of a MEK inhibitor to a BRAF inhibitor improves the blockade of the mitogen-activated protein kinase pathway. The combination of dabrafenib with the MEK inhibitor trametinib dimethyl sulfoxide (CombiDT therapy) increases response rate and survival compared with a BRAF inhibitor alone. Clinical trials have suggested that CombiDT therapy induces fewer cutaneous toxic effects than a single-agent BRAF inhibitor. To our knowledge, a direct comparison has not been performed before.. To compare the cutaneous toxic effects of BRAF inhibitor monotherapy and CombiDT therapy in a large cohort of patients.. We performed a retrospective cohort study from September 1, 2009, through November 30, 2013. The study population included 185 Australian patients with unresectable stages IIIC and IV melanoma referred from Crown Princess Mary Cancer Care Centre who underwent review at the Department of Dermatology, Westmead Hospital. Of these, 119 patients received dabrafenib; 36, vemurafenib; and 30, CombiDT therapy. Data analysis were performed in December 2013.. Multiple cutaneous adverse effects between BRAF inhibitor monotherapy and CombiDT therapy were identified and compared in a cohort of patients who underwent the same dermatologic assessment.. The most common cutaneous adverse effects seen in patients receiving the single-agent BRAF inhibitor dabrafenib or vemurafenib included Grover disease (51 patients [42.9%] and 14 [38.9%], respectively [P = .67]), plantar hyperkeratosis (47 [39.5%] and 14 [38.9%], respectively [P = .95]), verrucal keratosis (79 [66.4%] and 26 [72.2%], respectively [P = .51]), and cutaneous squamous cell carcinoma (31 [26.1%] and 13 [36.1%], respectively [P = .54]). Photosensitivity was more common with vemurafenib (14 patients [38.9%]) compared with dabrafenib (1 [0.8%]; P < .001). Compared with dabrafenib, CombiDT therapy showed a higher frequency of folliculitis (12 patients [40.0%] vs. 8 [6.7%]; P < .001) and a significant decrease of cutaneous squamous cell carcinoma (0 vs. 31 [26.1%]; P < .001), verrucal keratosis (0 vs. 79 [66.4%]; P < .001), and Grover disease (0 vs. 51 [42.9%]; P < .001).. This study confirms that the prevalence of cutaneous toxic effects differs among vemurafenib, dabrafenib, and CombiDT therapies. Cutaneous squamous cell carcinoma is the most concerning cutaneous toxic effect related to BRAF inhibitor monotherapy that did not appear with CombiDT therapy. Although CombiDT therapy has an improved profile of cutaneous toxic effects, continuous dermatologic assessments should be provided for all patients when receiving these treatments.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Cohort Studies; Female; Humans; Imidazoles; Indoles; Male; Melanoma; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Oximes; Prevalence; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Retrospective Studies; Skin Diseases; Skin Neoplasms; Sulfonamides; Vemurafenib

The degree of response and the duration of survival of patients treated with mitogen-activated protein kinase (MAPK) inhibitors are highly variable. Whether baseline clinicopathologic factors can predict the clinical course with treatment is largely unknown.. For 142 consecutive immunotherapy- and MAPK inhibitor-naive patients with BRAF-mutant metastatic melanoma who were treated during clinical trials with BRAF inhibitors (n = 111) or a combination of dabrafenib and trametinib (n = 31), clinicopathologic factors were correlated with the response to MAPK inhibitors and survival.. The median follow-up was 15.7 months (range, 0.6-60.5 months). The 2-, 3-, and 4-year overall survival (OS) rates were 43%, 24%, and 24%, respectively. A multivariate analysis demonstrated that the only clinicopathologic factors associated with longer progression-free survival (PFS) and OS were female sex and a normal pretreatment serum lactate dehydrogenase (LDH) level. The BRAF V600E genotype and an absence of primary melanoma ulceration were also independently associated with longer PFS but not OS. The median OS was 23.5 months for patients with normal LDH levels and 7.3 months for those with elevated LDH levels (hazard ratio, 0.31; P < .001). Complete responders had the best survival, but disease progression still occurred in 2 of 7 patients.. Long-term survival occurs for a minority of patients receiving MAPK inhibitor treatment alone. Sex, serum LDH, BRAF genotype, and primary melanoma ulceration status are independent factors associated with treatment outcomes. Patients with a complete response to treatment have the best survival, but relapses still occur.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Biomarkers, Tumor; Drug Therapy, Combination; Female; Follow-Up Studies; Genotype; Humans; Imidazoles; Indoles; L-Lactate Dehydrogenase; Male; MAP Kinase Kinase Kinases; Melanoma; Middle Aged; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Sex Factors; Skin Neoplasms; Sulfonamides; Survival Rate; Treatment Outcome; Vemurafenib; Young Adult

A middle-aged female with metastatic melanoma was found to have hemoperitoneum after starting systemic therapy with the BRAF and MEK inhibitors dabrafenib and trametinib. Etiology proved to be bleeding from a known hepatic metastasis. The patient was managed conservatively and eventually resumed systemic therapy with ongoing response. This case serves to illustrate the possible deleterious effects of rapid tumor response after initiation of targeted systemic therapy in patients with metastatic melanoma.

Topics: Antineoplastic Agents; Female; Hemoperitoneum; Humans; Imidazoles; Liver Neoplasms; Melanoma; Middle Aged; Oximes; Pyridones; Pyrimidinones; Skin Neoplasms

BRAF-mutant melanoma can be successfully treated by BRAF kinase inhibitors (BRAFi) and MEK kinase inhibitors (MEKi). However, the administration of BRAFi followed by MEKi did not generate promising response rate (RR). The purpose of this investigation was to evaluate the time to progression (TTP) with a mitogen-activated protein kinase (MAPK) pathway upstream inhibition strategy in BRAF mutated melanoma patients. BRAF mutation positive metastatic melanoma patients were identified within the Dermatology Cooperative Oncology Group (DeCOG) network and were treated first with a MEKi and upon progression with a selective BRAFi. A total of 23 melanoma patients (six females, 17 males, aged 47-80 years) were retrospectively analysed for TTP. The total median TTP was 8.9 months. The median TTP for MEKi was 4.8 (1.2-23.2) and subsequent for BRAFi 4.5 (1.2-15.7) months, respectively. A higher RR for MEKi (39%, nine partial responses and 0 complete responses) than previously reported was observed. Our analysis suggests that the reversed inhibition of the MAPK pathway is feasible in BRAF mutated melanoma. The median TTP (8.9 months) is close to the promising BRAF- and MEKi combination therapy (median progression-free survival (PFS) 9.4 months). The total treatment duration of the MAPK inhibition when a MEKi is administered first is similar compared to the reversed sequence, but TTP shifts in favour to the MEKi. This approach is feasible with reasonable tolerability. This clinical investigation encourages further studies in prospective clinical trials to define the optimal treatment schedule for the MAPK pathway inhibition and should be accompanied by molecular monitoring using repeated biopsies.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Disease Progression; Disease-Free Survival; Feasibility Studies; Female; Humans; Imidazoles; Indoles; Male; MAP Kinase Signaling System; Melanoma; Middle Aged; Mitogen-Activated Protein Kinases; Mutation; Outcome Assessment, Health Care; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Retrospective Studies; Sulfonamides; Time Factors; Vemurafenib

The MEK inhibitor trametinib is currently undergoing clinical trials as the treatment of metastatic melanoma both alone and in combination with the BRAF inhibitor dabrafenib. One of the most frequent side-effects associated with its use as a single agent is the development of acneiform eruptions. These eruptions seem to be reduced when dosed in combination with dabrafenib.. To investigate the prevalence of acneiform eruptions in patients taking the MEK inhibitor trametinib, both alone and in combination with dabrafenib.. All patients enrolled in the trametinib alone (n = 13) or trametinib and dabrafenib combination (n = 30) clinical trials at a single site underwent a retrospective file review. The development and management of acne or acneiform eruptions was noted.. In total, 77% of the trametinib group developed an acneiform eruption on the trial, while only 10% developed acneiform lesions in the combination trial. The patients were treated with oral doxycycline, topical antibiotics or topical antiseptic washes, with a good response. However the condition recurred if these treatments were ceased and the patient was still on trametinib therapy.. The MEK inhibitor trametinib is associated with the development of acneiform eruptions. When combined with dabrafenib the frequency of this side-effect is reduced.

Topics: Acneiform Eruptions; Administration, Cutaneous; Adult; Aged; Anti-Bacterial Agents; Anti-Infective Agents, Local; Antineoplastic Combined Chemotherapy Protocols; Clindamycin; Clinical Trials as Topic; Doxycycline; Drug Eruptions; Female; Humans; Imidazoles; Male; Melanoma; Middle Aged; Oximes; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Retrospective Studies; Skin Neoplasms; Triclosan

Targeted BRAF inhibitor therapy (vemurafenib, dabrafenib) is an effective, novel treatment for patients with metastatic melanoma with the V600E BRAF mutation. This therapy is associated with squamous cell carcinomas and keratoacanthomas. Granulomatous eruptions have not been previously reported.. Two patients with melanoma developed cutaneous granulomatous eruptions during targeted BRAF inhibitor therapy. In case 1, after 2 months of treatment with dabrafenib and trametinib (MEK inhibitor), a papular eruption concerning for progression of disease prompted cessation of treatment. After the histopathologic diagnosis of granulomas, the patient was treated with clobetasol ointment with resolution within days and resumption of therapy. In case 2, after 5 months of vemurafenib treatment, the patient developed a granulomatous eruption, which resolved 3 weeks after cessation of therapy.. We report 2 cases of cutaneous granulomatous eruptions on treatment with targeted BRAF inhibitors, a previously unreported association. Although additional investigations are necessary to better elucidate the pathogenic mechanisms, our report includes a treatment plan that prevents unnecessary discontinuation of therapy. Given the Food and Drug Administration approval of vemurafenib for metastatic melanoma, clinicians should be aware of this possible cutaneous reaction and treatment option to optimize patient management.

Topics: Administration, Cutaneous; Aged; Aged, 80 and over; Biopsy, Needle; Clobetasol; Disease Progression; Drug Eruptions; Female; Follow-Up Studies; Humans; Imidazoles; Immunohistochemistry; Lower Extremity; Male; Melanoma; Molecular Targeted Therapy; Neoplasm Invasiveness; Neoplasm Recurrence, Local; Neoplasm Staging; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Risk Assessment; Sampling Studies; Sentinel Lymph Node Biopsy; Skin Neoplasms; Survival Rate; Treatment Outcome

Dabrafenib and trametinib were approved for use as monotherapies in BRAF-mutant metastatic melanoma by the U.S. Food and Drug Administration (FDA) in 2013, and most recently, their use in combination has received accelerated FDA approval. Both drugs target the mitogen-activated protein kinase (MAPK) pathway: dabrafenib selectively inhibits mutant BRAF that constitutively activates the pathway, and trametinib selectively inhibits MEK1 and MEK2 proteins activated by RAF kinases. The phase III study of dabrafenib in BRAF(V600E) metastatic melanoma reported rapid tumor regression in most patients and a 59% objective RECIST response rate. The median progression-free survival (PFS) and overall survival (OS) were improved compared with dacarbazine. Toxicities were well tolerated and different from those reported for vemurafenib, the first FDA-approved BRAF inhibitor. Efficacy has been demonstrated in other BRAF-mutant genotypes. The phase III study of trametinib in BRAF inhibitor-naïve patients with BRAF(V600E) or BRAF(V600K) also showed benefit with a prolonged median PFS and OS compared with chemotherapy. Trametinib is ineffective in patients who have progressed on BRAF inhibitors. A phase II trial of combined dabrafenib and trametinib demonstrated higher response rates and longer median PFS than dabrafenib monotherapy, with less cutaneous toxicity. Here, we review the clinical development of both drugs as monotherapies and in combination, and discuss their role in the management of BRAF-mutant melanoma.

Topics: Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Disease-Free Survival; Exanthema; Fatigue; Humans; Imidazoles; Melanoma; Mutation; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Treatment Outcome

The U.S. Food and Drug Administration approved the use of trametinib and dabrafenib in combination for patients with metastatic or unresectable melanoma with BRAF V600K or V600E mutations-the first combination therapy approved for the disease.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Humans; Imidazoles; Melanoma; Molecular Targeted Therapy; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Treatment Outcome; United States; United States Food and Drug Administration

The central role of the BRAF-MEK-ERK pathway in controlling cell fate has made this pathway a primary target for deregulated activation in cancer. BRaf is activated by Ras proteins allowing Ras oncogenes to constitutively activate the pathway. Activating BRaf mutations are also frequent in several cancers, being the most common oncogenic mutation in thyroid carcinoma and melanoma. There are currently two inhibitors, vemurafenib and dabrafenib, approved for treatment of malignant melanoma having activating BRaf mutations. Concurrent administration of BRAF and MAP-ERK kinase (MEK) inhibitor (trametinib) is significantly more active in patients with BRAF-mutant melanoma than either single agent alone, but progression to resistance ultimately occurs by different mechanisms that increase the activation of extracellular signal-regulated kinase (ERK). Such adaptive changes in tumor cell signaling networks allow bypass of targeted oncoprotein inhibition. This is true with targeted inhibitors for BRaf and MEK as well as specific inhibitors for AKT, mTOR, and many receptor tyrosine kinases such as EGF receptor (EGFR) and HER2. It is this adaptive response to targeted kinase inhibitors that contributes to the failure of single-agent kinase inhibitors to have durable responses. This failure is seen in virtually all cancers treated with single-agent kinase inhibitors, most of which are not as dependent on a single signaling pathway such as BRaf-MEK-ERK in melanoma. Thus, understanding the breadth of adaptive reprogramming responses to specific targeted kinase inhibition will be critical to develop appropriate combination therapies for durable clinical responses.

Topics: Antineoplastic Combined Chemotherapy Protocols; Extracellular Signal-Regulated MAP Kinases; Humans; Imidazoles; Indoles; MAP Kinase Kinase 1; MAP Kinase Kinase 2; MAP Kinase Signaling System; Melanoma; Models, Biological; Mutation; Neoplasms; Oximes; Phosphorylation; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Sulfonamides; Vemurafenib

Recent advances in targeting BRAFV600E mutations, which occur in roughly 50% of melanomas and 70% of benign nevi, have improved response rates and survival in patients with melanoma. With increased survival, the importance of other comorbidities increases and requires consideration in long-term management. This case report discusses dynamic dermoscopic nevus changes that occur during dabrafenib therapy and offers some conclusions regarding BRAF mutations and the changes.. A man in his 30s had been monitored with whole-body dermoscopy at roughly 7-month intervals as part of a nevus surveillance study. Fourteen months after his initial visit, metastases were found, and the patient entered a clinical trial of dabrafenib with or without trametinib therapy. Continued dermoscopic monitoring for the next 12 months revealed that approximately 50% of the existing acquired melanocytic nevi involuted, while the remaining nevi did not change. Biopsy findings from 1 unchanged and 1 involuted nevus showed BRAF wild type in the unchanged nevus, BRAFV600E mutation in the involuting nevus, and no malignant histopathologic characteristics in either one.. Our observations indicate that a previously suggested hypothesis regarding involuting nevi in BRAF inhibitor therapy is correct: Nevi that involute while a patient is undergoing BRAF V600E inhibitor therapy possess the BRAF V600E mutation, while others that grow or remain unchanged are wild type. However larger-scale trials are required to gather conclusive data and create a more complete clinical picture.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Dermoscopy; Humans; Imidazoles; Male; Melanoma; Mutation; Nevus; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms

The clinical use of BRAF inhibitors for treatment of metastatic melanoma is limited by the development of drug resistance. In this study we investigated whether co-targeting the MAPK and the PI3K-AKT pathway can prevent emergence of resistance or provide additional growth inhibitory effects in vitro.. Anti-tumor effects of the combination of the BRAF inhibitor (BRAFi) dabrafenib and GSK2141795B (AKTi) in a panel of 23 BRAF mutated melanoma cell lines were evaluated on growth inhibition by an ATP-based luminescent assay, on cell cycle and apoptosis by flow cytometry and on cell signaling by western blot. Moreover, we investigated the possibilities of delaying or reversing resistance or achieving further growth inhibition by combining AKTi with dabrafenib and/or the MEK inhibitor (MEKi) trametinib by using long term cultures.. More than 40% of the cell lines, including PTEN-/- and AKT mutants showed sensitivity to AKTi (IC50 < 1.5 μM). The combination of dabrafenib and AKTi synergistically potentiated growth inhibition in the majority of cell lines with IC50 > 5 nM dabrafenib. Combinatorial treatment induced apoptosis only in cell lines sensitive to AKTi. In long term cultures of a PTEN-/- cell line, combinatorial treatment with the MAPK inhibitors, dabrafenib and trametinib, and AKTi markedly delayed the emergence of drug resistance. Moreover, combining AKTi with the MAPK inhibitors from the beginning provided superior growth inhibitory effects compared to addition of AKTi upon development of resistance to MAPK inhibitors in this particular cell line.. AKTi combined with BRAFi-based therapy may benefit patients with tumors harboring BRAF mutations and particularly PTEN deletions or AKT mutations.

Topics: Apoptosis; Cell Line, Tumor; Drug Resistance, Neoplasm; Humans; Imidazoles; MAP Kinase Kinase Kinases; Melanoma; Mutation; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins c-akt; Pyridones; Pyrimidinones; Signal Transduction; Xenograft Model Antitumor Assays

Combination therapy with BRAF and MEK inhibition is currently in clinical development for the treatment of BRAF-mutated malignant melanoma. BRAF inhibitors are associated with enhanced antigen-specific T-lymphocyte recognition in vivo. Consequently, BRAF inhibition has been proposed as proimmunogenic and there has been considerable enthusiasm for combining BRAF inhibition with immunotherapy. MEK inhibitors inhibit ERK phosphorylation regardless of BRAF mutational status and have been reported to impair T-lymphocyte and modulate dendritic cell function. In this study, we investigate the effects on isolated T lymphocytes and monocyte-derived dendritic cells (moDC) of a MEK (trametinib) and BRAF (dabrafenib) inhibitor combination currently being evaluated in a randomized controlled clinical trial. The effects of dabrafenib and trametinib, alone and in combination, were studied on isolated normal T lymphocytes and moDCs. Lymphocyte viability, together with functional assays including proliferation, cytokine production, and antigen-specific expansion, were assessed. MoDC phenotype in response to lipopolysaccharide stimulation was evaluated by flow cytometry, as were effects on antigen cross-presentation. Dabrafenib did not have an impact on T lymphocytes or moDCs, whereas trametinib alone or in combination with dabrafenib suppressed T-lymphocyte proliferation, cytokine production, and antigen-specific expansion. However, no significant decrease in CD4(+) or CD8(+) T-lymphocyte viability was observed following kinase inhibition. MoDC cross-presentation was suppressed in association with enhanced maturation following combined inhibition of MEK and BRAF. The results of this study demonstrate that MEK inhibition, alone or in combination with BRAF inhibition, can modulate immune cell function, and further studies in vivo will be required to evaluate the potential clinical impact of these findings.

Topics: Antigens, Neoplasm; Cell Differentiation; Cell Proliferation; Cross-Priming; Cytokines; Dendritic Cells; Epitopes, T-Lymphocyte; Humans; Imidazoles; Lipopolysaccharides; Lymphocyte Activation; Lymphocyte Subsets; Lymphocytes; Mitogen-Activated Protein Kinase Kinases; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

Panniculitis is a rare complication of BRAF inhibitor therapy that is used to treat patients with BRAF-mutated metastatic melanoma. We present a clinicopathologic review of 9 patients who developed panniculitis while on BRAF inhibitor therapy. In 13% of patients on vemurafenib, 3% of patients on dabrafenib and 10% on combination of dabrafenib + trametinib, tender erythematous nodular lesions of panniculitis appeared on legs, arms and trunk. Histological evaluation of 8 biopsies from 7 patients showed predominantly neutrophilic infiltrate in 4, lymphocytic in 1, and mixed in 3. Lesions with neutrophilic infiltrate appeared in earlier stages of treatment than those with mixed or lymphocytic infiltrate. All biopsies showed lobular involvement and 5 also had a septal component. In addition, 1 biopsy had lichenoid inflammation in the epidermis and the other had evidence of vasculitis. Most patients responded to conservative medical management without the need to reduce or to stop BRAF inhibitor therapy. Panniculitis seems to be a rare class effect of BRAF inhibitors that is predominantly lobular and neutrophilic, although other patterns can be seen.

Topics: Adult; Aged; Female; Humans; Imidazoles; Indoles; Male; Melanoma; Middle Aged; Oximes; Panniculitis; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Sulfonamides; Vemurafenib

BRAF inhibitors (BRAFi) and MEK inhibitors (MEKi) increase survival in BRAF mutant metastatic melanoma patients; however, they induce a well-known spectrum of cutaneous side effects during treatment. Whereas the BRAFi dabrafenib induces cutaneous squamous cell carcinomas and verrucal keratosis, the MEKi trametinib frequently induces acneiform eruptions that are reversible after drug discontinuation. Furthermore, when dabrafenib and trametinib are used in combination, there are fewer cutaneous toxicities. We report a patient with BRAF mutant metastatic melanoma treated with the BRAFi/MEKi combination therapy who developed an acneiform eruption after treatment discontinuation rather than during active therapy. Moreover, the eruption resolved when the combination treatment was reintroduced and recurred after increasing the dose of trametinib. The eruption may be explained by the longer half-life of trametinib (4.5 days) compared with dabrafenib (5.2 h). This is the first case reported with this particular side effect induced after stopping the treatment and could become more frequent as the BRAFi/MEKi combination of drugs is more frequently prescribed.

Topics: Acneiform Eruptions; Adrenal Cortex Hormones; Adult; Antineoplastic Combined Chemotherapy Protocols; Disease Progression; Drug Administration Schedule; Fatal Outcome; Female; Fever; Humans; Imidazoles; Melanoma; Mutation; Neoplasm Metastasis; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Time Factors; Treatment Outcome

Topics: Acneiform Eruptions; Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Imidazoles; Indoles; MAP Kinase Kinase Kinases; Melanoma; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Sulfonamides; Vemurafenib

Combination therapy with BRAF V600E inhibitor dabrafenib and MEK inhibitor trametinib significantly improves progression-free survival of patients with BRAF V600-positive metastatic melanoma, but their use can be associated with life-threatening toxicities. We report the case of a patient receiving dabrafenib and trametinib for metastatic melanoma who developed intracranial hemorrhage while on therapy. Combination therapy with dabrafenib and trametinib improves progression-free survival of patients with BRAF V600-positive metastatic melanoma. Nevertheless, it is associated with an increased incidence and severity of any hemorrhagic event. To the best of our knowledge, this is the first report of intracranial hemorrhage with pathological confirmation.. We present the case of a 48-year-old man with metastatic melanoma of unknown primary site. He had metastases to the right clavicle, brain, liver, adrenal gland, and the right lower quadrant of the abdomen. He progressed on treatment with alpha-interferon. He was found to have a 4.5-cm mass in the left frontotemporal lobe and underwent gross total resection followed by adjuvant CyberKnife stereotactic irradiation. He was subsequently started on ipilimumab. Treatment was stopped due to kidney injury. He was then placed on dabrafenib and trametinib. He returned for follow-up complaining of severe headache and developed an episode of seizure. MRI showed a large area of edema at the left frontal lobe with midline shift. Emergency craniotomy was performed. Intracranial hemorrhage was found intra-operatively. Pathology from surgery did not find tumor cells, reported as organizing hemorrhage and necrosis with surrounding gliosis; immunohistochemistry for S100 and HMB45 were negative.. This case demonstrates the life-threatening adverse effects that can be seen with the newer targeted biological therapies. It is therefore crucial to maintain a high index of suspicion when patients on this combination therapy present with new neurologic symptoms.

Topics: Antineoplastic Agents; Craniotomy; Diagnosis, Differential; Drug Therapy, Combination; Humans; Imidazoles; Intracranial Hemorrhages; Male; MAP Kinase Kinase 1; Melanoma; Middle Aged; Oximes; Positron-Emission Tomography; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Tomography, X-Ray Computed

Topics: Antineoplastic Combined Chemotherapy Protocols; Azetidines; Female; Humans; Imidazoles; Indoles; Male; MAP Kinase Kinase 1; Melanoma; Mitogen-Activated Protein Kinase Kinases; Oximes; Piperidines; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Sulfonamides; Vemurafenib

BRAF inhibitor (BRAFi) and MEK inhibitor (MEKi) frequently cause cutaneous adverse events.. We sought to investigate the cutaneous safety profile of BRAFi versus BRAFi and MEKi combination regimens.. We performed a retrospective cohort study, collecting data from 44 patients with melanoma treated either with BRAFi (vemurafenib or dabrafenib) or BRAFi and MEKi combination regimens (vemurafenib + cobimetinib or dabrafenib + trametinib). Patient characteristics, and the occurrence and severity of cutaneous adverse events, are described.. The development of cutaneous adverse events was significantly less frequent (P = .012) and occurred after longer treatment time (P = .025) in patients treated with BRAFi and MEKi combination regimen compared with patients treated with BRAFi monotherapy. Among patients who received both BRAFi and the combination of BRAFi and MEKi at different time points during their treatment course, the development of squamous cell carcinoma or keratoacanthoma was significantly less frequent when they received the combination regimen (P = .008). Patients receiving vemurafenib developed more cutaneous adverse events (P = .001) and in particular more photosensitivity (P = .010) than patients who did not.. There were a limited number of patients.. Combination regimen with BRAFi and MEKi shows fewer cutaneous adverse events and longer cutaneous adverse event-free interval compared with BRAFi monotherapy.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Azetidines; Carcinoma, Squamous Cell; Female; Follow-Up Studies; Humans; Imidazoles; Indoles; Kaplan-Meier Estimate; Male; Melanoma; Middle Aged; Oximes; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Retrospective Studies; Skin Neoplasms; Sulfonamides; Vemurafenib; Young Adult

One-third of BRAF-mutant metastatic melanoma patients treated with combined BRAF and MEK inhibition progress within 6 months. Treatment options for these patients remain limited. Here we analyse 20 BRAF(V600)-mutant melanoma metastases derived from 10 patients treated with the combination of dabrafenib and trametinib for resistance mechanisms and genetic correlates of response. Resistance mechanisms are identified in 9/11 progressing tumours and MAPK reactivation occurred in 9/10 tumours, commonly via BRAF amplification and mutations activating NRAS and MEK2. Our data confirming that MEK2(C125S), but not the synonymous MEK1(C121S) protein, confers resistance to combination therapy highlight the functional differences between these kinases and the preponderance of MEK2 mutations in combination therapy-resistant melanomas. Exome sequencing did not identify additional progression-specific resistance candidates. Nevertheless, most melanomas carried additional oncogenic mutations at baseline (for example, RAC1 and AKT3) that activate the MAPK and PI3K pathways and are thus predicted to diminish response to MAPK inhibitors.

Topics: Antineoplastic Combined Chemotherapy Protocols; Drug Resistance, Neoplasm; GTP Phosphohydrolases; Humans; Imidazoles; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Melanoma; Membrane Proteins; Oximes; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins c-akt; Pyridones; Pyrimidinones; rac1 GTP-Binding Protein; Skin Neoplasms

Increased expression of the Microphthalmia-associated transcription factor (MITF) contributes to melanoma progression and resistance to BRAF pathway inhibition. Here we show that the lack of MITF is associated with more severe resistance to a range of inhibitors, while its presence is required for robust drug responses. Both in primary and acquired resistance, MITF levels inversely correlate with the expression of several activated receptor tyrosine kinases, most frequently AXL. The MITF-low/AXL-high/drug-resistance phenotype is common among mutant BRAF and NRAS melanoma cell lines. The dichotomous behaviour of MITF in drug response is corroborated in vemurafenib-resistant biopsies, including MITF-high and -low clones in a relapsed patient. Furthermore, drug cocktails containing AXL inhibitor enhance melanoma cell elimination by BRAF or ERK inhibition. Our results demonstrate that a low MITF/AXL ratio predicts early resistance to multiple targeted drugs, and warrant clinical validation of AXL inhibitors to combat resistance of BRAF and NRAS mutant MITF-low melanomas.

Topics: Aminopyridines; Animals; Antineoplastic Agents; Axl Receptor Tyrosine Kinase; Benzamides; Cell Line, Tumor; Drug Resistance, Neoplasm; Extracellular Signal-Regulated MAP Kinases; Gene Expression Regulation, Neoplastic; Humans; Imatinib Mesylate; Imidazoles; Indoles; Melanoma; Mice; Microphthalmia-Associated Transcription Factor; Oximes; Piperazines; Prognosis; Protein Kinase Inhibitors; Proto-Oncogene Proteins; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidines; Pyrimidinones; Receptor Protein-Tyrosine Kinases; Signal Transduction; Skin Neoplasms; Sulfonamides; Vemurafenib; Xenograft Model Antitumor Assays

Topics: Antineoplastic Agents; Drug Approval; Drug Therapy, Combination; Humans; Imidazoles; Melanoma; Oximes; Pyridones; Pyrimidinones; Skin Neoplasms; United States; United States Food and Drug Administration

The discovery that some melanoma tumours harbour mutations in the BRAF gene (e.g. V600E) and the subsequent development of specific BRAF inhibitors have greatly improved the treatment of metastatic melanoma. Resistance of tumour cells to BRAF inhibitors is reduced by the addition of an MEK inhibitor; both BRAF and MEK inhibitors have been reported to produce a variety of dermatological toxic effects. Benign naevi often harbour BRAF mutations but few reports exist that document the response of naevus cells to BRAF inhibition. We report sarcoidal-type granulomatous inflammation in two patients with metastatic melanoma undergoing treatment with combination BRAF and MEK inhibitor therapy. This inflammation manifested in one patient as a nonspecific papular eruption; in the other, in association with clinical regression of multiple benign-appearing naevi during the course of therapy. The significance of sarcoidal-type inflammation occurring during treatment of metastatic melanoma with a combination of BRAF and MEK inhibitors is unclear. Its association with the clinical regression of benign-appearing naevi suggests a possible exaggerated inflammatory response to degenerating naevus cells in these lesions.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Female; Head and Neck Neoplasms; Humans; Imidazoles; Male; MAP Kinase Kinase Kinases; Melanoma; Middle Aged; Mutation; Neoplasm Metastasis; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Scalp; Skin Neoplasms

Topics: Antineoplastic Agents; Humans; Imidazoles; Melanoma; Neoplasm Staging; Oximes; Pyridones; Pyrimidinones; Skin Neoplasms; Treatment Outcome; United States; United States Food and Drug Administration

Mitogen-Activated Protein Kinase (MAPK) pathway activation has been implicated in many types of human cancer. BRAF mutations that constitutively activate MAPK signalling and bypass the need for upstream stimuli occur with high prevalence in melanoma, colorectal carcinoma, ovarian cancer, papillary thyroid carcinoma, and cholangiocarcinoma. In this report we characterize the novel, potent, and selective BRAF inhibitor, dabrafenib (GSK2118436). Cellular inhibition of BRAF(V600E) kinase activity by dabrafenib resulted in decreased MEK and ERK phosphorylation and inhibition of cell proliferation through an initial G1 cell cycle arrest, followed by cell death. In a BRAF(V600E)-containing xenograft model of human melanoma, orally administered dabrafenib inhibited ERK activation, downregulated Ki67, and upregulated p27, leading to tumor growth inhibition. However, as reported for other BRAF inhibitors, dabrafenib also induced MAPK pathway activation in wild-type BRAF cells through CRAF (RAF1) signalling, potentially explaining the squamous cell carcinomas and keratoacanthomas arising in patients treated with BRAF inhibitors. In addressing this issue, we showed that concomitant administration of BRAF and MEK inhibitors abrogated paradoxical BRAF inhibitor-induced MAPK signalling in cells, reduced the occurrence of skin lesions in rats, and enhanced the inhibition of human tumor xenograft growth in mouse models. Taken together, our findings offer preclinical proof of concept for dabrafenib as a specific and highly efficacious BRAF inhibitor and provide evidence for its potential clinical benefits when used in combination with a MEK inhibitor.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Drug Evaluation, Preclinical; Enzyme Activation; Female; Humans; Imidazoles; Melanoma; Mice; Mitogen-Activated Protein Kinases; Mutation; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Signal Transduction; Tumor Burden; Xenograft Model Antitumor Assays

Topics: Antineoplastic Agents; Humans; Imidazoles; Melanoma; Oximes; Pyridones; Pyrimidinones

Topics: Combined Modality Therapy; Drug Approval; Humans; Imidazoles; Melanoma; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; United States; United States Food and Drug Administration

Topics: Cell Proliferation; Colonic Neoplasms; Humans; Imidazoles; Male; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Middle Aged; Mutation; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins p21(ras); Pyridones; Pyrimidinones; ras Proteins; Treatment Outcome

The cutaneous effects of rapidly accelerated fibrosarcoma kinase B (BRAF) inhibitors are not well understood. Squamous cell carcinoma (SCC), keratoacanthoma, and photosensitivity have been described in patients taking BRAF inhibitors.. To characterize the timing and frequency of skin lesions in patients receiving BRAF inhibitor therapy, we utilized a retrospective case review of 53 patients undergoing treatment with BRAF inhibitors for 4-92 weeks of therapy. Patients were evaluated at baseline, and then followed at 4- to 12-week intervals. Charts were retrospectively reviewed, and the morphology and timing of cutaneous events were recorded.. Thirty-three of the 53 charts met exclusion/inclusion criteria, 15 were treated with vemurafenib, and 18 were treated with GSK 2118436/GSK 1120212. Of 33 patients treated with BRAF inhibitor, 13 developed photosensitivity (39.4%), 10 developed actinic keratoses (30.3%), 10 developed warts (30.3%), and 6 developed SCC (18.2%).. Multiple cutaneous findings were observed in the 33 patients taking BRAF inhibitors. The previously described association with SCC and photosensitivity was observed in these patients as well. Over half of the observed SCCs were invasive in nature. Photosensitivity continues to be frequent with BRAF inhibitors. Patients taking BRAF inhibitors should have regular full body skin exams. Further studies are necessary to better elucidate the rates of these adverse cutaneous effects.

Topics: Antineoplastic Agents; Carcinoma, Squamous Cell; Female; Humans; Imidazoles; Indoles; Keratoacanthoma; Keratosis, Actinic; Male; Melanoma; Middle Aged; Neoplasms; Oximes; Photosensitivity Disorders; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Retrospective Studies; Skin Diseases; Sulfonamides; Vemurafenib; Warts

To evaluate the effects of BRAF inhibition on the tumor microenvironment in patients with metastatic melanoma.. Thirty-five biopsies were collected from 16 patients with metastatic melanoma pretreatment (day 0) and at 10 to 14 days after initiation of treatment with either BRAF inhibitor alone (vemurafenib) or BRAF + MEK inhibition (dabrafenib + trametinib) and were also taken at time of progression. Biopsies were analyzed for melanoma antigens, T-cell markers, and immunomodulatory cytokines.. Treatment with either BRAF inhibitor alone or BRAF + MEK inhibitor was associated with an increased expression of melanoma antigens and an increase in CD8+ T-cell infiltrate. This was also associated with a decrease in immunosuppressive cytokines [interleukin (IL)-6 and IL-8] and an increase in markers of T-cell cytotoxicity. Interestingly, expression of exhaustion markers TIM-3 and PD1 and the immunosuppressive ligand PDL1 was increased on treatment. A decrease in melanoma antigen expression and CD8 T-cell infiltrate was noted at time of progression on BRAF inhibitor alone and was reversed with combined BRAF and MEK inhibition.. Together, these data suggest that treatment with BRAF inhibition enhances melanoma antigen expression and facilitates T-cell cytotoxicity and a more favorable tumor microenvironment, providing support for potential synergy of BRAF-targeted therapy and immunotherapy. Interestingly, markers of T-cell exhaustion and the immunosuppressive ligand PDL1 are also increased with BRAF inhibition, further implying that immune checkpoint blockade may be critical in augmenting responses to BRAF-targeted therapy in patients with melanoma.

Topics: Apoptosis; Biomarkers, Tumor; Blotting, Western; Cell Line, Tumor; Cell Proliferation; Fluorescent Antibody Technique; Humans; Imidazoles; Indoles; MAP Kinase Kinase 1; Melanoma; Melanoma-Specific Antigens; Neoplasm Staging; Oximes; Prognosis; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sulfonamides; Tumor Microenvironment; Vemurafenib