pyrimidinones and Skin-Neoplasms

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

Cutaneous melanoma represents one of the deadliest types of skin cancer. The prognosis strongly depends on the disease stage, thus early detection is crucial. New therapies, including BRAF and MEK inhibitors and immunotherapies, have significantly improved the survival of patients in the last decade. However, intrinsic and acquired resistance is still a challenge. In this review, we discuss two major aspects that contribute to the aggressiveness of melanoma, namely, the embryonic origin of melanocytes and melanoma cells and cellular plasticity. First, we summarize the physiological function of epidermal melanocytes and their development from precursor cells that originate from the neural crest (NC). Next, we discuss the concepts of intratumoral heterogeneity, cellular plasticity, and phenotype switching that enable melanoma to adapt to changes in the tumor microenvironment and promote disease progression and drug resistance. Finally, we further dissect the connection of these two aspects by focusing on the transcriptional regulators MSX1, MITF, SOX10, PAX3, and FOXD3. These factors play a key role in NC initiation, NC cell migration, and melanocyte formation, and we discuss how they contribute to cellular plasticity and drug resistance in melanoma.

Topics: Acrylonitrile; Aniline Compounds; Bridged Bicyclo Compounds, Heterocyclic; Cell Differentiation; Cell Movement; Cell Plasticity; Drug Resistance, Neoplasm; Forkhead Transcription Factors; Gene Expression Regulation, Neoplastic; Melanocytes; Melanoma; Microphthalmia-Associated Transcription Factor; MSX1 Transcription Factor; Neural Crest; PAX3 Transcription Factor; Phenotype; Pyrimidinones; Skin Neoplasms; SOXE Transcription Factors

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

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

Cutaneous T-cell lymphoma (CTCL) is characterized by the accumulation of neoplastic CD4+ T lymphocytes in the skin. Given the lack of curative treatments for CTCL, there is a significant need for new, superior therapies. Forodesine is a transition-state analogue that inhibits purine nucleoside phosphorylase. Because it selectively targets T lymphocytes, it represents a drug of interest for the treatment of CTCL. Areas covered: Phase I/II dose-ranging studies of intravenous (IV) and oral forodesine demonstrated its activity, safety, and tolerability for refractory CTCL. Response rates were 31% and 27%, respectively. No dose-limiting toxicities were observed. These studies were followed by a phase II trial of oral forodesine 200 mg daily. This oral formulation showed only partial activity, with a response rate of 11%, likely attributable to underdosing. Common adverse events in these trials included infection, fatigue, peripheral edema, nausea, pruritus, headache, and insomnia. Expert opinion: IV and oral formulations of forodesine have demonstrated partial activity and an acceptable safety profile in patients with refractory CTCL. A higher oral dose, or sequential therapy consisting of IV forodesine followed by maintenance oral forodesine, may be more effective. With proper dosing, forodesine may emerge as a safe and effective treatment for refractory CTCL.

Topics: Administration, Intravenous; Administration, Oral; Animals; Antineoplastic Agents; Dose-Response Relationship, Drug; Humans; Lymphoma, T-Cell, Cutaneous; Purine Nucleosides; Pyrimidinones; Skin Neoplasms

The mitogen-activated protein kinase (MAPK) cascade is an intracellular signaling pathway involved in the regulation of cellular proliferation and the survival of tumor cells. Several different mutations, involving BRAF or NRAS, exert an oncogenic effect by activating the MAPK pathway, resulting in an increase in cellular proliferation. These mutations have become targets for new therapeutic strategies in melanoma and other cancers. Selective MEK inhibitors have the ability to inhibit growth and induce cell death in BRAF- and NRAS-mutant melanoma cell lines. MEK inhibitor therapy in combination with a BRAF inhibitor is more effective and less toxic than treatment with a BRAF inhibitor alone, and has become the standard of care for patients with BRAF-mutated melanoma. Trametinib was the first MEK inhibitor approved for the treatment of BRAF-mutated metastatic melanoma not previously treated with BRAF inhibitors, and is also approved in combination with the BRAF inhibitor dabrafenib. Furthermore, cobimetinib is another MEK inhibitor approved for the treatment of BRAF-mutated metastatic melanoma in combination with a BRAF inhibitor, vemurafenib. The MEK inhibitor binimetinib in combination with the BRAF inhibitor encorafenib is in clinical development. The addition of an anti-PD-1/PD-L1 agent, such as pembrolizumab, durvalumab or atezolizumab, to combined BRAF and MEK inhibition has shown considerable promise, with several trials ongoing in metastatic melanoma. Binimetinib has also shown efficacy in NRAS-mutated melanoma patients. Future possibilities for MEK inhibitors in advanced melanoma, as well as other solid tumors, include their use in combination with other targeted therapies (e.g. anti-CDK4/6 inhibitors) and/or various immune-modulating antibodies.

Topics: Humans; MAP Kinase Kinase 1; Melanoma; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Skin Neoplasms; Treatment Outcome

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

The Ras-Raf-MEK-ERK (Map kinase) cellular pathway is a highly conserved eukaryotic signaling module that transduces extracellular signals from growth factors and cytokines into intracellular regulatory events that are involved in cell growth and proliferation or the contrary pathway of cell differentiation. Dysregulation of this pathway occurs in more than one-third of all malignancies, a process that has fostered the development of targeted Map kinase pathway inhibitors. Cutaneous melanomas, which arise from skin melanocytes, are the most aggressive form of skin cancer. Mutations that activate the Map kinase pathway occur in more than 90% of these melanomas. This has led to the development of the combination of dabrafenib and trametinib or vemurafenib and cobimetanib for the treatment of BRAF V600E mutant melanomas. Dabrafenib and vemurafenib target V600E/K BRAF mutants while trametinib and cobimetanib target MEK1/2. The latter two agents bind to MEK1/2 at a site that is adjacent to, but separate from, the ATP-binding site and are therefore classified as type III allosteric protein kinase inhibitors. These agents form a hydrogen bond with a conserved β3-lysine and they make numerous hydrophobic contacts with residues within the αC-helix, the β5 strand, and within the activation segment, regions of the protein kinase domain that exhibit greater diversity than those found within the ATP-binding site. One advantage of such allosteric inhibitors is that they do not have to compete with millimolar concentrations of cellular ATP, which most FDA-approved small molecule competitive inhibitors such as imatinib must do. Owing to the wide spread activation of this pathway in numerous neoplasms, trametinib and cobimetinib are being studied in combination with other targeted and cytotoxic drugs in a variety of clinical situations. Except for BRAF and NRAS mutations, there are no other biomarkers correlated with treatment responses following MEK1/2 inhibition and the discovery of such biomarkers would represent an important therapeutic breakthrough.

Topics: Antineoplastic Agents; Humans; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Melanoma; Melanoma, Cutaneous Malignant; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Skin Neoplasms

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

Melanoma has a tendency to metastasize to the brain. The development of brain metastasis is observed in all mutational subgroups. Overall, they are associated with poor prognosis. They are also associated with pain, neurological deterioration and thus, have a major impact on patients' quality of life. Historically, effective palliation by systemic therapy has been rare. The availability of new therapeutic agents, however, heralds a significant improvement in management options for these patients.. The development of targeted therapies and immune activating checkpoint inhibitors with durable benefit has led to a treatment paradigm change. Several clinical studies in patients with metastatic melanoma have demonstrated improved survival compared to chemotherapy. Many of these studies however excluded patients with brain involvement. Antitumor activity in brain metastasis has now been observed with some agents; further positive data are emerging. Surgery and stereotactic radiotherapy are also used for local control of oligometastatic disease. We discuss the usefulness of the available systemic treatments for management of brain metastases and how these are integrated with local treatments to enable optimal palliation.. Advances in the treatment of melanoma are providing significant palliative benefit for patients with brain metastases. Further investigations are needed to determine optimal treatment combinations and sequences.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Brain Neoplasms; Combined Modality Therapy; Disease-Free Survival; Humans; Immunotherapy; Indoles; Melanoma; Molecular Targeted Therapy; Nivolumab; Prognosis; Programmed Cell Death 1 Receptor; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Quality of Life; 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

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

The pharmacology, pharmacokinetics, clinical efficacy, safety, administration, cost, and place in therapy of trametinib for the treatment of metastatic melanoma are reviewed.. Approximately 40-60% of malignant melanomas have gene mutations at codon 600 of the BRAF gene that result in the activation of the mitogen-activated protein kinase (MAPK) pathway. Trametinib is the first-in-class mitogen-activated, extracellular signal-regulated kinase (MEK) inhibitor that targets a kinase in the MAPK pathway that plays a key role in oncogenic cell proliferation, survival, invasion, tumor angiogenesis, and escape from apoptosis. It is approved by the Food and Drug Administration for use in patients whose tumors express the BRAF V600E or V600K gene mutations. Moreover, trametinib is also indicated for use in combination with dabrafenib (a BRAF inhibitor). Trametinib is not indicated in patients who have received prior BRAF-inhibitor therapy due to poor response and possible cross-resistance. The most common adverse effects associated with the use of trametinib for both monotherapy and combination therapy are rash, diarrhea, peripheral edema, fatigue, and dermatitis. The recommended dosage of trametinib monotherapy is 2 mg orally once daily until disease progression or unacceptable toxicity occurs. With a daily dose of 2 mg, an estimated 30-day course of treatment would cost approximately $9135.. Trametinib, a novel MEK inhibitor, provides an alternative therapy for patients with BRAF V600 E/K metastatic melanoma as a single agent or in combination therapy for patients not previously treated with a BRAF inhibitor. More studies are needed to determine the safe and effective combination or sequencing of trametinib with other therapies.

Topics: Animals; Antineoplastic Agents; Humans; MAP Kinase Signaling System; Melanoma; Melanoma, Cutaneous Malignant; Pyridones; Pyrimidinones; Signal Transduction; Skin Neoplasms

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

Approximately 50% of patients with cutaneous metastatic melanoma harbor a somatic BRAF mutation. BRAF inhibitors are now established in the treatment paradigm of BRAF mutant melanoma, following the approval of vemurafenib by the US FDA in 2011. The vast majority of patients obtain some degree of tumor shrinkage with oral BRAF inhibitors, and responses are often rapid. However, resistance inevitably develops, with a median progression-free survival of 5-7 months. The oral MEK inhibitor trametinib has also shown activity in BRAF mutant melanoma in Phase III trials. We review the rationale for treating BRAF mutant melanoma with trametinib, as single-agent therapy and in combination with BRAF inhibitors, as well as the clinical data to date.

Topics: Antineoplastic Agents; Clinical Trials as Topic; Disease-Free Survival; Humans; Kaplan-Meier Estimate; MAP Kinase Kinase Kinases; Melanoma; Mutation, Missense; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms

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

The discovery of somatic mutations in melanoma has advanced our knowledge of the biology of the disease. The mutations, such as those in NRAS, BRAF, GNAQ and GNA11, promote the growth of melanoma cells in most part through the mitogen-activated protein kinase (MAPK) pathway. Understanding the molecular pathways of some of these mutations has resulted in the successful development of selective BRAF inhibitors. Yet, a cure for advanced melanoma is far from reality. Targeting MAPK/ERK kinase (MEK), an essential intermediary kinase protein within the MAPK pathway, may be a promising way to treat patients with BRAF or other genomic mutation.. The authors discuss the MAPK pathway in melanoma and review the preclinical and clinical studies of the MEK inhibitor, trametinib , in melanoma. They also discuss the potential of using trametinib in the targeted therapy of advanced melanoma.. Studies have demonstrated the activity of trametinib in BRAF-mutant melanoma, suggesting that it could be a very reasonable alternative to BRAF inhibitors for these patients. Current clinical investigations have shown great promise with the combination of trametinib and dabrafenib in patients with BRAF-mutant melanoma; a number of clinical trials of trametinib in combination with other targeted drugs are underway.

Topics: Animals; Antineoplastic Agents; Humans; MAP Kinase Signaling System; Melanoma; Mitogen-Activated Protein Kinase Kinases; Molecular Targeted Therapy; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Skin Neoplasms; Treatment Outcome

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

There are few approved therapies for cutaneous T-cell lymphoma (CTCL). The retinoids are the major biologic response modifiers used in CTCL, producing good response rates but few complete responses. For patients with early-stage disease, the oral retinoids can be combined with other therapies, such as psoralen plus ultraviolet A or interferon alpha, to improve response rates. Combined-modality therapy with oral retinoids, combined chemotherapy, electron-beam therapy, and topical mustargen has also proved effective. For the treatment of advanced-stage disease, the targeted therapy denileukin diftitox (Ontak) provides a nonimmunosuppressive alternative to conventional chemotherapy or radiation therapy. Of the conventional chemotherapies that have been tested in CTCL, gemcitabine (Gemzar) has demonstrated good efficacy in producing responses, particularly in patients with tumors. This agent can be used in combination with a maintenance therapy of bexarotene (Targretin) to manage the plaques and patches of mycosis fungoides. Several other targeted therapies are now also in testing, for example, alemtuzumab (CamPath), HuMax-CD4, several histone deacetylase inhibitors, and the transition-state inhibitor forodesine. These drugs, in combination with currently used therapies, may increase the number and combinations of therapies available for the treatment of this chronic condition to optimize long-lasting responses in CTCL.

Topics: Alemtuzumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Neoplasm; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Diphtheria Toxin; Dose-Response Relationship, Drug; Humans; Hydroxamic Acids; Immunologic Factors; Interferon-alpha; Interleukin-2; Lymphoma, T-Cell, Cutaneous; Mechlorethamine; Purine Nucleosides; Pyrimidinones; Radiotherapy, Adjuvant; Recombinant Fusion Proteins; Retinoids; Sezary Syndrome; Skin Neoplasms; Vorinostat

Primary cutaneous T-cell lymphomas (CTCLs) are a heterogeneous group of non-Hodgkin's lymphomas characterized by skin infiltration of neoplastic T lymphocytes. Mycosis fungoides and its leukemic variant Sézary syndrome represent the most common CTCL subtypes. Current treatment for patients with mycosis fungoides involves topical and systemic therapies for the cutaneous manifestations. However, no therapy is curative and patients often progress to advanced extracutaneous CTCL with visceral organ complications or relapsed disease that is frequently refractory to most topical and aggressive systemic regimens. The emergence of novel targeted therapies such as biologic agents, histone deacetylase inhibitors, and purine nucleoside phosphorylase inhibitors offers promise for more effective and safer treatment strategies for refractory CTCLs.

Topics: Clinical Trials as Topic; Histone Deacetylases; Humans; Immunologic Factors; Mycosis Fungoides; Purine Nucleosides; Purine-Nucleoside Phosphorylase; Pyrimidinones; Sezary Syndrome; Skin Neoplasms

Topics: Animals; Antineoplastic Agents; Arginase; Benz(a)Anthracenes; Benzopyrenes; Carcinogens; Cell Division; Cell Transformation, Neoplastic; Deoxyribonucleases; DNA; Fluorouracil; Humans; Liver Neoplasms; Methylcholanthrene; Mice; Mutation; Neoplasms; Neoplasms, Experimental; Nucleosides; Oncogenic Viruses; Orotic Acid; Phenanthrenes; Protein Binding; Pyrimidinones; Rats; Skin Neoplasms; Thymine; Uracil

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

This study suggests that trametinib has significant clinical activity in non-V600 BRAF mutation and BRAF fusion metastatic melanoma, albeit in a small cohort. All patients with metastatic melanoma should undergo sequencing of the BRAF gene to identify noncanonical BRAF mutations that may indicate benefit from treatment with trametinib.. Non-V600 BRAF mutations and BRAF fusions in aggregate occur in approximately 5% of all melanomas. Inhibition of the mitogen-activated protein kinase (MAPK) pathway has been implicated as a possible treatment strategy for these patients.. In this open-label, multicenter, phase II study, patients with advanced melanoma harboring mutations in BRAF outside V600 (non-V600) or BRAF fusions received trametinib 2.0 mg daily. Patients were divided into cohorts based on the intrinsic catalytic activity of BRAF mutation (high, cohort A; low/unknown, cohort B). The primary endpoint was objective response rate (ORR) for patients in cohort A; secondary endpoints included ORR in cohort B, safety, and survival in both treatment arms.. Among all patients, the ORR was 33% (three of nine patients), including 67% in cohort A and 17% in cohort B. Two patients had stable disease as best response, and six patients had some degree of tumor shrinkage. The median progression-free survival (PFS) was 7.3 months. Treatment-related adverse events occurred in all patients (100%); most (89%) were grade 1-2.. In contrast to recently described tumor-agnostic studies in a genetically similar population, trametinib had considerable activity in a small population of patients with melanoma harboring BRAF non-V600 mutations and fusions, providing rationale for sequencing in search of these genomic alterations.

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

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

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 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

Aberrant MAPK and PI3K pathway signaling may drive the malignant phenotype in NRAS-mutant and BRAF

Topics: Adult; Aged; Aged, 80 and over; Cohort Studies; Diamines; Female; GTP Phosphohydrolases; Humans; Male; MAP Kinase Kinase 1; Melanoma; Membrane Proteins; Middle Aged; Mutation; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Pyrazoles; Pyridones; Pyrimidinones; Skin Neoplasms; Survival Rate; Treatment Outcome; 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

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

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

Purpose TAK-733, an investigational, selective, allosteric MEK1/2 inhibitor, has demonstrated antitumor effects against multiple cancer cell lines and xenograft models. This first-in-human study investigated TAK-733 in patients with solid tumors. Methods Patients received oral TAK-733 once daily on days 1-21 in 28-day treatment cycles. Adverse events (AEs) were graded using the Common Terminology Criteria for AEs version 3.0. Response was assessed using RECIST v1.1. Blood samples for TAK-733 pharmacokinetics and pharmacodynamics (inhibition of ERK phosphorylation) were collected during cycle 1. Results Fifty-one patients received TAK-733 0.2-22 mg. Primary diagnoses included uveal melanoma (24 %), colon cancer (22 %), and cutaneous melanoma (10 %). Four patients had dose-limiting toxicities of dermatitis acneiform, plus fatigue and pustular rash in one patient, and stomatitis in one patient. The maximum tolerated dose was 16 mg. Common drug-related AEs included dermatitis acneiform (51 %), diarrhea (29 %), and increased blood creatine phosphokinase (20 %); grade ≥ 3 AEs were reported in 27 (53 %) patients. Median T

Topics: Adult; Aged; Antineoplastic Agents; Colonic Neoplasms; Extracellular Signal-Regulated MAP Kinases; Female; Humans; Male; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Maximum Tolerated Dose; Melanoma; Middle Aged; Phosphorylation; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Skin Neoplasms; Treatment Outcome; Uveal Neoplasms; Young Adult

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 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

We sought to determine the maximal tolerated dose of the MEK inhibitor trametinib with weekly paclitaxel, with a view to exploring the combination's activity in melanoma lacking a BRAF V600 mutation.. In this phase 1 study we used a fixed dose of paclitaxel (80 mg/m2 intravenous (IV) on days 1, 8 and 15 of each 4 week cycle) and escalated the dose of trametinib (to a maximum 2mg orally (PO) daily), following a 3+3 design. Eligible patients had advanced melanoma and could have received up to two previous lines of treatment for metastatic disease.. 15 patients were enrolled, all but one of whose melanoma was wild type for BRAF at codon 600. The maximal monotherapy dose of trametinib proved tolerable with weekly paclitaxel. The most frequent adverse events observed were rash and fatigue. Six (40%) partial responses were reported, including four of eight patients with NRAS mutations. Median progression free survival was 5.5 months (95% confidence interval (CI) 1.8-7.8 months) and overall survival, 14.1 months (95% CI 4.6-not reached).. Trametinib can safely be given with weekly paclitaxel at the full monotherapy dose. In this small group promising progression free and overall survival were observed in patients with melanoma lacking a V600 BRAF mutation.

Topics: Administration, Oral; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Male; Maximum Tolerated Dose; Melanoma; Middle Aged; Paclitaxel; Pyridones; Pyrimidinones; Skin Neoplasms

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

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

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

1. This study assessed the mass balance, metabolism and disposition of [(14)C]trametinib, a first-in-class mitogen-activated extracellular signal-related kinase (MEK) inhibitor, as an open-label, single solution dose (2 mg, 2.9 MBq [79 µCi]) in two male subjects with advanced cancer. 2. Trametinib absorption was rapid. Excretion was primarily via feces (∼81% of excreted dose); minor route was urinary (∼19% of excreted dose). The primary metabolic elimination route was deacetylation alone or in combination with hydroxylation. Circulating drug-related component profiles (composed of parent with metabolites) were similar to those found in elimination together with N-glucuronide of deacetylation product. Metabolite analysis was only possible from <50% of administered dose; therefore, percent of excreted dose (defined as fraction of percent of administered dose recovery over total dose recovered in excreta) was used to assess the relative importance of excretion and metabolite routes. The long elimination half-life (∼10 days) favoring sustained targeted activity was important in permitting trametinib to be the first MEK inhibitor with clinical activity in late stage clinical studies. 3. This study exemplifies the challenges and adaptability needed to understand the metabolism and disposition of an anticancer agent, like trametinib, with both low exposure and a long elimination half-life.

Topics: Absorption; Administration, Oral; Aged; Animals; Antineoplastic Agents; Carcinoma, Hepatocellular; Dose-Response Relationship, Drug; Humans; Liver Neoplasms; Male; Melanoma; Middle Aged; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Radiometry; Radiopharmaceuticals; Rats; 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

Forodesine is a potent inhibitor of purine nucleoside phosphorylase (PNP) that leads to intracellular accumulation of deoxyguanosine triphosphate (dGTP) in T and B cells, resulting in apoptosis. Forodesine has demonstrated impressive antitumor activity in early phase clinical trials in cutaneous T-cell lymphoma (CTCL).. In this phase II study, patients with CTCL who had already failed three or more systemic therapies were recruited. We investigated the response rate, safety and tolerability of oral forodesine treatment in subjects with cutaneous manifestations of CTCL, stages IB, IIA, IIB, III and IVA. The safety population encompassing all stages was used for analysis of accountability, demographics and safety. The efficacy population differed from the safety population by exclusion of stage IB and IIA patients.. All 144 patients had performance status 0-2. The median duration of CTCL from diagnosis was 53 months (5-516 months). The median number of pretreatments was 4 (range: 3-15). No complete remissions were observed. In the efficacy group of patients, 11% achieved partial remission and 50% had stable disease. The median time to response was 56 days and the median duration of response was 191 days. A total of 96% of all treated patients reported one or more adverse events (AEs) and 33% reported a serious AE. The majority of AEs were classified as mild or moderate in severity. The most commonly reported AEs (>10%) were peripheral edema, fatigue, insomnia, pruritus, diarrhea, headache and nausea. Overall eight patients died during the study: five due to sepsis and infections, one due to a second malignancy (esophageal cancer), one due to disease progression and one due to liver failure.. Oral forodesine at a dose of 200 mg daily is feasible and shows partial efficacy in this highly selected CTCL population and some durable responses.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Apoptosis; Female; Humans; Male; Middle Aged; Mycosis Fungoides; Purine Nucleosides; Purine-Nucleoside Phosphorylase; Pyrimidinones; Sezary Syndrome; Skin Neoplasms; Treatment Failure

BRAF mutations promote melanoma cell proliferation and survival primarily through activation of MEK. The purpose of this study was to determine the response rate (RR) for the selective, allosteric MEK1/MEK2 inhibitor trametinib (GSK1120212), in patients with metastatic BRAF-mutant melanoma.. This was an open-label, two-stage, phase II study with two cohorts. Patients with metastatic BRAF-mutant melanoma previously treated with a BRAF inhibitor (cohort A) or treated with chemotherapy and/or immunotherapy (BRAF-inhibitor naive; cohort B) were enrolled. Patients received 2 mg of trametinib orally once daily.. In cohort A (n = 40), there were no confirmed objective responses and 11 patients (28%) with stable disease (SD); the median progression-free survival (PFS) was 1.8 months. In cohort B (n = 57), there was one (2%) complete response, 13 (23%) partial responses (PRs), and 29 patients (51%) with SD (confirmed RR, 25%); the median PFS was 4.0 months. One patient each with BRAF K601E and BRAF V600R had prolonged PR. The most frequent treatment-related adverse events for all patients were skin-related toxicity, nausea, peripheral edema, diarrhea, pruritis, and fatigue. No cutaneous squamous cell carcinoma was observed.. Trametinib was well tolerated. Significant clinical activity was observed in BRAF-inhibitor-naive patients previously treated with chemotherapy and/or immunotherapy. Minimal clinical activity was observed as sequential therapy in patients previously treated with a BRAF inhibitor. Together, these data suggest that BRAF-inhibitor resistance mechanisms likely confer resistance to MEK-inhibitor monotherapy. These data support further evaluation of trametinib in BRAF-inhibitor-naive BRAF-mutant melanoma, including rarer forms of BRAF-mutant melanoma.

Topics: Adult; Aged; Antineoplastic Agents; Disease-Free Survival; Female; Humans; Kaplan-Meier Estimate; Male; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Melanoma; Middle Aged; Mutation; Neoplasm Staging; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Treatment Outcome

BCX1777 (forodesine), a novel purine nucleoside phosphorylase inhibitor, induces apoptosis, mainly in T cells. To evaluate the safety, tolerability, and pharmacokinetics of BCX1777, we conducted a phase I study in patients with relapsed or refractory peripheral T/natural killer-cell malignancies. Eligible patients had relapsed or refractory peripheral T/natural killer-cell malignancies without any major organ dysfunction. BCX1777 was administered orally once daily (dose escalation: 100, 200, and 300 mg) until disease progression requiring new therapy or unacceptable adverse events occurred. A total of 13 patients were enrolled and treated in three dose cohorts (100 mg/day, five patients; 200 mg/day, three patients; 300 mg/day, five patients). Although none of the patients developed dose-limiting toxicities, further dose escalation was not performed based on data from overseas. Therefore, the maximum tolerated dose was not determined. Adverse events of grade 3 or greater (≥2 patients) included lymphopenia (62%), anemia (15%), leukopenia (8%), and pyrexia (8%). Plasma pharmacokinetics parameter of BCX1777 (area under the plasma concentration-time curve) at day 1 in each cohort was 1948 ± 884, 4608 ± 1030, and 4596 ± 939 ng•h/mL, respectively. Disease control was achieved in approximately half of patients. One patient with anaplastic large cell lymphoma, which was negative for anaplastic lymphoma kinase, achieved a complete response, and two patients with cutaneous T-cell lymphoma achieved partial responses. BCX1777 was well tolerated at doses up to 300 mg once daily and showed preliminary evidence of activity in relapsed or refractory peripheral T/natural killer-cell malignancies, warranting further investigation.

Topics: Administration, Oral; Adult; Aged; Antineoplastic Agents; Area Under Curve; Cohort Studies; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Resistance, Neoplasm; Exanthema; Female; Humans; Lymphoma, Large-Cell, Anaplastic; Lymphoma, T-Cell; Lymphoma, T-Cell, Peripheral; Lymphopenia; Male; Metabolic Clearance Rate; Middle Aged; Mycosis Fungoides; Natural Killer T-Cells; Purine Nucleosides; Pyrimidinones; Recurrence; Skin Neoplasms; Treatment Outcome

MEK is a member of the MAPK signalling cascade that is commonly activated in melanoma. Direct inhibition of MEK blocks cell proliferation and induces apoptosis. We aimed to analyse safety, efficacy, and genotyping data for the oral, small-molecule MEK inhibitor trametinib in patients with melanoma.. We undertook a multicentre, phase 1 three-part study (dose escalation, cohort expansion, and pharmacodynamic assessment). The main results of this study are reported elsewhere; here we present data relating to patients with melanoma. We obtained tumour samples to assess BRAF mutational status, and available tissues underwent exploratory genotyping analysis. Disease response was measured by Response Evaluation Criteria in Solid Tumors, and adverse events were defined by common toxicity criteria. This study is registered with ClinicalTrials.gov, number NCT00687622.. 97 patients with melanoma were enrolled, including 81 with cutaneous or unknown primary melanoma (36 BRAF mutant, 39 BRAF wild-type, six BRAF status unknown), and 16 with uveal melanoma. The most common treatment-related adverse events were rash or dermatitis acneiform (n=80; 82%) and diarrhoea (44; 45%), most of which were grade 2 or lower. No cutaneous squamous-cell carcinomas were recorded. Of 36 patients with BRAF mutations, 30 had not received a BRAF inhibitor before; two complete responses (both confirmed) and ten partial responses (eight confirmed) were noted in this subgroup (confirmed response rate, 33%). Median progression-free survival of this subgroup was 5·7 months (95% CI 4·0-7·4). Of the six patients who had received previous BRAF inhibition, one unconfirmed partial response was recorded. Of 39 patients with BRAF wild-type melanoma, four partial responses were confirmed (confirmed response rate, 10%).. Our data show substantial clinical activity of trametinib in melanoma and suggest that MEK is a valid therapeutic target. Differences in response rates according to mutations indicate the importance of mutational analyses in the future.. GlaxoSmithKline.

Topics: Administration, Oral; Adult; Aged; Antineoplastic Agents; Disease-Free Survival; DNA Mutational Analysis; Drug Administration Schedule; Female; Humans; Kaplan-Meier Estimate; Male; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Melanoma; Middle Aged; Molecular Targeted Therapy; Mutation; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Time Factors; Treatment Outcome; United States; Uveal Neoplasms; Young Adult

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

Topics: Humans; Male; MAP Kinase Kinase 1; Melanoma; Mitogen-Activated Protein Kinase Kinases; Mutation; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms

BRAF V600 wild-type advanced melanomas quickly reach a therapeutic dead-end, after immunotherapy failure. Even if preclinical studies have suggested sensitivity to MEK inhibitors such as trametinib in NRAS, NF1 or GNA mutated melanoma, therapeutic options are limited for these patients. We present a retrospective monocentric study of 22 patients with advanced melanoma treated by trametinib after immunotherapy resistance. Melanomas harboured NRAS (20), NF1 (1) or GNA 11 (1) mutations. For most of them (18), anti-PD1 was associated with trametinib. A disease-control was reported in 36% of patients (8/22), with six stable diseases and two partial responses according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Median progression-free survival was 2 months (1-14) and median overall survival was 6.5 months (2-24). In patients with progressive disease (14/22), dissociated radiologic responses and clinical benefits such as pain reduction were seen in five patients. High blood level of lactate dehydrogenase (LDH) seemed associated with trametinib failure, without significance ( P  = 0.06). Adverse events (grade 1-3) occurred in 91% of patients during the first weeks of treatment, mainly papulo-pustular rashes (77%), leg oedemas (36%), asthenia (18%) and diarrhoea (14%). This real-life study showed that trametinib may benefit some metastatic melanoma that progressed after chemotherapy and immune checkpoint inhibitors. Objective disease control (partial response or stable disease) using RECIST criteria was observed in 36% of patients. Because of frequent side-effects which can alter the quality of life and the short response duration, this off-label option has to be discussed with the patient. Studies with combination therapy with trametinib to improve relapse-free survival and lower side-effects are ongoing.

Topics: Humans; Immunotherapy; Melanoma; Mutation; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Quality of Life; Retrospective Studies; Skin Neoplasms

BRAF V600 mutation is the most common oncogenic alternation in melanoma and is visible in around 50% of cutaneous and 10%-15% of acral or mucosal subtypes. Currently, immunotherapy with anti-PD-1 blockade and dual-targeted therapy with Dabrafenib plus trametinib (D + T) target therapy have been approved as adjuvant therapies for Stage III melanoma with BRAF V600 mutation. According to their phase III clinical trials, 3-year recurrence-free survival (RFS) is around 60% for both types of treatment. However, early disease control was slightly more effective with targeted therapy than immunotherapy. With different drug approval deadlines in China, anti-PD1 monotherapy, D + T combination, and Vemurafenib (V) monotherapy have all been used in real clinical practice as adjuvant settings for stage III BRAF-mut melanoma in recent years. We conducted this retrospective study to evaluate the efficacy of different treatments in the Chinese melanoma population.. Patients who underwent radical surgery and were diagnosed as Stage III melanoma harboring BRAF V600 mutation by pathological report were retrospectively identified at Fudan University Shanghai Cancer Center from January 2017 to December 2021. Patients with mucosal melanoma, or with follow-up of <6 months, or receiving other adjuvant treatment were excluded. Pearson's chi-squared test or Fisher's exact test was performed for univariable analysis of the different adjuvant groups. Log-rank analysis was used to identify prognostic factors for relapse-free survival (RFS).. Ninety-three patients with resected stage III melanoma with BRAF V600E mutation were identified in our study, including 25 patients receiving adjuvant anti-PD-1 immunotherapy (PD-1), 25 receiving adjuvant D + T, 23 receiving V, and 20 patients with observation-only (OBS). There were no statistical differences between treatment groups in baseline characteristics including age, gender, subtypes, primary thickness, ulceration, and nodal involvement. Median relapse-free survival (RFS) time was not reached in the D + T group, 15 months in the V group, 15 months in the PD-1 group, and 10 months in the OBS group, respectively. Compared to OBS, all three other groups showed a tendency to benefit from RFS, while only D + T achieved a statistical difference (p = 0.002). However, compared to D + T, anti-PD-1 monotherapy also showed significantly worse relapse control (p = 0.032).. For Chinese stage III melanoma with BRAF mutation, both novel targeted therapy and immunotherapy showed potential benefits in relapse-free survival compared to observation only. Dual-targeted D + T therapy may still be the best choice for adjuvant therapy because anti-PD-1 monotherapy has failed to report equivalent efficacy in real-world practice.

Topics: Adjuvants, Immunologic; Antineoplastic Combined Chemotherapy Protocols; China; Humans; Melanoma; Melanoma, Cutaneous Malignant; Mutation; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Retrospective Studies; Skin Neoplasms

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

Recent advances in the development of innovative treatments for MM (metastatic melanoma) significantly improved survival. BRAF inhibitor-targeted therapies are also indicated in stage IV BRAF-mutant melanoma, especially dabrafenib and trametinib in combination. The authors present here an impressive rapid (1 month) complete metabolic response on FDG PET/CT to BRAF inhibitors of an MM with a massive tumor burden estimated at more than 10 kg.

Topics: Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Fluorodeoxyglucose F18; Humans; Melanoma; Oximes; Positron Emission Tomography Computed Tomography; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Tumor Burden

Congenital melanocytic nevus (CMN) syndrome represents a mosaic RASopathy, typically caused by postzygotic NRAS codon 61 mutations, which originate in ectodermal precursor cells and result in melanocyte deposits in the skin and central nervous system (CNS). Affected patients are prone to develop uniformly fatal melanomas in the skin and CNS. Here, we report the case of a 2.7-year-old male with CMN syndrome, diffuse leptomeningeal melanosis and CNS melanoma, who underwent experimental therapy with the DNA methyltransferase inhibitor azacitidine in combination with the mitogen-activated protein kinase (MEK) inhibitor trametinib with exceptional clinical and radiological response. Response to combination therapy appeared to be more durable than the treatment response observed in several other severely affected patients treated with trametinib for late-stage disease. Correspondingly, concomitant exposure to trametinib and azacitidine prevented development of trametinib resistance in NRAS-mutated human melanoma cells in vitro. Also, azacitidine was shown to inhibit growth and mitogen-activated protein kinase 1/2 (ERK1/2) phosphorylation of melanoma cells and act synergistically with trametinib to inhibit the growth of trametinib-resistant melanoma cells. These observations suggest that azacitidine enhances trametinib monotherapy and may represent a promising candidate drug for combination therapies to enhance the efficacy of MEK inhibitors in RAS-driven diseases.

Topics: Azacitidine; Child, Preschool; GTP Phosphohydrolases; Humans; Male; Melanoma; Membrane Proteins; Meningeal Neoplasms; Mitogen-Activated Protein Kinase Kinases; Mutation; Nevus, Pigmented; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Skin Neoplasms

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

Topics: Aged; Antineoplastic Agents; Carcinoma, Squamous Cell; Class I Phosphatidylinositol 3-Kinases; Drug Combinations; Humans; Male; MAP Kinase Kinase 1; Metformin; Mutation; Neoplasm Recurrence, Local; Pyridones; Pyrimidinones; Skin Neoplasms; Time Factors; Treatment Outcome

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

The effect of serine/threonine-protein kinase B-Raf/mitogen-activated protein kinase (BRAF/MEK) inhibitors on the immune system is not clearly described, but rare cases of autoimmune phenomena have been reported. The clinical case we present below is the first report of a necrotizing myopathy related to dabrafenib/trametinib treatment. A 48-year-old man started dabrafenib/trametinib for stage IV BRAF-V600E mutated cutaneous melanoma. After the first month, he presented with grade 3 pyrexia (Common Terminology Criteria for Adverse Events [CTCAE] v.5.0.) and increased creatinine-kinase levels. A diagnosis of immune-mediated necrotizing myopathy, antisignal recognition particle (anit-SRP) positive, was made. At disease progression, dabrafenib/trametinib was restarted, triggering a new episode of grade 2 pyrexia and myositis. Treatment was changed to encorafenib/binimetinib without repeating pyrexia or limiting creatinine-kinase elevation, presenting even a loss of anti-SRP antibodies. Given the temporal relationship, the fact that re-exposition induced a new worsening of the myopathy and the loss of the anti-SRP antibodies after changing treatment, we infer that there possibly is a clear relationship between dabrafenib/trametinib treatment and the myopathy.

Topics: Antineoplastic Combined Chemotherapy Protocols; Creatinine; Fever; Humans; Imidazoles; Male; Melanoma; Middle Aged; Mitogen-Activated Protein Kinase Kinases; Mutation; Myositis; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms

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

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

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

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

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

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

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: 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

Hotspot mutations of the oncogenes BRAF and NRas are the most common genetic alterations in cutaneous melanoma. Still, the nanoscale organization and signal coupling of these proteins remain incompletely understood, particularly upon expression of oncogenic NRas mutants. Here we employed single-molecule localization microscopy to study the nanoscale organization of NRas and BRAF at the plasma membrane (PM) of melanoma cells. NRas and BRAF resided in self-clusters that did not associate well in resting cells. In EGF-activated cells, NRas clusters became more diffused while overall protein levels at the PM increased; thus allowing enhanced association of NRas and BRAF and downstream signaling. In multiple melanoma cell lines, mutant NRas resided in more pronounced self-clusters relative to wild-type (WT) NRas yet associated more with the clustered and more abundant BRAF. In cells resistant to trametinib, a clinical MEK inhibitor (MEKi), a similar coclustering of NRas and BRAF was observed upon EGF activation. Strikingly, treatment of cells expressing mutant NRas with trametinib reversed the effect of mutant NRas expression by restoring the nonoverlapping self-clusters of NRas and BRAF and by reducing their PM levels and elevated pERK levels caused by mutant NRas. Our results indicate a new mechanism for signal regulation of NRas in melanoma through its nanoscale dynamic organization and a new mechanism for MEKi function in melanoma cells carrying NRas mutations but lacking MEK mutations. SIGNIFICANCE: Nanoscale dynamic organization of WT and mutant NRas relative to BRAF serves as a regulatory mechanism for NRas signaling and may be a viable therapeutic target for its sensitivity to MEKi.

Topics: Cell Line, Tumor; Cell Membrane; Epidermal Growth Factor; Extracellular Signal-Regulated MAP Kinases; GTP Phosphohydrolases; Humans; MAP Kinase Kinase 1; Melanoma; Melanoma, Cutaneous Malignant; Membrane Proteins; Mutation; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Signal Transduction; Single Molecule Imaging; Skin Neoplasms

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

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

Topics: Antineoplastic Combined Chemotherapy Protocols; Azetidines; Biomarkers, Tumor; Female; Gene Fusion; Humans; Immune Checkpoint Inhibitors; Melanoma; Middle Aged; Mitogen-Activated Protein Kinase Kinases; Mutation; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Treatment Outcome

Despite clinical benefit from treatment with dabrafenib and trametinib in melanoma patients with BRAF mutations, half relapse within months and one-third are unresponsive to treatment. We evaluated the anticancer potential of metformin in combination with trametinib plus paclitaxel, against four melanoma cell lines.. Metformin with trametinib and paclitaxel was tested for effects on cell viability, signaling molecules in MAPK and mTOR pathways, factors involved in epithelial-mesenchymal transition (EMT), and cell motility.. The combination of metformin with trametinib and paclitaxel showed differential growth inhibitory effects; synergistic effects were observed in a cell line in which metformin suppresses ERK activity, whereas the combination showed antagonistic effects in a cell line with metformin-induced ERK activation. Trametinib or paclitaxel increased the expression of EMT regulators and melanoma cell motility, which were suppressed by combining metformin with trametinib and paclitaxel.. The combined treatment of metformin with trametinib and paclitaxel showed divergent effects on melanoma cell viability. Metformin might be useful as a potential adjuvant against cell proliferation and metastatic activity in melanoma patients.

Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cell Survival; Drug Synergism; Epithelial-Mesenchymal Transition; Humans; Melanoma; Metformin; Mutation; Paclitaxel; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Signal Transduction; Skin Neoplasms

We previously reported that methiothepin, a small molecule known as a nonselective serotonin 5-HT receptor antagonist, inhibited the doxorubicin efflux activity of the Hedgehog receptor Ptch1 and enhanced the cytotoxic, pro-apoptotic, anti-proliferative, and anti-clonogenic effects of doxorubicin on adrenocortical carcinoma cells. Here, we show that methiothepin also inhibits doxorubicin efflux and increases doxorubicin cytotoxicity in melanoma cells which endogenously overexpress Ptch1. Melanoma patients having the BRAF

Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Doxorubicin; Drug Resistance, Neoplasm; Humans; Melanoma; Methiothepin; Patched-1 Receptor; Pyridones; Pyrimidinones; Skin Neoplasms; Vemurafenib

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

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

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

NRAS mutations are the most common alterations among RAS isoforms in cutaneous melanoma, with patients harboring these aggressive tumors having a poor prognosis and low survival rate. The main line of treatment for these patients is MAPK pathway-targeted therapies, such as MEK inhibitors, but, unfortunately, the response to these inhibitors is variable due to tumor resistance. Identifying genetic modifiers involved in resistance toward MEK-targeted therapy may assist in the development of new therapeutic strategies, enhancing treatment response and patient survival. Our whole-genome CRISPR-Cas9 knockout screen identified the target Kelch domain-containing F-Box protein 42 (FBXO42) as a factor involved in NRAS-mutant melanoma-acquired resistance to the MEK1/2 inhibitor trametinib. We further show that FBXO42, an E3 ubiquitin ligase, is involved in the TAK1 signaling pathway, possibly prompting an increase in active P38. In addition, we demonstrate that combining trametinib with the TAK1 inhibitor, takinib, is a far more efficient treatment than trametinib alone in NRAS-mutant melanoma cells. Our findings thus show a new pathway involved in NRAS-mutant melanoma resistance and provide new opportunities for novel therapeutic options.

Topics: Base Sequence; Biomarkers, Tumor; Cell Line, Tumor; CRISPR-Cas Systems; Drug Resistance, Neoplasm; F-Box Proteins; Genetic Testing; Genome, Human; GTP Phosphohydrolases; Humans; MAP Kinase Kinase Kinases; MAP Kinase Signaling System; Melanoma; Membrane Proteins; Mitogen-Activated Protein Kinase Kinases; Models, Biological; Mutation; Protein Binding; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Skin Neoplasms

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

TYRP1 mRNA is of interest due to its potential non-coding role as a sponge sequestering tumor-suppressive miRs in melanoma. To our knowledge, there is no report on changes in TYRP1 expression in melanomas after development of resistance to targeted therapies. We used patient-derived drug-naïve RAS

Topics: Cell Line, Tumor; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Humans; Melanoma; Membrane Glycoproteins; Microphthalmia-Associated Transcription Factor; Mutation; Neoplasm Recurrence, Local; Oxidoreductases; Protein Isoforms; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; RNA, Messenger; Skin Neoplasms; Vemurafenib

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

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

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

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

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

Cutaneous melanoma is one of the most aggressive forms of skin neoplasms and represents a major cause of neoplastic or cancer death in Europe. Without adequate therapy, the 5-year survival rate is 15% when the disease metastasizes to distant organs. The objective of our study was to evaluate the status quo of the current treatment standards in stage IV melanoma and rationale for therapy decisions in Germany and Austria between January 2016 and September 2018.. In this retrospective, anonymized registry, data of male and female patients with unresectable advanced/metastatic BRAF-positive cutaneous melanoma treated in the first, second, and third line with registered substances were analyzed using descriptive statistics.. Ninety-nine patients (50.5% male) received a total of 172 treatment lines. The first (99 patients), second (56 patients), and third (17 patients) treatment lines were documented. Within the 80.8% of patients with stage IV melanoma, targeted therapy (TT) was more frequently administered as a first-line treatment than immunotherapy (IO) with checkpoint inhibitors (59.6% TT vs. 40.4% IO). Across all lines, patients received TT in 54.7% and IO in 43.0% of the cases. As targeted agents, dabrafenib plus trametinib was predominantly prescribed (72.3%), whereas the monotherapy with anti-programmed cell death protein 1 and anti-cytotoxic T lymphocyte-associated protein 4 antibodies or their combination was prescribed similarly often (50.0% vs. 47.3%). Most commonly, the treatment type was switched from TT to IO or vice versa upon disease progression. The most frequent rationales for prescribing either TT or IO were remission pressure (72.9%) or physician's preference (45.0%), respectively. Disease progression was a more frequent cause of treatment discontinuation than undesired events.. Patients in Germany and Austria with unresectable advanced or metastatic BRAF-mutant melanoma predominantly receive guideline-recommended treatments. TT was more frequently administered than IO while the rationale for prescribing a specific treatment type differed between the two.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Austria; Cross-Sectional Studies; Female; Germany; Humans; Imidazoles; Male; Melanoma; Middle Aged; Molecular Targeted Therapy; Neoplasm Metastasis; Oximes; Practice Guidelines as Topic; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Retrospective Studies; Skin Neoplasms; Young Adult

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

Microneedles (MNs) technology has many advantages and is an ideal local transdermal drug delivery method. Here we synthesized photocrosslinkable dextran methacrylate (DexMA), and its degree of substitution is 5 % higher than the previous method. We used DexMA hydrogel for the first time to develop a new type of MNs for continuous transdermal administration. The prepared hydrogel MNs can successfully penetrate the epidermal layer and achieve sustained drug release. Doxorubicin (DOX) and trametinib (Tra) are anticancer drugs approved by FDA. Besides, Tra can also reverse P-gp-mediated multidrug resistance (MDR) to effectively block the efflux of DOX by P-gp. We used MNs to simultaneously load Tra and DOX, and achieved synergy in a B16 cell xenograft nude mouse model. The DexMA hydrogel MNs developed in this study can be used to enhance the transdermal delivery of small molecule drugs and reduce systemic toxicity and side effects.

Topics: Administration, Cutaneous; Animals; Antineoplastic Agents; Cell Line, Tumor; Dextrans; Doxorubicin; Drug Delivery Systems; Drug Liberation; Drug Resistance, Neoplasm; Hydrogels; Melanoma, Experimental; Methacrylates; Mice; Mice, Nude; Neoplasm Transplantation; Permeability; Pyridones; Pyrimidinones; Skin; Skin Neoplasms; Tumor Burden

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

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

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

Malignant melanoma is the most aggressive type of skin cancer and is closely associated with the development of brain metastases. Despite aggressive treatment, the prognosis has traditionally been poor, necessitating improved therapies. In melanoma, the mitogen activated protein kinase and the phosphoinositide 3-kinase signaling pathways are commonly altered, and therapeutically inhibiting one of the pathways often upregulates the other, leading to resistance. Thus, combined treatment targeting both pathways is a promising strategy to overcome this. Here, we studied the in vitro and in vivo effects of the PI3K inhibitor buparlisib and the MEK1/2 inhibitor trametinib, used either as targeted monotherapies or in combination, on patient-derived melanoma brain metastasis cell lines. Scratch wound and trans-well assays were carried out to assess the migratory capacity of the cells upon drug treatment, whereas flow cytometry, apoptosis array and Western blots were used to study apoptosis. Finally, an in vivo treatment experiment was carried out on NOD/SCID mice. We show that combined therapy was more effective than monotherapy. Combined treatment also more effectively increased apoptosis, and inhibited tumor growth in vivo. This suggests a clinical potential of combined treatment to overcome ceased treatment activity which is often seen after monotherapies, and strongly encourages the evaluation of the treatment strategy on melanoma patients with brain metastases.

Topics: Aminopyridines; Animals; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Cell Line, Tumor; Melanoma; Mice, Inbred NOD; Mice, SCID; Mitogen-Activated Protein Kinases; Morpholines; Phosphatidylinositol 3-Kinases; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Signal Transduction; Skin Neoplasms; Treatment Outcome; Tumor Burden; Xenograft Model Antitumor Assays

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

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

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

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

Patients with malignant melanoma often relapse after treatment with BRAF and/or mitogen-activated protein kinase kinase (MEK) inhibitors (MEKi) owing to development of drug resistance.. To establish the temporal pattern of CD271 regulation during development of resistance by melanoma to trametinib, and determine the association between development of resistance to trametinib and induction of prosurvival autophagy.. Immunohistochemistry for CD271 and p62 was performed on human naevi and primary malignant melanoma tumours. Western blotting was used to analyse expression of CD271, p62 and LC3 in melanoma subpopulations. Flow cytometry and immunofluorescence microscopy was used to evaluate trametinib-induced cell death and CD271 expression. MTS viability assays and zebrafish xenografts were used to evaluate the effect of CD271 and autophagy modulation on trametinib-resistant melanoma cell survival and invasion, respectively.. CD271 and autophagic signalling are increased in stage III primary melanomas vs. benign naevi. In vitro studies demonstrate MEKi of BRAF-mutant melanoma induced cytotoxic autophagy, followed by the emergence of CD271-expressing subpopulations. Trametinib-induced CD271 reduced autophagic flux, leading to activation of prosurvival autophagy and development of MEKi resistance. Treatment of CD271-expressing melanoma subpopulations with RNA interference and small-molecule inhibitors to CD271 reduced the development of MEKi resistance, while clinically applicable autophagy modulatory agents - including Δ9-tetrahydrocannabinol and Vps34 - reduced survival of MEKi-resistant melanoma cells. Combined MEK/autophagy inhibition also reduced the invasive and metastatic potential of MEKi-resistant cells in an in vivo zebrafish xenograft.. These results highlight a novel mechanism of MEKi-induced drug resistance and suggest that targeting autophagy may be a translatable approach to resensitize drug-resistant melanoma cells to the cytotoxic effects of MEKi.

Topics: Animals; Apoptosis; Autophagy; Biomarkers, Tumor; Cell Line, Tumor; Cell Survival; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Humans; Melanoma; Mitogen-Activated Protein Kinase Kinases; Neoplasm Recurrence, Local; Nerve Tissue Proteins; Nevus; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Receptors, Nerve Growth Factor; RNA-Binding Proteins; Skin; Skin Neoplasms; Xenograft Model Antitumor Assays; Zebrafish

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

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

Giant congenital nevi are melanocytic proliferations of the skin that may be complicated by melanoma, neurocutaneous melanocytosis, pain, pruritus, and disfigurement. Current treatment options include surgical resection and medical management of associated symptoms. There is limited efficacy in these modalities. No effective pharmacologic treatments are available for the treatment of these lesions. We present the case of a 7-year-old girl with a giant congenital melanocytic nevus that had an

Topics: Antineoplastic Agents; Child; Female; Humans; Nevus, Pigmented; Pyridones; Pyrimidinones; Skin Neoplasms; Treatment Outcome

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

The aim of this study was to describe inflammatory side effects in patients treated with BRAF and MEK inhibitors at a single tertiary care institution. This was a retrospective chart review of patients prescribed single-agent or combination BRAF and MEK inhibitors from January 2010 until May 2015. The primary outcome was the presence of inflammatory side effects. Among 124 patients, 56.4% were male, the median age was 59 years, and most (91.1%) were treated for metastatic melanoma. Most patients (74.2%) developed inflammatory side effects, some with multiple occurrences, for a total of 211 occurrences. The overall prevalence of inflammatory side effects did not differ across therapies. In a subanalysis, patients treated with both single-agent and combination therapies were more likely to experience an inflammatory side effect on single-agent therapy (P = 0.0126 for BRAF inhibitor, P = 0.0833 for MEK inhibitor). The most common inflammatory side effects for the entire cohort included arthralgias/myalgias (32.9%), nonacneiform rash (28.0%), pyrexia (25.5%), and erythema nodosum (11.2%), although side effects differed across the class of therapy. Corticosteroids were initiated in 73 side effect instances among 47 patients. Drug interruption or dose reduction was reported in 78 side effect instances in 50 patients. Fifteen side effect instances led to treatment termination. There is a high prevalence of inflammatory side effects encompassing all organ systems in patients treated with BRAF and MEK inhibitors. There is no significant difference in the prevalence of inflammatory side effects in patients treated with single-agent versus combination therapies, however, side effect profile differs across agents.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Female; Humans; Inflammation; Male; MAP Kinase Kinase 1; Melanoma; Middle Aged; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyrimidinones; Retrospective Studies; Skin Neoplasms; Treatment Outcome; Young Adult

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: 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

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

Gastrointestinal toxicities of MEK inhibitors in melanoma patients are frequent. In clinical trials, the most common digestive adverse events were nausea, vomiting, and diarrhoea. However, severe toxicities such as colitis and gastrointestinal perforation, some with fatal outcomes, have been reported. These rare but severe adverse events are not well described. We performed a retrospective analysis of all patients with stage IV and unresectable stage III melanoma treated with a MEK inhibitors at Saint-Louis Hospital, Paris, between 1 August 2013 and 15 October 2018. Among 119 patients exposed to MEK inhibitors, 78 were treated with trametinib, 19 with cobimetinib, four with binimetinib, and 18 patients with two different MEK inhibitors at separate times. All grade digestive adverse events were observed in 39 (32.7%) patients. Grade 3 and 4 adverse events occurred in 6 (5%) patients: 2 (1.7%) developed perforations, 3 (2.5%) had colitis and 1 (0.8%) had grade 4 diarrhoea. These adverse events were all reversible following a permanent discontinuation of the MEK inhibitors, or a temporary interruption followed by resumption at a dose lower than conventional posology. There were no fatal outcomes; however one patient had a permanent ileostomy. The mechanism underlying these toxicities is not well known. Clinicians should be aware of such toxicities.

Topics: Adult; Aged; Antineoplastic Agents; Azetidines; Benzimidazoles; Databases, Factual; Enzyme Inhibitors; Female; Gastrointestinal Tract; Humans; Male; MAP Kinase Kinase 1; Melanoma; Middle Aged; Piperidines; Pyridones; Pyrimidinones; Retrospective Studies; Skin Neoplasms; Treatment Outcome

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

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

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

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

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: 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

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

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

The treatment of melanoma requires complete removal of tumor cells and simultaneous tissue regeneration of tumor-initiated cutaneous defects. Herein, copper silicate hollow microspheres (CSO HMSs)-incorporated bioactive scaffolds were designed for chemo-photothermal therapy of skin cancers and regeneration of skin tissue. CSO HMSs were synthesized with interior hollow and external nanoneedle microstructure, showing excellent drug-loading capacity and photothermal effects. With incorporation of drug-loaded CSO HMSs into the electrospun scaffolds, the composite scaffolds exhibited excellent photothermal effects and controlled NIR-triggered drug release, leading to distinctly synergistic chemo-photothermal therapy of skin cancer both in vitro and in vivo. Furthermore, such CSO HMSs-incorporated scaffolds could promote proliferation and attachment of normal skin cells and accelerate skin tissue healing in tumor-bearing and diabetic mice. Taken together, CSO HMSs-incorporated scaffolds may be used for complete eradication of the remaining tumor cells after surgery and simultaneous tissue healing, which offers an effective strategy for therapy and regeneration of tumor-initiated tissue defects.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Copper; Drug Carriers; Drug Delivery Systems; Hyperthermia, Induced; Male; Melanoma; Mice, Inbred BALB C; Mice, Nude; Nanostructures; Phototherapy; Pyridones; Pyrimidinones; Silicates; Skin Neoplasms; Tissue Scaffolds

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

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

While advances in laboratory automation has dramatically increased throughout of compound screening efforts, development of robust cell-based assays in relevant disease models remain resource-intensive and time-consuming, presenting a bottleneck to drug discovery campaigns. To address this issue, we present a modified gene trap approach to efficiently generate pathway-specific reporters that result in a robust "on" signal when the pathway of interest is inhibited. In this proof-of-concept study, we used vemurafenib and trametinib to identify traps that specifically detect inhibition of the mitogen-activated protein kinase (MAPK) pathway in a model of BRAFV600E driven human malignant melanoma. We demonstrate that insertion of our trap into particular loci results in remarkably specific detection of MAPK pathway inhibitors over compounds targeting any other pathway or cellular function. The accuracy of our approach was highlighted in a pilot screen of ~6000 compounds where 40 actives were detected, including 18 MEK, 10 RAF, and 3 ERK inhibitors along with a few compounds representing previously under-characterized inhibitors of the MAPK pathway. One such compound, bafetinib, a second generation BCR/ABL inhibitor, reduced phosphorylation of ERK and when combined with trametinib, both in vitro and in vivo, reduced growth of vemurafenib resistant melanoma cells. While piloted in a model of BRAF-driven melanoma, our results set the stage for using this approach to rapidly generate reporters against any transcriptionally active pathway across a wide variety of disease-relevant cell-based models to expedite drug discovery efforts.

Topics: Animals; Antineoplastic Agents; Cell Line; Cell Line, Tumor; Drug Discovery; Female; HEK293 Cells; Humans; Melanoma; Melanoma, Cutaneous Malignant; Mice; Mitogen-Activated Protein Kinases; Phosphorylation; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidines; Pyrimidinones; Skin Neoplasms; Vemurafenib

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

Systemic melanoma therapies have the potential to affect basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cuSCC) development. In this study, we aim to compare the incidence of BCC and cuSCC in patients with metastatic melanoma treated with antiprogrammed cell death-1 (anti-PD1), BRAF inhibitor (BRAFi) monotherapy or dabrafenib and trametinib combination therapy (CombiDT) with a group of control patients having similar risk factors. We reviewed the records of melanoma patients on anti-PD1, BRAFi, or CombiDT, and patients from the High-Risk Melanoma Clinic, Westmead Hospital. We also performed an immunohistochemical analysis of BCCs under anti-PD1 compared with controls using PD1, PD-L1, CD3, CD8, and CD20 stains. For the results, in all, 340 patients were included; 82 on anti-PD1, 134 on BRAFi, 69 on CombiDT, and 55 controls. BRAFi had the highest incidence of BCC (12.7%), followed by CombiDT (10.1%) and anti-PD1 (2.4%). The incidence of BCC was significantly lower in patients on anti-PD1 (2.4% vs. 19.4%; P<0.001) compared with controls. Patients on anti-PD1 were 8.54 times less likely to develop BCC than the controls [hazard ratio, 0.117 (95% confidence interval, 0.026-0.526), P=0.005]. BRAFi and CombiDT showed no significant differences in BCC incidence compared with controls. BRAFi had the highest cuSCC incidence (23.9%), followed by anti-PD1 (7.3%) and CombiDT (2.9%). The incidence of cuSCC was significantly higher in patients on BRAFi (23.9% vs. 3.5%; P<0.001) compared with controls, but anti-PD1 and CombiDT showed no differences in cuSCC incidence compared with controls. Immunohistochemistry analysis of 10 BCC from under anti-PD1 and 8 BCC from controls patients showed that while all BCC had negative PD-L1 staining, the percentage of PD1 staining in anti-PD1 group is significantly lower than that of the control group (independent t test, 8% vs. 26%; P<0.001). In conclusion, our study suggests that anti-PD1 therapy decreases the incidence of BCC, as a result of the PD1/PD-L1 blockade. Future studies investigating the role of anti-PD1 in suppressing or treating BCC may be warranted.

Topics: Adult; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Australia; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Female; Humans; Immunotherapy; Incidence; Male; Melanoma; Middle Aged; Neoplasm Staging; Nivolumab; Programmed Cell Death 1 Receptor; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Skin Neoplasms

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

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

Trametinib, a mitogen-activated extracellular signal-regulated kinase (MEK) inhibitor, has demonstrated great promise in treating metastatic melanoma associated with BRAF V600E and V600K mutations; however, it also is highly associated with cutaneous adverse events (AEs). As both BRAF and MEK inhibitors become increasingly used to treat malignant melanoma, it is important to better characterize these AEs so that we can manage them. Herein, we present a case of a 66-year-old man who developed erythematous scaly papules on the face and bilateral upper extremities after beginning therapy with trametinib. The severity of the reaction worsened on trametinib monotherapy compared to combination therapy with a BRAF inhibitor. Biopsy revealed a xanthogranulomatous reaction.

Topics: Acrylonitrile; Aged; Aniline Compounds; Antineoplastic Agents; Diagnosis, Differential; Granuloma; Humans; Male; Melanoma; Neoplasm Staging; Pyridones; Pyrimidinones; Skin Neoplasms; Xanthomatosis

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: Aged; Antineoplastic Agents; Biopsy; Diagnosis, Differential; Humans; Male; Melanoma; Melanoma, Cutaneous Malignant; Neoplasms, Second Primary; Pleura; Pleural Cavity; Pleural Neoplasms; Positron-Emission Tomography; Pyridones; Pyrimidinones; 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

Topics: Animals; Antibodies, Monoclonal; Antineoplastic Agents; Clinical Trials as Topic; Costimulatory and Inhibitory T-Cell Receptors; Humans; Immunotherapy; MAP Kinase Kinase Kinases; Melanoma; Molecular Targeted Therapy; Mutation; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms

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

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

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

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

A majority of patients with BRAF-mutated metastatic melanoma respond to therapy with BRAF inhibitors (BRAFi), but relapses are common owing to acquired resistance. To unravel BRAFi resistance mechanisms we have performed gene expression and mass spectrometry based proteome profiling of the sensitive parental A375 BRAF V600E-mutated human melanoma cell line and of daughter cell lines with induced BRAFi resistance. Increased expression of two novel resistance candidates, aminopeptidase-N (CD13/ANPEP) and ETS transcription factor FLI1 was observed in the BRAFi-resistant daughter cell lines. In addition, increased levels of the previously reported resistance mediators, receptor tyrosine kinase ephrine receptor A2 (EPHA2) and the hepatocyte growth factor receptor MET were also identified. The expression of these proteins was assessed in matched tumor samples from melanoma patients obtained before BRAFi and after disease progression. MET was overexpressed in all progression samples while the expression of the other candidates varied between the individual patients. Targeting CD13/ANPEP by a blocking antibody induced apoptosis in both parental A375- and BRAFi-resistant daughter cells as well as in melanoma cells with intrinsic BRAFi resistance and led to dephosphorylation of EPHA2 on S897, previously demonstrated to cause inhibition of the migratory capacity. AKT and RSK, both reported to induce EPHA2 S897 phosphorylation, were also dephosphorylated after inhibition of CD13/ANPEP. FLI1 silencing also caused decreases in EPHA2 S897 phosphorylation and in total MET protein expression. In addition, silencing of FLI1 sensitized the resistant cells to BRAFi. Furthermore, we show that BRAFi in combination with the multi kinase inhibitor dasatinib can abrogate BRAFi resistance and decrease both EPHA2 S897 phosphorylation and total FLI1 protein expression. This is the first report presenting CD13/ANPEP and FLI1 as important mediators of resistance to BRAF inhibition with potential as drug targets in BRAFi refractory melanoma.

Topics: Antineoplastic Agents; Apoptosis; CD13 Antigens; Cell Cycle Checkpoints; Cell Line, Tumor; Dasatinib; Drug Resistance, Neoplasm; Ephrin-A2; Gene Expression Regulation, Neoplastic; Humans; Indoles; Melanoma; Microfilament Proteins; Phosphorylation; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-met; Pyridones; Pyrimidinones; Receptor, EphA2; Receptors, Cytoplasmic and Nuclear; Ribosomal Protein S6 Kinases, 90-kDa; RNA, Small Interfering; Signal Transduction; Skin Neoplasms; Sulfonamides; Trans-Activators; Vemurafenib

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

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

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

Primary melanoma of the CNS in children is extremely rare, and usually linked to congenital melanocytic naevus syndrome, caused by mosaicism for oncogenic NRAS mutations. Outcome is fatal in all cases. Data from murine and in vitro studies suggest that MEK inhibition is a possible therapeutic option.. Four children with NRAS-mutated CNS melanoma were treated with Trametinib on a compassionate basis.. All four had an improvement in symptoms and objectively in signs. These varied from mild improvement for 1 month, to a sustained symptom-free period of 9 months in one case. In all cases there was eventual disease progression through treatment, followed by rapid death after discontinuation. There were no clinically-significant side effects.. Trametinib is the first therapy to show any objective or measurable effect in NRAS-mutated primary CNS melanoma, with few side effects in this small series. The role of this therapy should be explored further in this rare paediatric tumour.

Topics: Central Nervous System Neoplasms; Child, Preschool; Female; GTP Phosphohydrolases; Humans; Infant; Male; MAP Kinase Kinase 1; Melanoma; Membrane Proteins; Mutation; Prognosis; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; 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

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

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 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

Approximately 7 % of melanomas have a BRAF mutation beyond codon 600. These mutations can be BRAF activating without being addressable by an approved BRAF inhibitor. The case of a patient with fulminant metastatic melanoma and a BRAF(L597Q) mutation is presented. It is demonstrated that the tumor shows an excellent response to the MEK inhibitor trametinib. This is an example for possible targeted therapy in a non-V600-mutated melanoma resulting in a 17-month overall survival.

Topics: Antineoplastic Agents; Humans; Male; Melanoma; Middle Aged; Mutation; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Treatment Outcome

Topics: Animals; Antineoplastic Agents; Apoptosis; Azetidines; Carcinoma, Squamous Cell; Cell Line, Tumor; Cellular Senescence; Humans; Mitogen-Activated Protein Kinases; Molecular Targeted Therapy; Piperidines; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Skin Neoplasms; Xenograft Model Antitumor Assays

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

BRAF inhibitors are highly effective therapies for the treatment of BRAF(V600)-mutated melanoma, with the main toxicity being a variety of hyperproliferative skin conditions due to paradoxical activation of the mitogen-activated protein kinase (MAPK) pathway in BRAF wild-type cells. Most of these hyperproliferative skin changes improve when a MEK inhibitor is co-administered, as it blocks paradoxical MAPK activation. Here we show how the BRAF inhibitor vemurafenib accelerates skin wound healing by inducing the proliferation and migration of human keratinocytes through extracellular signal-regulated kinase (ERK) phosphorylation and cell cycle progression. Topical treatment with vemurafenib in two wound-healing mice models accelerates cutaneous wound healing through paradoxical MAPK activation; addition of a mitogen-activated protein kinase kinase (MEK) inhibitor reverses the benefit of vemurafenib-accelerated wound healing. The same dosing regimen of topical BRAF inhibitor does not increase the incidence of cutaneous squamous cell carcinomas in mice. Therefore, topical BRAF inhibitors may have clinical applications in accelerating the healing of skin wounds.

Topics: Administration, Topical; Animals; Carcinogenesis; Carcinogens; Carcinoma, Squamous Cell; Cell Cycle; Cell Line, Tumor; Female; Humans; Incidence; Indoles; Keratinocytes; MAP Kinase Signaling System; Mice; Mice, Inbred BALB C; Mitogen-Activated Protein Kinase Kinases; Mitogen-Activated Protein Kinases; Neoplasms, Experimental; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin; Skin Neoplasms; Sulfonamides; Treatment Outcome; Vemurafenib; Wound Healing

Therapy of melanoma patients harboring activating mutations in the BRAF (V-raf murine sarcoma viral oncogene homolog B1) oncogene with a combination of BRAF and MEK inhibitors is plagued by the development of drug resistance. Mutational events, as well as adaptive mechanisms, contribute to the development of drug resistance. In this context we uncover here the role of a miRNA, miR-579-3p. We first show that low expression of miR-579-3p is a negative prognostic factor correlating with poor survival. Expression levels of miR-579-3p decrease from nevi to stage III/IV melanoma samples and even further in cell lines resistant to BRAF/MEK inhibitors. Mechanistically, we demonstrate that miR-579-3p acts as an oncosuppressor by targeting the 3'UTR of two oncoproteins: BRAF and an E3 ubiquitin protein ligase, MDM2. Moreover miR-579-3p ectopic expression impairs the establishment of drug resistance in human melanoma cells. Finally, miR-579-3p is strongly down-regulated in matched tumor samples from patients before and after the development of resistance to targeted therapies.

Topics: 3' Untranslated Regions; Antineoplastic Agents; Base Sequence; Binding Sites; Cell Line, Tumor; Cell Movement; Cell Proliferation; Disease Progression; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Humans; Indoles; Melanoma; MicroRNAs; Prognosis; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins c-mdm2; Pyridones; Pyrimidinones; Skin Neoplasms; Sulfonamides; Survival Analysis; Vemurafenib

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

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

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

MEK inhibitors are being evaluated in clinical trials for treatment of different malignant neoplasms; trametinib dimethyl sulfoxide was approved by the US Food and Drug Administration for melanoma in 2013. We present 3 cases of patients receiving MEK inhibitors who developed an atypical eruption.. Three patients who were receiving different MEK inhibitors (selumetinib, cobimetinib, and trametinib) developed an eruption, all associated with unique duskiness. Drug hypersensitivity was confirmed by histopathologic testing in 2 of the 3 cases. The skin eruption responded well to corticosteroids and did not recur when treatment with the MEK inhibitor was restarted in 2 of the patients.. The typical skin reaction associated with MEK inhibitors is a papulopustular eruption. To our knowledge, the dusky erythema that occurred in the 3 patients described here has not previously been reported for this drug class.

Topics: Adult; Azetidines; Benzimidazoles; Drug Eruptions; Erythema; Female; Glucocorticoids; Humans; Male; Melanoma; Middle Aged; Mitogen-Activated Protein Kinase Kinases; Piperidines; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Skin Neoplasms

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

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: 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

Malignant melanoma has an increasing incidence rate and the metastatic disease is notoriously resistant to standard chemotherapy. Loss of cell cycle checkpoints is frequently found in many cancer types and makes the cells reliant on compensatory mechanisms to control progression. This feature may be exploited in therapy, and kinases involved in checkpoint regulation, such as Wee1 and Chk1/2, have thus become attractive therapeutic targets.. In the present study we combined a Wee1 inhibitor (MK1775) with Chk1/2 inhibitor (AZD7762) in malignant melanoma cell lines grown in vitro (2D and 3D cultures) and in xenografts models.. Our in vitro studies showed that combined inhibition of Wee1 and Chk1/2 synergistically decreased viability and increased apoptosis (cleavage of caspase 3 and PARP), which may be explained by accumulation of DNA-damage (increased expression of γ-H2A.X)--and premature mitosis of S-phase cells. Compared to either inhibitor used as single agents, combined treatment reduced spheroid growth and led to greater tumour growth inhibition in melanoma xenografts.. These data provide a rationale for further evaluation of the combination of Wee1 and Chk1/2 inhibitors in malignant melanoma.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Cycle Checkpoints; Cell Cycle Proteins; Cell Line, Tumor; Cell Proliferation; Checkpoint Kinase 2; Drug Synergism; Humans; Melanoma; Melanoma, Cutaneous Malignant; Mice; Nuclear Proteins; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; Pyrimidinones; Skin Neoplasms; Thiophenes; Urea; Xenograft Model Antitumor Assays

Topics: Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Brain Neoplasms; Carrier Proteins; Disease Progression; DNA Mutational Analysis; Female; Humans; Intracellular Signaling Peptides and Proteins; Magnetic Resonance Imaging; Male; MAP Kinase Kinase Kinases; Melanoma; Membrane Proteins; Middle Aged; Neoplasm Metastasis; Oncogene Proteins, Fusion; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Treatment Outcome

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

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

Keratoacanthomas (KAs) and cutaneous squamous cell carcinomas (cuSCCs) develop in 15-30% of patients with BRAF(V600E) metastatic melanoma treated with BRAF inhibitors (BRAFi). These lesions resemble mouse skin tumors induced by the two-stage DMBA/TPA skin carcinogenesis protocol; in this protocol BRAFi accelerates tumor induction. Since prior studies demonstrated cyclooxygenase 2 (COX-2) is necessary for DMBA/TPA tumor induction, we hypothesized that COX-2 inhibition might prevent BRAFi-accelerated skin tumors. Celecoxib, a COX-2 inhibitor, significantly delayed tumor acceleration by the BRAFi inhibitor PLX7420 and decreased tumor number by 90%. Tumor gene expression profiling demonstrated that celecoxib partially reversed the PLX4720-induced gene signature. In PDV cuSCC cells, vemurafenib (a clinically approved BRAFi) increased ERK phosphorylation and soft agar colony formation; both responses were greatly decreased by celecoxib. In clinical trials trametinib, a MEK inhibitor (MEKi) increases BRAFi therapy efficacy in BRAF(V600E) melanomas and reduces BRAFi-induced KA and cuSCC frequency. Trametinib also reduced vemurafenib-induced PDV soft agar colonies, but less efficiently than celecoxib. The trametinb/celecoxib combination was more effective than either inhibitor alone. In conclusion, celecoxib suppressed both BRAFi-accelerated skin tumors and soft-agar colonies, warranting its testing as a chemopreventive agent for non-melanoma skin lesions in patients treated with BRAFi alone or in combination with MEKi.

Topics: Animals; Carcinoma, Squamous Cell; Celecoxib; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Female; Gene Expression Regulation, Neoplastic; Humans; Indoles; Keratoacanthoma; Melanoma; Mice; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyrazoles; Pyridones; Pyrimidinones; Skin Neoplasms; Sulfonamides; Vemurafenib

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

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

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

BRAF and MEK inhibitors are not established treatments for non-V600 mutation-positive metastatic melanoma. We carried out a retrospective analysis of efficacy and safety in four patients with BRAF K601E and one patient with L597Q mutation-positive metastatic melanoma treated with the MEK inhibitor trametinib. Three patients achieved a RECIST partial response, including the patient with an L597Q mutation. Paired biopsies available in one of the five patients showed reduced phospho-ERK signalling and this corresponded to a metabolic response on F-fluorodeoxyglucose-PET scanning. Trametinib toxicity was manageable. Trametinib has antitumour activity in patients with BRAF K601E and L597Q mutation-positive metastatic melanoma.

Topics: Aged; Antineoplastic Agents; Biopsy; Extracellular Signal-Regulated MAP Kinases; Female; Fluorodeoxyglucose F18; Humans; Male; MAP Kinase Signaling System; Melanoma; Middle Aged; Mutation; Neoplasm Metastasis; Phosphorylation; Positron-Emission Tomography; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Retrospective Studies; Signal Transduction; Skin Neoplasms; 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

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

Trametinib is an orally bioavailable mitogen-activated protein kinase (MAPK) kinase (MEK) inhibitor with antineoplastic activity. The compound specifically binds to MEK1 and MEK2, resulting in inhibition of growth factor-mediated cell signalling and cellular proliferation in various cancers. Originally developed by Japan Tobacco, GlaxoSmithKline has licensed exclusive worldwide rights to the compound and conducted development in a number of different cancer types. Trametinib, as a monotherapy, has been approved in the US for the treatment of unresectable or metastatic malignant melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test. The compound, as a monotherapy, has also been submitted for regulatory review in the EU for BRAF mutation-positive malignant melanoma, and is in phase III development in Europe, Argentina, Canada and Oceania. Phase II development is underway for pancreatic cancer, non-small cell lung cancer and relapsed or refractory leukaemias. GlaxoSmithKline is also developing trametinib for use in combination with dabrafenib in BRAF V600 mutation-positive metastatic cutaneous melanoma; the combination is at the preregistration stage in the EU and a phase III clinical programme is underway worldwide. Phase II development for this combination is also underway in colorectal cancer. Several phase I trials have also been initiated to evaluate trametinib in combination with other drugs for the treatment of various solid tumours and haematological malignancies. A paediatric oral solution formulation has been assessed against the oral tablet formulation in a phase I trial. This article summarizes the milestones in the development of trametinib leading to this first approval for unresectable or metastatic BRAF mutation-positive malignant melanoma.

Topics: Clinical Trials as Topic; Drug Approval; Humans; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Melanoma; Melanoma, Cutaneous Malignant; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Skin Neoplasms

Advanced melanoma traditionally has had poor prognosis with limited, modestly effective and relatively toxic systemic treatment options like cytotoxic chemotherapy (dacarbazine) and immunomodulating agents (high-dose interleukin-2 and ipilimumab) which have response rates of 6-20%. With the identification of BRAF mutations found to be present in 50% of melanomas and the clinical success of serine/threonine-protein kinase B-raf inhibitors the prognostic landscape of melanoma has changed considerably. Vemurafenib and dabrafenib have been at the forefront of antimelanoma-targeted agents with a tolerable side effect profile and efficacy that compared well with the standard chemotherapy. These characteristics have led to the regulatory approval of both agents for the treatment of melanoma. However, these agents are not curative and have a short life span primarily due to rapidly occurring drug resistance. More recently, mitogen-activated protein kinase kinase (MEK) inhibitors have been found to have strong anticancer activity independently as well as when combined with other agents like B-raf inhibitors due to their activity downstream of RAF. Preclinical data and limited clinical data suggest that MEK inhibitors may be a component of effective therapy for a broad spectrum of cancers with other oncogenic drivers.

Topics: Animals; Antineoplastic Agents; Drug Evaluation, Preclinical; Drug Resistance, Neoplasm; Humans; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Melanoma; Pyridones; Pyrimidinones; Skin Neoplasms

TAK733 is a novel allosteric, non-ATP-binding, inhibitor of the BRAF substrates MEK-1/2.. The growth inhibitory effects of TAK733 were assessed in a panel of 27 cutaneous and five uveal melanoma cell lines genotyped for driver oncogenic mutations. Flow cytometry, Western blots and metabolic tracer uptake assays were used to characterize the changes induced by exposure to TAK733.. Fourteen cutaneous melanoma cell lines with different driver mutations were sensitive to the antiproliferative effects of TAK733, with a higher proportion of BRAFV600E mutant cell lines being highly sensitive with IC50s below 1 nM. The five uveal melanoma cell lines had GNAQ or GNA11 mutations and were either moderately or highly sensitive to TAK733. The tested cell lines wild type for NRAS, BRAF, GNAQ and GNA11 driver mutations were moderately to highly resistant to TAK733. TAK733 led to a decrease in pERK and G1 arrest in most of these melanoma cell lines regardless of their origin, driver oncogenic mutations and in vitro sensitivity to TAK733. MEK inhibition resulted in increase in pMEK more prominently in NRASQ61L mutant and GNAQ mutant cell lines than in BRAFV600E mutant cell lines. Uptake of the metabolic tracers FDG and FLT was inhibited by TAK733 in a manner that closely paralleled the in vitro sensitivity assays.. The MEK inhibitor TAK733 has antitumor properties in melanoma cell lines with different oncogenic mutations and these effects could be detectable by differential metabolic tracer uptake.

Topics: Antineoplastic Agents; Cell Cycle; Cell Line, Tumor; Drug Resistance, Neoplasm; Humans; Inhibitory Concentration 50; MAP Kinase Signaling System; Melanoma; Phosphatidylinositol 3-Kinases; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Pyridones; Pyrimidinones; Radioactive Tracers; Signal Transduction; Skin Neoplasms; Uveal Neoplasms

The v-raf murine sarcoma viral oncogene homolog B1 (BRAF) gene is mutated at position 600 in about 50% of melanoma. Mutant BRAF activates the downstream effectors of the RAS-RAF-MEK-MAPK pathways and is a driver oncogene in these melanoma cells. Selective BRAF-V600 inhibitors (vemurafenib, dabrafenib) have high antitumor activity against BRAF-V600-mutant melanoma with objective tumor response rates. Resistance, however, develops within less than a year in the majority of patients. Several different mechanisms have been found to mediate acquired resistance, but these do not involve the occurrence of secondary mutations in the BRAF gene. Two patients with BRAF-V600E mutant melanoma who had documented progression during treatment with dabrafenib/GSK1120212 and dabrafenib, respectively, were rechallenged with dabrafenib and vemurafenib after a treatment-free interval of 8 and 4 months during which further progression was documented. Both patients showed a marked clinical response and, in both, objective tumor regression (qualifying as a mixed and a partial response according to RECIST) was documented. These two case observations indicate that resistance to BRAF-selective inhibitors can be reversible following treatment interruption.

Topics: Adult; Antineoplastic Agents; Disease Progression; Female; Humans; Male; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Melanoma; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Treatment Outcome

Topics: Antineoplastic Agents; Female; Humans; Male; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Melanoma; Neoplasms; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Skin Neoplasms; Uveal Neoplasms

Topics: Antineoplastic Agents; Female; Humans; Male; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Melanoma; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Skin Neoplasms; Uveal Neoplasms

A series of conformationally flexible and restricted dimers of monastrol as well as related dihydropyrimidones have been synthesized by employing one-pot Biginelli multicomponent reaction. These dimers have been evaluated for cytotoxic potency against selected human cancer cell lines and some of the compounds have exhibited more cytotoxic potency than the parent monastrol. Further, the DNA binding ability by thermal denaturation studies and antimicrobial activities of these compounds are also discussed.

Topics: Anti-Infective Agents; Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Colonic Neoplasms; Differential Thermal Analysis; Dimerization; DNA; Drug Screening Assays, Antitumor; Female; Gram-Negative Bacteria; Gram-Positive Bacteria; Humans; Inhibitory Concentration 50; Lung Neoplasms; Microbial Sensitivity Tests; Molecular Conformation; Pyrimidines; Pyrimidinones; Skin Neoplasms; Structure-Activity Relationship; Thiones

The effects of two cyclic nucleotide phosphodiesterase type 4 (PDE4) inhibitors on proliferation of cell lines representing different stages of mouse skin tumorigenesis were studied. Skin papillomas and carcinomas become resistant to the growth inhibition by glucocorticoids. Their control of cellular functions is mediated by a well-known transcription factor, glucocorticoid receptor. The primary aim of the present study was to determine whether the PDE4 inhibitors, that raise intracellular cAMP levels, can increase the sensitivity of mouse skin papillomas and carcinomas to the glucocorticoids. We sought to establish the effect of cAMP signaling on the glucocorticoid receptor function using well-known model representing non-tumorigenic keratinocyte cell line (3PC), papilloma (MT1/2) and squamous cell carcinoma cell line (Ca3/7). These cells were treated with the glucocorticoid fluocinolone acetonide (FA) alone or in concert with PDE4 inhibitors--rolipram or YM976. Results of our study revealed that both PDE4 inhibitors may increase the sensitivity of transformed cell lines to the growth inhibitory effect of FA. In the transformed cell lines, changes in the viability of cells were accompanied by an increase in mRNA level of two negative regulators of the cell cycle--p21 and p27 proteins. Co-treatment with PDE4 inhibitors and FA caused inhibition of an endogenous glucocorticoid-responsive gene (MT-1) expression. Thus, the PDE4 inhibitors exerted a differential effect on non-transformed and transformed keratinocytes and on glucocorticoid receptor signal transduction. These findings warrant further studies to clarify the mechanism by which PDE4 inhibitors modulate glucocorticoid receptor signal transduction in transformed cells.

Topics: Animals; Carcinoma, Squamous Cell; Cell Line; Cell Line, Tumor; Cell Transformation, Neoplastic; Dose-Response Relationship, Drug; Drug Interactions; Fluocinolone Acetonide; Glucocorticoids; Keratinocytes; Mice; Papilloma; Phosphodiesterase Inhibitors; Pyridines; Pyrimidinones; Rolipram; Skin; Skin Neoplasms; Time Factors

Induction of mitochondrial permeability transition (MPT) and cytosolic translocation of cytochrome C are considered essential components of the apoptotic pathway. Hence, there is the realization that mitochondrial-specific drugs could have potential for use as chemotherapeutic agents to trigger apoptosis in tumor cells. Recently, we showed that photoproducts of merocyanine 540 (pMC540) induced tumor cell apoptosis. In this study, we focused on identifying mitochondrial-specific compounds from pMC540 and studied their apoptotic potential. One purified fraction, C5, induced a drop in mitochondrial transmembrane potential and cytosolic translocation of cytochrome C in HL60 human leukemia cells. Moreover, the addition of C5 to purified rat liver mitochondria induced MPT as indicated by mitochondrial matrix swelling, which was completely inhibited by cyclosporin A, an inhibitor of the inner-membrane pore. Supernatant of C5-treated mitochondria showed a dose-dependent increase in cytochrome C, which was also inhibited in the presence of cyclosporin A, strongly indicating a direct effect on the inner-membrane pore. Despite the strong mitochondrial reactivity, C5 elicited minimal cytotoxicity (less than 25%) against HL60 leukemia and M14 melanoma cells because of inefficient caspase activation. However, prior exposure to C5 significantly enhanced the apoptotic response to etoposide or the CD95 receptor. Thus, we demonstrate that MPT induction and cytochrome C release by the novel compound C5, in the absence of effective caspase activation, is insufficient for triggering efficient apoptosis in tumor cells. However, when used in combination with known apoptosis inducers, such compounds could enhance the sensitivity of tumor cells to apoptosis. (Blood. 2000;95:1773-1780)

Topics: Animals; Antineoplastic Agents; Apoptosis; Biological Transport; Caspase Inhibitors; Caspases; Cyclosporine; Cytochrome c Group; Cytosol; Enzyme Activation; Enzyme Inhibitors; Etoposide; Fluorescence; HL-60 Cells; Humans; Intracellular Membranes; Melanoma; Mitochondria; Mitochondria, Liver; Neoplasm Proteins; Oligopeptides; Permeability; Photochemistry; Pyrimidinones; Radiation-Sensitizing Agents; Rats; Rats, Wistar; Signal Transduction; Skin Neoplasms; Staurosporine; Tumor Cells, Cultured

Topics: Animals; Chromatography, Ion Exchange; Deoxyribonucleosides; In Vitro Techniques; Neoplasm Transplantation; Pyrimidinones; Rabbits; Skin Neoplasms; Transplantation, Homologous; Tumor Virus Infections