gdc-0973 and Melanoma

The treatment of metastatic melanoma has been revolutionized by the introduction of immune checkpoint inhibitors and BRAF/MEK inhibition. Nevertheless, almost half of patients will progress or show primary resistance to treatment. The combination of BRAF/MEK and immune checkpoint inhibition might achieve higher response rates and improve long-term disease control. The IMspire150 trial investigated the combination of atezolizumab, cobimetinib and vemurafenib versus cobimetinib and vemurafenib alone.. This review covers the efficacy and safety of atezolizumab, cobimetinib and vemurafenib for patients with advanced or metastatic BRAF mutant melanoma. The combination is compared with the current standard of care including BRAF/MEK inhibition and treatment with immune checkpoint inhibitors.. Atezolizumab plus cobimetinib and vemurafenib showed superior progression-free survival in metastatic melanoma compared to cobimetinib and vemurafenib alone. Triplet therapy might be an option in situations of urgent need for disease control, when oncologists choose BRAF/MEK inhibition over immune checkpoint inhibition as first line treatment. At this time results are not mature yet, and longer follow-up including overall survival data is needed. The future role of this combination will also be determined by a comparison with the combination of ipilimumab and nivolumab.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Azetidines; Humans; Immune Checkpoint Inhibitors; Melanoma; Mitogen-Activated Protein Kinase Kinases; Mutation; Piperidines; Proto-Oncogene Proteins B-raf; Skin Neoplasms; Vemurafenib

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

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

We sought to identify patient subgroups with distinct postprogression overall survival (ppOS) outcomes and investigate the impact of original treatment assignment and initial postprogression treatment (ppRx) on ppOS.. Recursive partitioning analysis (RPA) was performed to model relationships between prespecified covariates and ppOS in patients with BRAF. RPA identified baseline lactate dehydrogenase (LDH), baseline disease stage, Eastern Cooperative Oncology Group performance status at PD, and ppRx as significant prognostic factors for ppOS. Median ppOS was longest in patients with normal baseline LDH, stage M1c disease at baseline, and ppRx with immunotherapy or targeted therapy (12.2 months; 95% CI 10.3-16.1) and shortest in those with elevated baseline LDH > 2 × upper limit of normal (2.3 months; 95% CI 1.8-2.7). Original treatment assignment did not impact ppOS. Across treatment cohorts, patients treated with immunotherapy or targeted therapy after PD had better ppOS than those given other treatments.. A combination of factors at baseline (LDH, disease stage) and PD (performance status, ppRx) impact ppOS outcomes. ppRx with immunotherapy or targeted therapy is an independent prognostic factor for improved overall survival following progression regardless of original treatment. Trial registration The trials included in this analysis are registered with ClinicalTrials.gov: NCT00949702 (BRIM-2), NCT01006980 (BRIM-3), NCT01271803 (BRIM-7), and NCT01689519 (coBRIM).

Topics: Antineoplastic Combined Chemotherapy Protocols; Azetidines; Dacarbazine; Humans; Melanoma; Mutation; Piperidines; Prognosis; Proto-Oncogene Proteins B-raf; Skin Neoplasms; Vemurafenib

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

Approximately 50% of cutaneous melanomas harbor activating mutations of the BRAF-oncogene, making BRAF inhibitors (BRAFi) the standard treatment for this disease. However, disease responses are limited in duration mainly due to acquired resistance. Dual MAPK pathway inhibition with addition of a MEK inhibitor (MEKi) to a BRAFi improved the efficacy and tolerability compared with BRAFi alone. Cobimetinib (Cotellic

Topics: Administration, Oral; Antineoplastic Combined Chemotherapy Protocols; Azetidines; Clinical Trials as Topic; Drug Resistance, Neoplasm; Humans; MAP Kinase Kinase 1; MAP Kinase Signaling System; Melanoma; Piperidines; Proto-Oncogene Proteins B-raf; Skin Neoplasms; Survival Analysis; Time Factors; Treatment Outcome

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

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

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

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

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

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

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

To review and summarize data on cobimetinib, which was approved by the US Food and Drug Administration (FDA) in November 2015 for use in combination with vemurafenib for unresectable or metastatic melanoma with a BRAFV600E or V600K mutation.. A literature search using PubMed was conducted using the terms cobimetinib, MEK inhibitor, and melanoma from January 2000 to June 2016.. The literature search was confined to human studies published in English. Trials of cobimetinib for melanoma were prioritized.. Cobimetinib is a reversible inhibitor of MEK1 and MEK2. Its FDA approval was based on a phase III, randomized trial of vemurafenib monotherapy (n = 248) or vemurafenib and cobimetinib (n = 247) in unresectable stage IIIC or IV melanoma with a BRAFV600 mutation. Cobimetinib was administered as 60 mg orally daily for 21 days/7 days off, whereas vemurafenib was administered as 960 mg twice daily. Vemurafenib and cobimetinib were associated with an objective response rate of 68%, and median progression-free survival of 9.9 months. The overall survival was not reached at the time of first interim analysis. Clinically relevant grade ≥3 adverse events were diarrhea (6%), rash (6%), photosensitivity (2%), elevated liver function tests (LFTs) (8%-12%), increased creatine kinase (11%), and retinal detachment (3%).. Cobimetinib combined with vemurafenib is an alternative BRAF/MEK inhibitor therapy for unresectable or metastatic melanoma with BRAFV600 mutation. The role of cobimetinib in melanoma and other solid tumors is likely to expand as the results from ongoing studies become available.

Topics: Antineoplastic Combined Chemotherapy Protocols; Azetidines; Clinical Trials as Topic; Disease-Free Survival; Humans; Indoles; Melanoma; Mutation; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Sulfonamides; United States; United States Food and Drug Administration; Vemurafenib

The MEK inhibitor cobimetinib (Cotellic(®)) is indicated for the treatment of patients with BRAF (V600) mutation-positive unresectable or metastatic melanoma, in combination with the BRAF inhibitor vemurafenib (Zelboraf(®)). In the pivotal coBRIM trial, previously untreated patients with BRAF (V600) mutation-positive unresectable, stage IIIC or stage IV melanoma received cobimetinib 60 mg once daily for the first 21 days of each 28-day cycle plus vemurafenib 960 mg twice daily or vemurafenib alone. Compared with vemurafenib alone, cobimetinib plus vemurafenib significantly prolonged progression-free survival (primary endpoint) and was associated with a significantly higher overall response rate and significantly prolonged overall survival. Cobimetinib plus vemurafenib had a manageable tolerability profile. In conclusion, cobimetinib plus vemurafenib is a valuable option for use in BRAF (V600) mutation-positive unresectable or metastatic melanoma.

Topics: Animals; Antineoplastic Agents; Azetidines; Disease-Free Survival; Drug Therapy, Combination; Humans; Indoles; Melanoma; Mutation; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Sulfonamides; Vemurafenib

Cobimetinib combined with vemurafenib is a new approved MEK inhibitor for first line treatment of metastatic melanoma patients with BRAF V600 mutations. It improves tumor response rates and progression free survival compared to vemurafenib alone, while decreasing toxicities due to the paradoxical activation of the MAPK signaling pathway.. This review covers the pharmacology, efficacy, and toxicity data derived from clinical and preclinical studies on cobimetinib. It also reports ongoing trials evaluating cobimetinib to better understand future developments for this drug.. The combination of cobimetinib and vemurafenib seems to be more toxic than the combination therapy dabrafenib and trametinib even if these four drugs have never been compared in a randomized trial. The future of this combination depends on its capacity to be combined simultaneously or sequentially with immune based therapies to improve the durability of responses.

Topics: Antineoplastic Combined Chemotherapy Protocols; Azetidines; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Disease-Free Survival; Humans; Indoles; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Melanoma; Mutation; Piperidines; Proto-Oncogene Proteins B-raf; Skin Neoplasms; Sulfonamides; Vemurafenib

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 recent years, melanoma patients' outcome and survival improved, mainly because of systemic treatment improvement with targeted therapy and checkpoint blockade. Targeted therapy with BRAF and MEK inhibitors was approved to treat patients with unresectable or metastatic melanoma, harboring BRAF V600 mutations. This paper addresses the safety and efficacy of cobimetinib, when used in combination with vemurafenib, in the previous mentioned setting.. This article presents an overview on the rationale for clinical development of cobimetinib, as well as the mechanism of action, the efficacy and safety, and the most important trials that led to the approval of the combination therapy with vemurafenib. We searched the PubMed for published papers related to safety and efficacy of cobimetinib, and resistance mechanisms to BRAF inhibition. The abstract databases of the American Society of Clinical Oncology and European Society for Medical Oncology were also searched for updates on the mentioned clinical trials. Expert commentary: Patients treated with targeted therapy experience a rapid tumor response. However, virtually all patients will develop resistance to treatment. Therapeutic combinations to overcome resistance mechanisms are currently addressed. In the future, targeted therapy strategy will include three or more drugs, probably from different therapeutic classes.

Topics: Antineoplastic Combined Chemotherapy Protocols; Azetidines; Drug Resistance, Neoplasm; Humans; Indoles; Melanoma; Mutation; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Skin Neoplasms; Sulfonamides; Vemurafenib

Historically, metastatic melanoma has had extremely poor survival outcomes. The outlook, however, is rapidly changing as new molecularly targeted therapies have vastly improved patient outcomes. One such therapy is the potent mitogen-activated protein kinase kinase (MEK) 1/2 inhibitor cobimetinib. Recently, cobimetinib was approved for the treatment of metastatic or unresectable melanoma with serine/threonine-protein kinase B-raf (BRAF) V600E or V600K mutations when used in combination with the BRAF inhibitor vemurafenib. Currently, multiple clinical trials are investigating this drug combination for the treatment of various cancer types (e.g., breast, melanoma, colorectal). In the phase III coBRIM trial, this combination therapy showed improved melanoma response rates and patient progression-free survival when compared to vemurafenib alone. Additionally, toxicities were generally found to be manageable with dose modification or interruption. However, tumor response to BRAF/MEK inhibition, though rapid, is often short-lived as tumors develop resistance to this combination therapy. Therefore, new trials are beginning to investigate the addition of a third targeted agent or immunotherapy in order to increase the durability of treatment response. These trials are already showing promising preliminary results.

Topics: Azetidines; Clinical Trials as Topic; Drug Interactions; Humans; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Melanoma; Mutation; Piperidines; Proto-Oncogene Proteins B-raf

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

Genentech (a subsidiary of Roche) and Exelixis are developing cobimetinib, an orally available small molecule, for the treatment of various cancers, including malignant melanoma and breast cancer. Cobimetinib inhibits the MEK (mitogen-activated protein kinase) component of the MAPK/ERK signalling pathway, which is frequently over-activated in human tumours. The product has been approved in Switzerland in combination with vemurafenib for the treatment of patients with unresectable or metastatic BRAF V600 mutation-positive melanoma, and is under regulatory review for the same indication in several countries, including the USA and the EU. This article summarizes the milestones in the development of cobimetinib leading to this first approval for unresectable or metastatic BRAF V600 mutation-positive melanoma melanoma.

Topics: Animals; Antineoplastic Agents; Azetidines; Drug Approval; Humans; MAP Kinase Signaling System; Melanoma; Melanoma, Cutaneous Malignant; Mitogen-Activated Protein Kinases; Piperidines; Skin Neoplasms

Topics: Animals; Azetidines; Humans; Imidazoles; Indoles; Melanoma; Mutation; Oximes; Piperidines; Proto-Oncogene Proteins B-raf; Sulfonamides; Vemurafenib

To evaluate the efficacy and safety of cobimetinib plus atezolizumab in the treatment of patients with advanced BRAF. This phase 1b, open-label, international multicentre study enrolled 3 cohorts. Herein, we report on patients in cohorts A and B who had progressed on prior anti‒PD-1 therapy. Patients in cohort A received cobimetinib 60 mg once daily for 21 days followed by a 7-day break and concurrent intravenous atezolizumab 840 mg every 2 weeks. Patients in cohort B received the same dosing regimen as cohort A except for cycle 1 in which patients received cobimetinib only for the first 14 days prior to initiation of atezolizumab on cycle 1 day 15. Coprimary end-points were objective response rate and disease control rate. Secondary end-points were duration of response, progression free survival and overall survival.. Between 19th June 2017 and 12th December 2018, 103 patients were enrolled. Median follow-up was 6.9 months (interquartile range, 4.8-10.1 months); objective response rate was 14.6% and disease control rate was 38.8% (95% confidence interval, 29.39-48.94). The median duration of response, progression-free survival and overall survival was 12.7 months, 3.8 months and 14.7 months, respectively. The most common adverse events were diarrhoea (75/103; 72.8%), dermatitis acneiform (57/103; 55.3%) and nausea (52/103; 50.5%). Thirty-four patients (33.0%) died: 33 (91.7%) due to progressive disease and one (1%) due to treatment-related oesophagitis.. Combination therapy with cobimetinib and atezolizumab in patients with advanced BRAF. This study is registered with ClinicalTrials.gov; NCT03178851.

Topics: Antineoplastic Combined Chemotherapy Protocols; Humans; Melanoma; Mutation; Proto-Oncogene Proteins B-raf

Primary analysis of the phase 3 IMspire150 study showed improved investigator-assessed progression-free survival with first-line atezolizumab, vemurafenib, and cobimetinib (atezolizumab group) versus placebo, vemurafenib, and cobimetinib (control group) in patients with BRAF. The multicentre, double-blind, placebo-controlled, randomised, phase 3 IMspire150 study was done at 108 academic and community hospitals in 20 countries. Patients aged 18 years or older with previously untreated unresectable stage IIIc or stage IV melanoma and an Eastern Cooperative Oncology Group performance status of 0 or 1 were eligible for inclusion. Patients were randomly assigned (1:1) to receive either atezolizumab (840 mg intravenously on day 1 and 15) or placebo plus vemurafenib (960 mg or 720 mg twice daily orally) and cobimetinib (60 mg once daily orally; 21 days on and 7 days off) in 28-day cycles. Atezolizumab and placebo were added to treatment regimens from cycle two onwards. Randomisation was done centrally (Durham, NC, USA) based on a permuted block randomisation scheme (block size of 4) using an interactive web-based response system and was stratified by geographical region and baseline lactate dehydrogenase concentration. Overall survival was analysed in the intention-to-treat population and safety was analysed in all patients who received at least one dose of study drug according to actual treatment received. The primary endpoint was investigator-assessed progression-free survival, which was previously reported. Here, we report the second, prespecified, interim overall survival analysis, which was planned after about 270 overall survival events had occurred. The trial is ongoing, but is no longer enrolling patients, and it is registered with ClinicalTrials.gov, NCT02908672.. Between Jan 13, 2017, and April 26, 2018, 514 patients (median age 54 years [IQR 43-63]; 299 [58%] men and 215 [42%] women) were enrolled in the trial and randomly assigned to the atezolizumab group (256 [50%] patients) or the control group (258 [50%] patients). At the data cutoff (Sept 8, 2021), 273 patients had died (126 in the atezolizumab group and 147 in the control group). Median follow-up was 29·1 months (IQR 10·1-45·4) for the atezolizumab group versus 22·8 months (10·6-44·1) for the control group. Median overall survival was 39·0 months (95% CI 29·9-not estimable) in the atezolizumab group versus 25·8 months (22·0-34·6) in the control group (HR 0·84 [95% CI 0·66-1·06]; p=0·14). The most common adverse events of any grade in the atezolizumab group were blood creatine phosphokinase increased (123 [53%] of 231 patients), diarrhoea (116 [50%]), and pyrexia (115 [50%]). The most common adverse events of any grade in the control group were diarrhoea (157 [56%] of 280 patients), blood creatine phosphokinase increased (135 [48%]), and rash (119 [43%]). The most common grade 3-4 adverse events were increased lipase (54 [23%] of 231 patients in the atezolizumab group vs 62 [22%] of 280 patients in the control group), increased blood creatine phosphokinase (51 [22%] vs 50 [18%]), and increased alanine aminotransferase (32 [14%] vs 26 [9%]). Serious adverse events were reported in 112 (48%) patients in the atezolizumab group and 117 (42%) patients in the control group. Grade 5 adverse events were reported in eight (3%) patients in the atezolizumab group versus six (2%) patients in the control group. Two grade 5 adverse events (hepatitis fulminant and hepatic failure) in the atezolizumab group were considered to be associated with the triplet combination, and one event in the control group (pulmonary haemorrhage) was considered to be associated with cobimetinib.. Additional follow-up of the IMspire150 trial showed that overall survival was not significantly improved with atezolizumab, vemurafenib, and cobimetinib compared with placebo, vemurafenib, and cobimetinib in patients with BRAF. F Hoffmann-La Roche.

Topics: Antineoplastic Combined Chemotherapy Protocols; Double-Blind Method; Female; Humans; Male; Melanoma; Middle Aged; Mutation; Proto-Oncogene Proteins B-raf; Vemurafenib

ImmunoCobiVem investigated whether a planned switch to atezolizumab after achieving tumour control during run-in with vemurafenib + cobimetinib improves progression-free survival (PFS) and overall survival (OS) compared to continuous targeted therapy (TT) in patients with previously untreated advanced BRAF. In this multicenter phase 2 study, patients received vemurafenib plus cobimetinib. After 3months, patients without progressive disease (PD) were randomly assigned (1:1) to continue vemurafenib + cobimetinib (Arm A) or switch to atezolizumab (Arm B) until first documented PD (PD1). Primary outcome was PFS1 (time from start of run-in until PD1 or death). OS and safety were also assessed.. In patients with BRAF

Topics: Antineoplastic Combined Chemotherapy Protocols; Humans; Melanoma; Mutation; Proto-Oncogene Proteins B-raf; Skin Neoplasms; Vemurafenib

Novel therapies have achieved unprecedented benefit in survival of advanced melanoma patients. While immunotherapy (ICI) can be administered independent of mutational status, BRAF and MEK kinase inhibitors represent another effective treatment option for patients with BRAF mutant melanoma. Given the benefits these therapies demonstrate, the natural instinct was to combine. Three studies have investigated the benefit of combination of ICI using anti-PD-1 or anti-PD-L1 antibody and targeted therapy (TT) with BRAF and MEK inhibitors over TT and placebo. Among these studies, statistically significantly superior duration of response was observed, however overall and progression-free survival were only numerically superior, if at all. One triple combination was approved for BRAF mutant metastatic melanoma; however, the expected synergistic effect of triple therapy could not be universally confirmed and the observed benefits with triple seem to depend on statistical considerations rather than a biological reason. As patients with BRAF mutant melanoma have both ICI and TT as their first-line treatment options, the question whether the sequence matters was addressed. Two prospective trials compared first-line ICI, followed by TT at progression, or vice-versa, with additional "sandwich" approach (8 weeks of TT followed by ICI until progression, then TT again) in the Secombit study. The benefit of first-line ICI was demonstrated in both studies with Secombit study showing the "sandwich" approach to have similar effect. Current data advices for immunotherapy based regiments in patients with BRAF mutant melanoma or, possibly, sandwich approach. Whether triple therapy is superior to ICI monotherapy still needs to be addressed considering not only efficacy, but also safety.

Topics: Antineoplastic Combined Chemotherapy Protocols; Humans; Melanoma; Mutation; Prospective Studies; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Skin Neoplasms; Vemurafenib

The phase III IMspire150 study (NCT02908672) demonstrated significantly improved progression-free survival (PFS) with atezolizumab, vemurafenib, and cobimetinib (atezolizumab group) versus placebo, vemurafenib, and cobimetinib (control group) in patients with BRAF. Five hundred fourteen patients were randomized to atezolizumab (n = 256) or control (n = 258). Outcomes were evaluated in subgroups defined by key biomarkers, including programmed death-ligand 1 (PD-L1) expression, lactate dehydrogenase (LDH) level, tumor mutational burden (TMB), and interferon-γ (IFN-γ) gene signature. Exploratory recursive partitioning analysis was then used to model associations between PFS and baseline covariates, including key biomarkers.. PFS benefit for atezolizumab versus control was greater in patients with high TMB [≥10 mutations/Mb; hazard ratio (HR) 0.73; 95% confidence interval (CI) 0.52-1.02; P = 0.067] versus low TMB (<10 mutations/Mb; HR 0.92; 95% CI 0.65-1.30; P = 0.64) and similar between patients with strong IFN-γ (≥median; HR 0.76; 95% CI 0.54-1.06) versus weak IFN-γ (

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Azetidines; B7-H1 Antigen; Biomarkers, Tumor; Humans; Melanoma; Mutation; Piperidines; Proto-Oncogene Proteins B-raf; Vemurafenib

Targeted therapy and immunotherapy have shown intracranial activity in melanoma with CNS metastases, but there remains an unmet need, particularly for patients with symptomatic CNS metastases. We aimed to evaluate atezolizumab in combination with cobimetinib or vemurafenib plus cobimetinib in patients with melanoma with CNS metastases.. TRICOTEL was a multicentre, open-label, single-arm, phase 2 study done in two cohorts: a BRAF. Between Dec 13, 2018, and Dec 7, 2020, 65 patients were enrolled in the BRAF. Adding atezolizumab to vemurafenib plus cobimetinib provided promising intracranial activity in patients with BRAF. F Hoffmann-La Roche.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Azetidines; Central Nervous System Neoplasms; Humans; Melanoma; Mutation; Neoplasms, Second Primary; Piperidines; Proto-Oncogene Proteins B-raf; Vemurafenib

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

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

Emerging data suggest that the combination of MEK inhibitors and immunotherapeutic agents may result in improved efficacy in melanoma. We evaluated whether combining MEK inhibition and immune checkpoint inhibition was more efficacious than immune checkpoint inhibition alone in patients with previously untreated BRAF. IMspire170 was an international, randomized, open-label, phase III study. Patients were randomized 1 : 1 to receive cobimetinib (60 mg, days 1-21) plus anti-programmed death-ligand 1 atezolizumab (840 mg every 2 weeks) in 28-day cycles or anti-programmed death-1 pembrolizumab (200 mg every 3 weeks) alone until loss of clinical benefit, unacceptable toxicity, or consent withdrawal. The primary outcome was progression-free survival (PFS), assessed by an independent review committee in the intention-to-treat population.. Between 11 December 2017, and 29 January 2019, 446 patients were randomized to receive cobimetinib plus atezolizumab (n = 222) or pembrolizumab (n = 224). Median follow-up was 7.1 months [interquartile range (IQR) 4.8-9.9] for cobimetinib plus atezolizumab and 7.2 months (IQR 4.9-10.1) for pembrolizumab. Median PFS was 5.5 months [95% confidence interval (CI) 3.8-7.2] with cobimetinib plus atezolizumab versus 5.7 months (95% CI 3.7-9.6) with pembrolizumab [stratified hazard ratio 1.15 (95% CI 0.88-1.50); P = 0.30]. Hazard ratios for PFS were consistent across prespecified subgroups. In exploratory biomarker analyses, higher tumor mutational burden was associated with improved clinical outcomes in both treatment arms. The most common grade 3-5 adverse events (AEs) were increased blood creatine phosphokinase (10.0% with cobimetinib plus atezolizumab versus 0.9% with pembrolizumab), diarrhea (7.7% versus 1.9%), rash (6.8% versus 0.9%), hypertension (6.4% versus 3.7%), and dermatitis acneiform (5.0% versus 0). Serious AEs occurred in 44.1% of patients with cobimetinib plus atezolizumab and 20.8% with pembrolizumab.. Cobimetinib plus atezolizumab did not improve PFS compared with pembrolizumab monotherapy in patients with BRAF

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Azetidines; Humans; Melanoma; Piperidines; Proto-Oncogene Proteins B-raf

Studies carried out in vitro and in a mouse model have shown that BRAF inhibitors enhance the effects of IFN-α on BRAFV600E melanoma cells through the inhibition of ERK. Therefore, the combination of vemurafenib and IFN-α in patients with BRAFV600E melanoma may provide therapeutic benefits; MEK inhibition may prevent the reactivation of the MAPK pathway induced by BRAF inhibitor resistance.. In a phase I study, adult patients with advanced BRAFV600-mutated melanoma were treated with vemurafenib + PEG-IFN-α-2b or vemurafenib + cobimetinib + PEG-IFN-α-2b, to assess the safety of the combination and the upregulation of IFN-α/β receptor-1 (IFNAR1).. Eight patients were treated; 59 adverse events with four serious ones (three related to study treatments) were reported. Patients with a pre-treatment IFNAR1 expression on ≤ 35% melanoma cells had a median progression-free survival of 12.0 months (range: 5.6-18.4 months) and a median overall survival of 31.0 months (range: 19.8-42.2 months), while patients with a pre-treatment IFNAR1 expression on > 35% of melanoma cells had a median progression-free survival of 4.0 months (range: 0-8.8; p = 0.03), and a median overall survival of 5 months (p = 0.02). Following treatment, responders had higher levels of growth-suppressor genes, including GAS1 and DUSP1, and genes involved in a metabolically robust immune response, including FAP.. Our study supports the overall safety of the vemurafenib + PEG-IFN-α-2b + cobimetinib combination. IFNAR1 expression levels correlated with response to treatment, including survival. Vemurafenib + PEG-IFN-α-2b + cobimetinib would have difficulty finding a niche in the current treatment scenario for advanced melanoma, but we speculate that our findings may contribute to identify subjects particularly responsive to treatment.. The study was registered at clinicaltrials.gov (NCT01959633). Registered 10 October 2013, https://clinicaltrials.gov/ct2/show/NCT01959633.

Topics: Adult; Animals; Antineoplastic Combined Chemotherapy Protocols; Azetidines; Cell Cycle Proteins; GPI-Linked Proteins; Humans; Interferons; Melanoma; Mice; Mutation; Piperidines; Proto-Oncogene Proteins B-raf; Skin Neoplasms; Vemurafenib

The randomized phase III coBRIM study (NCT01689519) demonstrated improved progression-free survival (PFS) and overall survival (OS) with addition of cobimetinib to vemurafenib compared with vemurafenib in patients with previously untreated BRAFV600 mutation-positive advanced melanoma. We report long-term follow-up of coBRIM, with at least 5 years since the last patient was randomized.. Eligible patients were randomized 1:1 to receive either oral cobimetinib (60 mg once daily on days 1-21 in each 28-day cycle) or placebo in combination with oral vemurafenib (960 mg twice daily).. 495 patients were randomized to cobimetinib plus vemurafenib (n = 247) or placebo plus vemurafenib (n = 248). Median follow-up was 21.2 months for cobimetinib plus vemurafenib and 16.6 months for placebo plus vemurafenib. Median OS was 22.5 months (95% CI, 20.3-28.8) with cobimetinib plus vemurafenib and 17.4 months (95% CI, 15.0-19.8) with placebo plus vemurafenib; 5-year OS rates were 31% and 26%, respectively. Median PFS was 12.6 months (95% CI, 9.5-14.8) with cobimetinib plus vemurafenib and 7.2 months (95% CI, 5.6-7.5) with placebo plus vemurafenib; 5-year PFS rates were 14% and 10%, respectively. OS and PFS were longest in patients with normal baseline lactate dehydrogenase levels and low tumor burden, and in those achieving complete response. The safety profile remained consistent with previously published reports.. Extended follow-up of coBRIM confirms the long-term clinical benefit and safety profile of cobimetinib plus vemurafenib compared with vemurafenib monotherapy in patients with BRAFV600 mutation-positive advanced melanoma.

Topics: Antineoplastic Combined Chemotherapy Protocols; Azetidines; Follow-Up Studies; Humans; Melanoma; Mutation; Piperidines; Proto-Oncogene Proteins B-raf; Skin Neoplasms; Vemurafenib

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

To report the 5-year overall survival (OS) landmark and the long-term safety profile of vemurafenib plus cobimetinib (BRAF plus MEK inhibition, respectively) in the BRIM7 study.. Median OS was 31.8 months [95% confidence interval (CI), 24.5-not estimable] in the BRAFi-naïve cohort. The landmark OS rate plateaued at 39.2% at years 4 and 5 of follow-up. In the vemurafenib monotherapy-PD cohort, the median OS was 8.5 months (95% CI, 6.7-11.1), and the landmark OS rate plateaued at 14.0% from 3 years of follow-up. No increase was observed in the frequency and severity of adverse events with long-term follow-up. No new toxicities were detected, and there was no increase in the frequency of symptomatic MEK inhibitor class-effect adverse events.. A subset of patients with advanced

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Azetidines; Cohort Studies; Disease-Free Survival; Female; Follow-Up Studies; Humans; Male; Maximum Tolerated Dose; Melanoma; Middle Aged; Mutation; Patient Safety; Piperidines; Proto-Oncogene Proteins B-raf; Skin Neoplasms; Treatment Outcome; Vemurafenib; Young Adult

IMspire150 aimed to evaluate first-line combination treatment with BRAF plus MEK inhibitors and immune checkpoint therapy in BRAF. IMspire150 was a randomised, double-blind, placebo-controlled phase 3 study done at 112 institutes in 20 countries. Patients with unresectable stage IIIc-IV, BRAF. Between Jan 13, 2017, and April 26, 2018, 777 patients were screened and 514 were enrolled and randomly assigned to the atezolizumab group (n=256) or control group (n=258). At a median follow-up of 18·9 months (IQR 10·4-23·8), progression-free survival as assessed by the study investigator was significantly prolonged with atezolizumab versus control (15·1 vs 10·6 months; hazard ratio [HR] 0·78; 95% CI 0·63-0·97; p=0·025). Common treatment-related adverse events (>30%) in the atezolizumab and control groups were blood creatinine phosphokinase increased (51·3% vs 44·8%), diarrhoea (42·2% vs 46·6%), rash (40·9%, both groups), arthralgia (39·1% vs 28·1%), pyrexia (38·7% vs 26·0%), alanine aminotransferase increased (33·9% vs 22·8%), and lipase increased (32·2% vs 27·4%); 13% of patients in the atezolizumab group and 16% in the control group stopped all treatment because of adverse events.. The addition of atezolizumab to targeted therapy with vemurafenib and cobimetinib was safe and tolerable and significantly increased progression-free survival in patients with BRAF. F Hoffmann-La Roche and Genentech.

Topics: Adult; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Azetidines; Double-Blind Method; Drug Administration Schedule; Female; Humans; Kaplan-Meier Estimate; Male; Melanoma; Middle Aged; Mutation; Neoplasm Metastasis; Neoplasm Staging; Piperidines; Progression-Free Survival; Proto-Oncogene Proteins B-raf; Vemurafenib

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

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

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

The prognostic significance of programmed death ligand-1 (PD-L1) on treatment outcomes in patients receiving BRAF with or without MEK inhibitors is not well understood. This retrospective exploratory analysis evaluated the association of tumour PD-L1 expression with progression-free survival (PFS) and overall survival (OS) among 210 patients in the coBRIM trial treated with cobimetinib plus vemurafenib or placebo plus vemurafenib. In the vemurafenib cohort, there was a trend of increased PFS and OS in those with PD-L1

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Azetidines; B7-H1 Antigen; Disease-Free Survival; Female; Gene Expression Regulation, Neoplastic; Humans; Male; Melanoma; Middle Aged; Mutation; Piperidines; Proto-Oncogene Proteins B-raf; Survival Rate; Vemurafenib

In the coBRIM study, cobimetinib plus vemurafenib (C+V) significantly improved survival outcomes vs placebo and vemurafenib (P+V) in patients with advanced/metastatic BRAF. Patients completing the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (QLQ-C30) at baseline and ⩾1 time point thereafter constituted the analysis population. Change from baseline ⩾10 points was considered clinically meaningful.. Mean baseline scores for all QLQ-C30 domains were similar between arms. Most on-treatment scores for QLQ-C30 domains were also comparable between arms. A transient deterioration in role function in cycle 1 day 15 (C1D15; -14.7 points) in the P+V arm and improvement in insomnia in the C+V arm at C2D15 (-12.4 points) was observed. Among patients who experienced a ⩾10-point change from baseline (responders), between-group differences were greatest for insomnia (16%), social functioning (10%), fatigue (9%) and pain (7%), all favouring C+V. Diarrhoea, photosensitivity reaction, pyrexia, and rash did not meaningfully affect global health status (GHS). Serous retinopathy was associated with a transient decrease in GHS at C1D15 assessment.. In patients with advanced/metastatic BRAF

Topics: Antineoplastic Combined Chemotherapy Protocols; Azetidines; Double-Blind Method; Female; Humans; Longitudinal Studies; Male; Melanoma; Mutation; Piperidines; Placebos; Proto-Oncogene Proteins B-raf; Quality of Life; Vemurafenib

In the coBRIM phase III trial, the addition of cobimetinib, an MEK inhibitor, to vemurafenib, a BRAF inhibitor, significantly improved progression-free survival [hazard ratio (HR), 0.58; P < 0.0001] and overall survival (HR, 0.70; P = 0.005) in advanced BRAF-mutated melanoma. Here, we report on the incidence, course, and management of key adverse events (AEs) in the coBRIM study.. Patients were randomly assigned 1:1 to receive vemurafenib (960 mg twice a day) and either cobimetinib (60 mg once a day, 21 days on/7 days off) or placebo. In addition to standard safety evaluations, patients underwent regular ophthalmic, cardiac, and dermatologic surveillance examinations.. Of 495 patients recruited to the study, 493 patients received treatment and constituted the safety population (cobimetinib combined with vemurafenib, 247; vemurafenib, 246). At data cut-off (30 September 2015), median follow-up was 18.5 months. Nearly every patient experienced an AE. In patients who received cobimetinib combined with vemurafenib, the frequency of grade ≥3 AEs was higher than in patients who received vemurafenib alone (75% versus 61%). Most AEs, including grade ≥3 AEs, occurred within the first treatment cycle. After the first cycle (28 days), the incidence of common AEs (rash, diarrhoea, photosensitivity, elevated creatine phosphokinase, serous retinopathy, pyrexia, and liver laboratory abnormalities) decreased substantially over time. Most AEs were managed conservatively by supportive care measures, dose modifications of study treatment, and, occasionally, permanent treatment discontinuation.. These data indicate that most AEs arising from treatment with cobimetinib combined with vemurafenib generally occur early in the treatment course, are mild or moderate and are manageable by patient monitoring, dose modification and supportive care.. NCT01689519.

Topics: Aged; Azetidines; Disease-Free Survival; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Indoles; Male; MAP Kinase Kinase Kinases; Melanoma; Middle Aged; Mutation; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Sulfonamides; Vemurafenib

Serous chorioretinopathy has been associated with MEK inhibitors, including cobimetinib. We describe the clinical features of serous retinopathy observed with cobimetinib in patients with BRAF. In the coBRIM study, 493 patients were treated in two randomly assigned treatment groups: cobimetinib and vemurafenib (n = 247) or vemurafenib (n = 246). All patients underwent prospective ophthalmic examinations at screening, at regular intervals during the study, and whenever ocular symptoms developed. Patients with serous retinopathy were identified in the study database using a group of relevant and synonymous adverse event terms.. Eighty-six serous retinopathy events were reported in 70 patients (79 events in 63 cobimetinib and vemurafenib-treated patients vs seven events in seven vemurafenib-treated patients). Most patients with serous retinopathy identified by ophthalmic examination had no symptoms or had mild symptoms, among them reduced visual acuity, blurred vision, dyschromatopsia, and photophobia. Serous retinopathy usually occurred early during cobimetinib and vemurafenib treatment; median time to onset was 1.0 month. Most events were managed by observation and continuation of cobimetinib without dose modification and resolved or were resolving by the data cutoff date (19 Sept 2014).. Cobimetinib treatment was associated with serous retinopathy in patients with BRAF

Topics: Adult; Aged; Azetidines; Central Serous Chorioretinopathy; Female; Humans; Indoles; Male; Melanoma; Middle Aged; Mutation; Piperidines; Proto-Oncogene Proteins B-raf; Recurrence; Skin Neoplasms; Sulfonamides; Time Factors; Vemurafenib

The combination of cobimetinib with vemurafenib improves progression-free survival compared with placebo and vemurafenib in previously untreated patients with BRAF(V600)-mutant advanced melanoma, as previously reported in the coBRIM study. In this Article, we report updated efficacy results, including overall survival and safety after longer follow-up, and selected biomarker correlative studies.. In this double-blind, randomised, placebo-controlled, multicentre study, adult patients (aged ≥18 years) with histologically confirmed BRAF(V600) mutation-positive unresectable stage IIIC or stage IV melanoma were randomly assigned (1:1) using an interactive response system to receive cobimetinib (60 mg once daily for 21 days followed by a 7-day rest period in each 28-day cycle) or placebo, in combination with oral vemurafenib (960 mg twice daily). Progression-free and overall survival were primary and secondary endpoints, respectively; all analyses were done on the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01689519, and is ongoing but no longer recruiting participants.. Between Jan 8, 2013, and Jan 31, 2014, 495 eligible adult patients were enrolled and randomly assigned to the cobimetinib plus vemurafenib group (n=247) or placebo plus vemurafenib group (n=248). At a median follow-up of 14·2 months (IQR 8·5-17·3), the updated investigator-assessed median progression-free survival was 12·3 months (95% CI 9·5-13·4) for cobimetinib and vemurafenib versus 7·2 months (5·6-7·5) for placebo and vemurafenib (HR 0·58 [95% CI 0·46-0·72], p<0·0001). The final analysis for overall survival occurred when 255 (52%) patients had died (Aug 28, 2015). Median overall survival was 22·3 months (95% CI 20·3-not estimable) for cobimetinib and vemurafenib versus 17·4 months (95% CI 15·0-19·8) for placebo and vemurafenib (HR 0·70, 95% CI 0·55-0·90; p=0·005). The safety profile for cobimetinib and vemurafenib was tolerable and manageable, and no new safety signals were observed with longer follow-up. The most common grade 3-4 adverse events occurring at a higher frequency in patients in the cobimetinib and vemurafenib group compared with the vemurafenib group were γ-glutamyl transferase increase (36 [15%] in the cobimetinib and vemurafenib group vs 25 [10%] in the placebo and vemurafenib group), blood creatine phosphokinase increase (30 [12%] vs one [<1%]), and alanine transaminase increase (28 [11%] vs 15 [6%]). Serious adverse events occurred in 92 patients (37%) in the cobimetinib and vemurafenib group and 69 patients (28%) in the vemurafenib group. Pyrexia (six patients [2%]) and dehydration (five patients [2%]) were the most common serious adverse events reported in the cobimetinib and vemurafenib group. A total of 259 patients have died: 117 (47%) in the cobimetinib and vemurafenib group and 142 (58%) in the vemurafenib group. The primary cause of death was disease progression in most patients: 109 (93%) of 117 in the cobimetinib and vemurafenib group and 133 (94%) of 142 in the vemurafenib group.. These data confirm the clinical benefit of cobimetinib combined with vemurafenib and support the use of the combination as a standard first-line approach to improve survival in patients with advanced BRAF(V600)-mutant melanoma.. F Hoffmann-La Roche-Genentech.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Azetidines; Biomarkers, Tumor; Double-Blind Method; Female; Follow-Up Studies; Humans; Indoles; Male; Melanoma; Middle Aged; Mutation; Neoplasm Metastasis; Neoplasm Staging; Piperidines; Prognosis; Proto-Oncogene Proteins B-raf; Skin Neoplasms; Sulfonamides; Survival Rate; Vemurafenib; Young Adult

Addition of a MEK inhibitor to a BRAF inhibitor enhances tumour growth inhibition, delays acquired resistance, and abrogates paradoxical activation of the MAPK pathway in preclinical models of BRAF-mutated melanoma. We assessed the safety and efficacy of combined BRAF inhibition with vemurafenib and MEK inhibition with cobimetinib in patients with advanced BRAF-mutated melanoma.. We undertook a phase 1b study in patients with advanced BRAF(V600)-mutated melanoma. We included individuals who had either recently progressed on vemurafenib or never received a BRAF inhibitor. In the dose-escalation phase of our study, patients received vemurafenib 720 mg or 960 mg twice a day continuously and cobimetinib 60 mg, 80 mg, or 100 mg once a day for either 14 days on and 14 days off (14/14), 21 days on and 7 days off (21/7), or continuously (28/0). The primary endpoint was safety of the drug combination and to identify dose-limiting toxic effects and the maximum tolerated dose. Efficacy was a key secondary endpoint. All patients treated with vemurafenib and cobimetinib were included in safety and efficacy analyses (intention-to-treat). The study completed accrual and all analyses are final. This study is registered with ClinicalTrials.gov, number NCT01271803.. 129 patients were treated at ten dosing regimens combining vemurafenib and cobimetinib: 66 had recently progressed on vemurafenib and 63 had never received a BRAF inhibitor. Dose-limiting toxic effects arose in four patients. One patient on a schedule of vemurafenib 960 mg twice a day and cobimetinib 80 mg once a day 14/14 had grade 3 fatigue for more than 7 days; one patient on a schedule of vemurafenib 960 mg twice a day and cobimetinib 60 mg once a day 21/7 had a grade 3 prolongation of QTc; and two patients on a schedule of vemurafenib 960 mg twice a day and cobimetinib 60 mg 28/0 had dose-limiting toxic effects-one developed grade 3 stomatitis and fatigue and one developed arthralgia and myalgia. The maximum tolerated dose was established as vemurafenib 960 mg twice a day in combination with cobimetinib 60 mg 21/7. Across all dosing regimens, the most common adverse events were diarrhoea (83 patients, 64%), non-acneiform rash (77 patients, 60%), liver enzyme abnormalities (64 patients, 50%), fatigue (62 patients, 48%), nausea (58 patients, 45%), and photosensitivity (52 patients, 40%). Most adverse events were mild-to-moderate in severity. The most common grade 3 or 4 adverse events were cutaneous squamous-cell carcinoma (12 patients, 9%; all grade 3), raised amounts of alkaline phosphatase (11 patients, 9%]), and anaemia (nine patients, 7%). Confirmed objective responses were recorded in ten (15%) of 66 patients who had recently progressed on vemurafenib, with a median progression-free survival of 2·8 months (95% CI 2·6-3·4). Confirmed objective responses were noted in 55 (87%) of 63 patients who had never received a BRAF inhibitor, including six (10%) who had a complete response; median progression-free survival was 13·7 months (95% CI 10·1-17·5).. The combination of vemurafenib and cobimetinib was safe and tolerable when administered at the respective maximum tolerated doses. The combination has promising antitumour activity and further clinical development is warranted in patients with advanced BRAF(V600)-mutated melanoma, particularly in those who have never received a BRAF inhibitor; confirmatory clinical testing is ongoing.. F Hoffmann-La Roche/Genentech.

Topics: Adult; Aged; Azetidines; Disease-Free Survival; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Indoles; Infusions, Intravenous; Male; Maximum Tolerated Dose; Melanoma; Middle Aged; Mutation; Neoplasm Invasiveness; Neoplasm Staging; Patient Selection; Piperidines; Prospective Studies; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Risk Assessment; Skin Neoplasms; Sulfonamides; Survival Rate; Treatment Outcome; Vemurafenib

The combined inhibition of BRAF and MEK is hypothesized to improve clinical outcomes in patients with melanoma by preventing or delaying the onset of resistance observed with BRAF inhibitors alone. This randomized phase 3 study evaluated the combination of the BRAF inhibitor vemurafenib and the MEK inhibitor cobimetinib.. We randomly assigned 495 patients with previously untreated unresectable locally advanced or metastatic BRAF V600 mutation-positive melanoma to receive vemurafenib and cobimetinib (combination group) or vemurafenib and placebo (control group). The primary end point was investigator-assessed progression-free survival.. The median progression-free survival was 9.9 months in the combination group and 6.2 months in the control group (hazard ratio for death or disease progression, 0.51; 95% confidence interval [CI], 0.39 to 0.68; P<0.001). The rate of complete or partial response in the combination group was 68%, as compared with 45% in the control group (P<0.001), including rates of complete response of 10% in the combination group and 4% in the control group. Progression-free survival as assessed by independent review was similar to investigator-assessed progression-free survival. Interim analyses of overall survival showed 9-month survival rates of 81% (95% CI, 75 to 87) in the combination group and 73% (95% CI, 65 to 80) in the control group. Vemurafenib and cobimetinib was associated with a nonsignificantly higher incidence of adverse events of grade 3 or higher, as compared with vemurafenib and placebo (65% vs. 59%), and there was no significant difference in the rate of study-drug discontinuation. The number of secondary cutaneous cancers decreased with the combination therapy.. The addition of cobimetinib to vemurafenib was associated with a significant improvement in progression-free survival among patients with BRAF V600-mutated metastatic melanoma, at the cost of some increase in toxicity. (Funded by F. Hoffmann-La Roche/Genentech; coBRIM ClinicalTrials.gov number, NCT01689519.).

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Azetidines; Disease-Free Survival; Female; Humans; Indoles; Kaplan-Meier Estimate; Male; MAP Kinase Kinase 1; Melanoma; Middle Aged; Mutation; Piperidines; Proto-Oncogene Proteins B-raf; Sulfonamides; Survival Rate; Vemurafenib

Combined treatment with BRAFi and/or MEK inhibitors (MEKi) improves outcomes in advanced melanoma patients in comparison with monotherapy.. We aim to report real-world treatment efficacy and safety of vemurafenib (V) and vemurafenib + cobimetinib (V + C) from 10 years of practice.. A total of 275 consecutive patients with unresectable or metastatic BRAF mutated melanoma started first-line V or V + C treatment between 1 October 2013 and 31 December 2020. Survival analyses were performed using the Kaplan-Meier method, and Log-rank and Chi-square tests were used for comparison between groups.. The estimated median overall survival (mOS) was 10.3 months in the V group, and 12.3 months in the V + C group (p = 0.0005; HR = 1.58, 95% CI 1.2-2.1), although the latter group of patients had lactate dehydrogenase elevated numerically more often. Estimated median progression-free survival (mPFS) was 5.5 months in the V group, and 8.3 months in the V + C group (p = 0.0002; HR = 1.62, 95% CI 1.3-2.1). Complete response, partial response, stable disease, and progressive disease as best responses were recorded in the V/V + C groups in 7%/10%, 52%/46%, 26%/28%, and 15%/16% of patients, respectively. The numbers of patients with any grade of adverse effects were similar in both groups.. We confirmed significant improvement in the mOS and mPFS of unresectable and/or metastatic BRAF mutated-melanoma patients treated outside clinical trials with V + C as compared with V, with no major increase in toxicity for the combination.

Topics: Antineoplastic Combined Chemotherapy Protocols; Humans; Melanoma; Mutation; Proto-Oncogene Proteins B-raf; Skin Neoplasms; Vemurafenib

Topics: Anemia; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Azetidines; Humans; Melanoma; Piperidines; Proto-Oncogene Proteins B-raf; Skin Neoplasms; Stevens-Johnson Syndrome; Vemurafenib

Melanoma is a complex and heterogenous disease, displays the deadliest form of skin cancer, and accounts for approx. 80% of all skin cancer deaths. In this study, we reported on the synthesis and pharmacological effects of a novel shikonin derivative (SK119), which is active in a nano-molar range and exhibits several promising in vitro effects in different human melanoma cells. SK119 was synthesized from shikonin as part of our search for novel, promising shikonin derivatives. It was screened against a panel of melanoma and non-tumorigenic cell lines using XTT viability assays. Moreover, we studied its pharmacological effects using apoptosis and Western blot experiments. Finally, it was combined with current clinically used melanoma therapeutics. SK119 exhibited IC

Topics: Apoptosis; Azetidines; Cell Line; Humans; Melanoma; Naphthoquinones; Piperidines; Proto-Oncogene Proteins B-raf; Skin Neoplasms; Vemurafenib

Cobimetinib combined with vemurafenib was available in France in 2015 through a 'Temporary Authorization for Use' program (TAU, preapproval access pending its marketing on 2016) for patients with v-raf murine sarcoma viral oncogene homolog B1-mutant advanced melanoma. This study aimed to provide real-world outcomes in patients previously registered in this TAU. This noninterventional, ambispective, multicentre French study, conducted in patients previously registered in TAU, aimed to estimate overall survival (OS) and progression-free survival (PFS) and to describe the tolerability of the therapeutic combination. At first cobimetinib intake (in combination with vemurafenib), 88% of the 185 evaluable patients had disease stage IV (brain metastasis: 70% of them), 31% had elevated lactate dehydrogenases, and 10% had an Eastern Cooperative Oncology Group (ECOG) index ≥2. Median OS was 16.1 months (95% CI, 12.5-20.7). Brain metastasis ( P < 0.001), ECOG index ≥2 ( P = 0.007), and hepatic impairment ( P = 0.037) were found as independent factors significantly associated with shorter survival. Median PFS was 7.3 months (95% CI, 5.2-8.4). ECOG index ≥2 ( P = 0.006) was significantly associated with shorter PFS. Between cobimetinib start and inclusion, increased CPK (3% of patients), retinal serous detachment (3%), decreased left ventricular ejection fraction (3%), increased transaminases (3%), and rash (3%) were the most reported serious adverse events. This study provides real-world outcomes in France for the vemurafenib-cobimetinib combination available in patients with BRAF-mutant-advanced melanoma. Our data tend to confirm in the real-life setting that this combination therapy is effective in such patients, with a safety profile consistent with previous interventional studies.

Topics: Adult; Animals; Antineoplastic Combined Chemotherapy Protocols; Azetidines; Brain Neoplasms; Humans; Melanoma; Mice; Mutation; Piperidines; Proto-Oncogene Proteins B-raf; Skin Neoplasms; Stroke Volume; Vemurafenib; Ventricular Function, Left

In the IMspire150 trial, triplet treatment with atezolizumab and vemurafenib plus cobimetinib significantly improved progression-free survival (PFS) compared with vemurafenib plus cobimetinib alone for treatment of BRAF V600 variation metastatic melanoma. However, considering high cost of this combination, it is unclear if the incremental cost is worth the additional survival benefit.. To evaluate the cost-effectiveness of atezolizumab and vemurafenib plus cobimetinib vs vemurafenib plus cobimetinib alone in patients with newly diagnosed unresectable BRAF V600 variation metastatic melanoma from the US health care perspective.. This economic evaluation study used a 3-state partitioned survival model to assess the cost-effectiveness of the combination of atezolizumab with vemurafenib plus cobimetinib vs vemurafenib plus cobimetinib alone. The observed Kaplan-Meier curves for overall survival and PFS were digitized from the IMspire150 trial (January 2017-April 2018) and the long-term survivals (over a lifetime horizon) beyond the end of the trial were extrapolated using 7 different survival models. The cost and health preference data were collected from a literature review. This study was performed from March 2021 through June 2021.. The outcomes of interest were expected life-years (LYs) gained and quality-adjusted life-years (QALYs), costs, and incremental cost-effectiveness ratio (ICER), expressed as cost per LYs and per QALYs saved.. Adding atezolizumab to vemurafenib and cobimetinib provided an additional 3.267 QALYs compared with the doublet regimen of vemurafenib plus cobimetinib, at an ICER of $271 669 per QALY, which is not considered cost-effective at the willingness-to-pay threshold of $150 000 per QALY. However, the scenario analyses found that atezolizumab combined with vemurafenib plus cobimetinib could be cost-effective at 20-year (ICER, $121 432 per QALY) and 30-year ($98 092 per QALY) time horizons when both strategies were stopped after 2 years of treatments, and over a lifetime horizon ($122 220 per QALY) when only immunotherapy with atezolizumab was stopped after 2 years of treatment.. These findings suggest that the atezolizumab and vemurafenib plus cobimetinib regimen provides significant survival benefits over vemurafenib plus cobimetinib alone, and a price reduction would be encouraged to maximize the value of its survival gain.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Azetidines; Cost-Benefit Analysis; Humans; Immunotherapy; Melanoma; Neoplasm Metastasis; Piperidines; Progression-Free Survival; Proto-Oncogene Proteins B-raf; Quality-Adjusted Life Years; Vemurafenib

Topics: Animals; Azetidines; Cell Line, Tumor; Cell Proliferation; Drug Resistance, Neoplasm; Dual Specificity Phosphatase 6; Gene Knockdown Techniques; Humans; MAP Kinase Signaling System; Melanoma; Mice; MicroRNAs; Mitogen-Activated Protein Kinase 7; Mutation; Phosphorylation; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Vemurafenib; Xenograft Model Antitumor Assays

Topics: Acneiform Eruptions; Azetidines; Hidradenitis Suppurativa; Humans; Melanoma; Piperidines; Vemurafenib

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

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

Metastatic melanoma is an aggressive skin cancer and associated with a poor prognosis. In clinical terms, targeted therapy is one of the most important treatments for patients with BRAF

Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Azetidines; Biomarkers, Tumor; Cell Dedifferentiation; Cell Proliferation; Connective Tissue Growth Factor; Drug Resistance, Neoplasm; Forkhead Transcription Factors; Gene Expression Regulation, Neoplastic; Humans; Melanoma; Molecular Targeted Therapy; Mutation; Piperidines; Prognosis; Signal Transduction; Survival Rate; Tumor Cells, Cultured; 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

Combination therapy in the treatment of metastatic melanoma has been associated with more durable response rate compared to monotherapy. However, previous studies have shown that combined target therapy commonly causes a wide spectrum of adverse events. These adverse reactions are usually manageable, however, it is always necessary to compare drug efficacy with its potential adverse effects. Toxic epidermal necrolysis represents severe mucocutaneous reaction, usually triggered by medications and characterized by extensive necrosis and detachment of the epidermis. Here we present a first case of toxic epidermal necrolysis induced by combined target therapy (vemurafenib plus cobimetinib). The case was observed in a young patient with BRAF mutant melanoma who was started on first-line metastatic immunotherapy with pembrolisumab.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Azetidines; Humans; Male; Melanoma; Piperidines; Proto-Oncogene Proteins B-raf; Stevens-Johnson Syndrome; Vemurafenib

Rash is one of the most common severe adverse events associated with use of vemurafenib for the treatment of melanoma, either as monotherapy or in combination with cobimetinib. The study aimed to identify pre-treatment patient characteristics predictive of developing severe rash with vemurafenib therapy.. This was a secondary pooled analysis of individual patient data from the BRIM-2, BRIM-3 and coBRIM clinical trials, including all patients treated with vemurafenib alone and vemurafenib plus cobimetinib. Patient age, sex, performance status, body weight, body mass index, liver function markers and estimated glomerular filtration rate were assessed for association with development of severe (grade 3 or 4) rash using logistic regression.. Of 962 patients treated with vemurafenib, 150 (16%) patients experienced severe rash. Female sex was identified as a significant risk factor for severe rash development (P < 0.001), having a two-fold increased risk compared to males (22% vs 11%, odds ratio [OR] 2.17; 95% CI 1.52 to 3.09). Low body weight was also associated with increased risk of severe rash (P = 0.002), but this association was not significant after adjustment for sex. The association between sex and risk of severe rash was consistent across clinical trials and treatments (vemurafenib monotherapy, vemurafenib plus cobimetinib).. Females had approximately two-fold increased risk of developing severe rash compared to males in clinical trials of vemurafenib alone or in combination with cobimetinib.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Australia; Azetidines; Clinical Trials as Topic; Exanthema; Female; Humans; Incidence; Male; Melanoma; Middle Aged; Neoplasm Staging; Piperidines; Risk Factors; Sex Factors; Skin Neoplasms; Vemurafenib

Topics: Antineoplastic Combined Chemotherapy Protocols; Azetidines; Biopsy; Drug Hypersensitivity Syndrome; Female; Glucocorticoids; Humans; Lung; Lung Neoplasms; Melanoma; Middle Aged; Piperidines; Positron Emission Tomography Computed Tomography; Skin; Skin Neoplasms; Treatment Outcome; Vemurafenib

Topics: Antibodies, Monoclonal, Humanized; Azetidines; Double-Blind Method; Humans; Melanoma; Mutation; Piperidines; Proto-Oncogene Proteins B-raf; Vemurafenib

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

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

New primary melanomas (NPMs) in the era of combination treatments for melanoma constitute a challenge for physicians, especially due to the increased incidence of NPMs in patients treated with BRAF inhibitors. We present the unique case of a patient that developed an invasive NPM while under treatment with a combination of vemurafenib, cobimetinib, and atezolizumab. A 39-year-old white male was treated with vemurafenib, cobimetinib, and atezolizumab for a stage IV (T0, N3, M1) BRAF-V600E mutated malignant melanoma in the context of a clinical trial. Eight months from treatment initiation he was diagnosed with an NPM on his back that was found to be BRAF-wild type and neuroblastoma ras mutated, while he was in complete remission. Wide excision of the lesion followed, and the patient was not withdrawn from study treatment. Twenty-two months from treatment initiation, he is still in complete remission. NPMs are a well-known adverse effect of BRAF inhibitors and pose a challenge for the treating physician since these lesions are BRAF-wild type and usually have aggressive biologic behaviour. Invasive NPMs require an aggressive management strategy with clear guidelines to prevent the emergence of advanced or metastatic disease. The emergence of invasive NPMs in patients treated with triple regimens with BRAF/mitogen-activated protein kinase kinase inhibitors and PD1/PDL1 inhibitors is at least unexpected and constitutes a therapeutic stalemate for the physician. Through this case report, we aim to increase awareness about the diagnosis and management of patients with NPM and to express our concerns regarding further management of NPMs in patients under triple combination treatment.

Topics: Adult; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Azetidines; Humans; Male; Melanoma; Neoplasm Metastasis; Piperidines; Skin Neoplasms; Vemurafenib

This pooled analysis investigated the prognostic value of depth of response in two cohorts of patients with BRAF. The data were pooled from BRIM-2, BRIM-3, BRIM-7 and coBRIM. Association of depth of response with survival was estimated by Cox proportional hazards regression, adjusted for clinically relevant covariates. Depth of response was analysed in previously identified prognostic subgroups based on disease characteristics and gene signatures.. Greater tumour reduction and longer time to maximal response were significantly associated with longer progression-free survival (PFS) and overall survival (OS) when evaluated as continuous variables. Patients with the deepest responses had long-lasting survival outcomes (median PFS: 14 months; OS: 32 months with vemurafenib; not estimable with cobimetinib plus vemurafenib). Cobimetinib plus vemurafenib improved depth of response versus vemurafenib monotherapy regardless of other prognostic factors, including gene signatures.. Greater depth of response was associated with improved survival, supporting its utility as a measure of treatment efficacy in melanoma and further evaluation of its incorporation into existing prognostic models. Cobimetinib plus vemurafenib improved outcomes across quartiles of response regardless of prognostic factors or gene signatures and provided durable survival benefits in patients with deep responses.

Topics: Administration, Oral; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Azetidines; Clinical Trials as Topic; Gene Expression; Humans; Injections, Intravenous; Kaplan-Meier Estimate; Melanoma; Mitogen-Activated Protein Kinase Kinases; Multicenter Studies as Topic; Piperidines; Placebos; Progression-Free Survival; Proto-Oncogene Proteins B-raf; Randomized Controlled Trials as Topic; Time Factors; Treatment Outcome; Tumor Burden; Vemurafenib

Topics: Aged; Azetidines; Female; Granuloma; Humans; Melanoma; Middle Aged; Piperidines; Protein Kinase Inhibitors; Sarcoidosis; Skin Neoplasms; Vemurafenib

A 38-year-old man with a diagnosis of BRAF-mutated metastatic melanoma was referred to our clinic. He had been under treatment with 60-mg oral cobimetinib daily for 21 days/7 day off in combination with 960 mg vemurafenib twice daily. The patient had symptoms of blurred vision and photophobia in his right eye. A slit-lamp examination revealed bilateral central corneal stromal opacity and epithelial microcystic edema Involvement was more severe in the right eye compared with the left eye. Fourteen days after the first visit, the patient's symptoms and slit-lamp findings were largely resolved. We suggest that endothelium pump failure was involved in this acute corneal decompensation case similar to the mechanism in retinal pigment epithelium.

Topics: Acute Disease; Administration, Oral; Adult; Azetidines; Corneal Edema; Drug-Related Side Effects and Adverse Reactions; Humans; Male; MAP Kinase Kinase 1; Melanoma; Piperidines; Skin Neoplasms; Vision Disorders

Topics: Adult; Aged; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily G, Member 2; Azetidines; Cytochrome P-450 CYP3A; Female; Genetic Association Studies; Genotype; Humans; Male; Melanoma; Middle Aged; Neoplasm Proteins; Pharmacogenomic Variants; Piperidines; Polymorphism, Single Nucleotide; Protein Kinase Inhibitors; Vemurafenib

Topics: Adult; Aged; Aged, 80 and over; Azetidines; Drug Hypersensitivity Syndrome; Drug Therapy, Combination; Female; Humans; Male; Melanoma; Middle Aged; Piperidines; Prognosis; Risk Assessment; Sampling Studies; Severity of Illness Index; Skin Neoplasms; Vemurafenib

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

Under a combination therapy with cobimetinib/vemurafenib for the treatment of BRAF-V600 positive metastatic melanoma, symptomatic or asymptomatic bilateral serous retinopathy can occur, which is reversible after dose reduction or treatment discontinuation. In the case presented the progress of bilateral serous retinopathy was documented by optical coherence tomography (OCT). After therapy discontinuation, subfoveal fluid levels varied until remission was reached six months later.

Topics: Antineoplastic Combined Chemotherapy Protocols; Azetidines; Indoles; Melanoma; Mutation; Piperidines; Proto-Oncogene Proteins B-raf; Sulfonamides; Vemurafenib

Molecularly-targeted agents have improved outcomes for a subset of patients with

Topics: Adenine; Animals; Azetidines; c-Mer Tyrosine Kinase; Cell Line, Tumor; Cell Proliferation; Cell Survival; Drug Synergism; Female; GTP Phosphohydrolases; Humans; Melanoma; Membrane Proteins; Mice; Mutation; Phosphorylation; Piperazines; Piperidines; Proto-Oncogene Proteins B-raf; Signal Transduction; Vemurafenib

With the advent of immune-checkpoint inhibitors and targeted treatments (TT), there have been unprecedented response rates and survival in advanced melanoma, but the optimal sequencing of these two treatments modalities is unknown. Combining or sequencing these agents could potentially result in unique toxicities. Cutaneous adverse events (CAE) after sequential exposure to these agents represents one toxicity that needs further description.. After retrospectively reviewing charts of patients from 2015 to 2018, we identified six patients who experienced CAEs after recent exposure to sequential immunotherapy and TT or vice versa for the treatment for metastatic melanoma at the University of North Carolina, Chapel Hill. Skin biopsies were available in five patients.. Five patients received TT after immunotherapy, and one patient received immunotherapy after TT. TT consisted of vemurafenib/cobimetinib (V/C) in five patients with four patients starting V/C immediately before manifesting with a CAE. In patients receiving V/C after immunotherapy, the median time from beginning V/C to development of CAE was 14.5 days. The clinical presentation of diffuse morbilliform rash, fevers, hypotension, and end-organ damage raised concern for Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome. Histopathological features of lympho-eosinophilic infiltrate were supportive of a drug eruption. Immunotherapy or TT were re-initiated in five patients within 1-8 weeks after resolution of the index CAE. This resulted in two patients re-experiencing the CAE. Both of these patients were off prednisone at the time of therapy re-initiation, whereas none of the patients who were restarted on targeted therapy with a steroid overlap had a rash recurrence.. Sequential treatment using immunotherapy and TT, especially the sequence of V/C after immunotherapy appears to be the most common trigger for CAE with a median time to onset of approximately 2 weeks. Although the clinical presentation of these CAEs can be dramatic, they respond well to prednisone therapy. This unique presentation suggests that it may be reasonably safe to re-challenge certain patients with a steroid overlap after rash resolution.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Immunological; Azetidines; Exanthema; Female; Humans; Immunotherapy; Male; MAP Kinase Kinase Kinases; Melanoma; Middle Aged; Nivolumab; Piperidines; Programmed Cell Death 1 Receptor; Protein Kinase Inhibitors; Skin; Skin Neoplasms; Vemurafenib

Vemurafenib and cobimetinib are extremely effective in treating V600E-mutated metastatic melanoma, but their use is associated with toxic cardiac effects. Vemurafenib-induced prolonged QTc interval may be associated with ventricular fibrillation and sudden cardiac death. Cobimetinib-induced myocardial damage may lead to severely reduced heart function and lethal heart failure. Few data are available about the time course of recovery after these side effects. We provide the first description of cardiac recovery after potentially fatal cardiac side effects due to vemurafenib and cobimetinib administration. A 51-year-old woman was admitted to our hospital with diarrhea, vomiting, and asthenia. At admission, her left ventricular ejection fraction (LVEF) was severely reduced and QTc interval was extremely elongated (normal range QTc ≤ 440 ms). Blood levels of troponin I (normal values below 0.07 ng/mL) and brain natriuretic peptide (brain natriuretic peptide (BNP), normal range < 100 pg/mL) were elevated. During hospitalization, she developed recurrent runs of torsades de pointes degenerating into ventricular fibrillation, requiring direct current electric shock (DC shocks). Vemurafenib and cobimetinib were discontinued. Three weeks later, QTc was still higher than 500 ms and LVEF lower than 30%: an implantable cardioverter-defibrillator (ICD) was implanted. Myocardial function improved within 1 month, and QTc intervals became 500 ms 1 week later. After 6 months, a normal ejection fraction (> 55%) was observed, and the QTc interval was 455 ms. The patient died rather from metastatic melanoma recurrence 8 months later. This case report highlights the time-course of recovery after combined vemurafenib-cobimetinib-induced severe myocardial damage. Further research is warranted to assess whether and how antineoplastic therapy may be resumed after QT normalization and heart function recovery.
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Topics: Azetidines; Cardiotoxicity; Female; Humans; Melanoma; Middle Aged; Neoplasm Recurrence, Local; Piperidines; Vemurafenib

This study aimed to evaluate the impact of early adverse events on overall survival (OS), progression-free survival (PFS) and objective response within a pooled secondary analysis of participants treated with first-line vemurafenib or vemurafenib plus cobimetinib in the clinical trials BRIM3 and coBRIM. The study included 583 participants who received vemurafenib monotherapy and 247 who received vemurafenib plus cobimetinib. Adverse events requiring vemurafenib/cobimetinib dose adjustment within the first 28 days of therapy were significantly associated with OS (hazard ratio (HR) [95% CI]: dose reduced/interrupted = 0.79 [0.65-0.96]; drug withdrawn = 1.18 [0.71-1.96]; p = 0.032), PFS (HR [95% CI]: dose reduced/interrupted = 0.82 [0.67-0.99]; drug withdrawn = 1.58 [0.97-2.58]; p = 0.017) and objective response (odds ratio (OR) [95% CI]: dose reduced/interrupted = 1.35 [0.99-1.85]; drug withdrawn = 0.17 [0.06-0.43]; p = <0.001). Arthralgia occurring within the first 28 days of vemurafenib or vemurafenib plus cobimetinib therapy was also significantly associated with favourable OS (p = 0.026), PFS (p = 0.042) and objective response (p = 0.047).

Topics: Antineoplastic Combined Chemotherapy Protocols; Azetidines; Clinical Trials as Topic; Dose-Response Relationship, Drug; Humans; Melanoma; Neoplasm Staging; Piperidines; Progression-Free Survival; Survival Analysis; Vemurafenib

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

Previous investigations identified transcriptional signatures associated with innate resistance to anti-programmed cell death protein 1 therapy in melanoma. This analysis aimed to increase understanding of the role of baseline genetic features in the variability of response to BRAF and MEK inhibitor therapy for. This exploratory analysis compared genomic features, using whole-exome and RNA sequencing, of baseline tumors from patients who had complete response versus rapid progression (disease progression at first postbaseline assessment) on treatment with cobimetinib combined with vemurafenib or vemurafenib alone. Associations of gene expression with progression-free survival or overall survival were assessed by Cox proportional hazards modeling.. These findings suggest that enriched immune infiltration might be a shared feature favoring response to both targeted and immune therapies, while features of innate resistance to targeted and immune therapies were distinct.

Topics: Alleles; Antineoplastic Combined Chemotherapy Protocols; Azetidines; Biomarkers, Tumor; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Exome Sequencing; Gene Expression Profiling; Genomics; Humans; Melanoma; Mutation; Piperidines; Proto-Oncogene Proteins B-raf; Randomized Controlled Trials as Topic; Retrospective Studies; Treatment Outcome; Vemurafenib

Emerging research suggests that multiple tumor compartments can influence treatment responsiveness and relapse, yet the search for therapeutic resistance mechanisms remains largely focused on acquired genomic alterations in cancer cells. Here we show how treatment-induced changes occur in multiple tumor compartments during tumor relapse and can reduce benefit of follow-on therapies. By using serial biopsies, next-generation sequencing, and single-cell transcriptomics, we tracked the evolution of multiple cellular compartments within individual lesions during first-line treatment response, relapse, and second-line therapeutic interventions in an autochthonous model of melanoma. We discovered that although treatment-relapsed tumors remained genetically stable, they converged on a shared resistance phenotype characterized by dramatic changes in tumor cell differentiation state, immune infiltration, and extracellular matrix (ECM) composition. Similar alterations in tumor cell differentiation were also observed in more than half of our treatment-relapsed patient tumors. Tumor cell-state changes were coincident with ECM remodeling and increased tumor stiffness, which alone was sufficient to alter tumor cell fate and reduce treatment responses in melanoma cell lines in vitro. Despite the absence of acquired mutations in the targeted pathway, resistant tumors showed significantly decreased responsiveness to second-line therapy intervention within the same pathway. The ability to preclinically model relapse and refractory settings-while capturing dynamics within and crosstalk between all relevant tumor compartments-provides a unique opportunity to better design and sequence appropriate clinical interventions.

Topics: Animals; Antineoplastic Agents; Azetidines; Biomarkers, Tumor; Cell Line, Tumor; DNA Copy Number Variations; Drug Resistance, Neoplasm; Exome Sequencing; Extracellular Matrix; Female; High-Throughput Nucleotide Sequencing; Humans; Male; Melanoma; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mutation; Piperidines; Proto-Oncogene Proteins B-raf; Vemurafenib

Topics: Antineoplastic Combined Chemotherapy Protocols; Azetidines; Female; Humans; Melanoma; Middle Aged; Mutation; Piperidines; Posterior Leukoencephalopathy Syndrome; Prognosis; Proto-Oncogene Proteins B-raf; Vemurafenib; Withholding Treatment

Undifferentiated sarcoma has been hypothesized as an intermediate step in the progression of malignant melanoma to rhabdomyosarcoma. The current report describes a new case of rhabdomyosarcomatous transformation in a malignant melanoma and documents the temporal progression of the malignant melanoma to rhabdomyosarcoma in different metastatic sites via undifferentiated sarcoma. A 65-year-old female with a past medical history of malignant melanoma presented with a new lung mass. A core biopsy revealed a malignant spindle cell neoplasm that was negative for all melanocytic markers, suggesting the possibility of a primary pulmonary sarcomatoid carcinoma or sarcoma. The subsequent lobectomy demonstrated an undifferentiated spindle cell neoplasm with areas of rhabdomyoblastic differentiation. Review of the skin lesion and lymph nodes confirmed the diagnosis of the primary cutaneous malignant melanoma, but also revealed that the nodal metastases had largely transformed into an undifferentiated sarcoma with similar morphology as the spindle cell neoplasm in the lung. Molecular studies demonstrated an identical

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Azetidines; Biomarkers, Tumor; Cell Transformation, Neoplastic; Diagnosis, Differential; Disease Progression; Drug Resistance, Neoplasm; Female; Humans; Lung; Lung Neoplasms; Melanoma; Neoadjuvant Therapy; Piperidines; Pneumonectomy; Proto-Oncogene Proteins B-raf; Rhabdomyosarcoma; Skin; Skin Neoplasms; Vemurafenib

Radiation recall dermatitis is an uncommon inflammatory reaction of the skin appearing after several days to several years at the site of previous irradiation; it is precipitated by the use of triggering drugs, although rarely by BRAF or MEK inhibitors.. We report an unusual case of recall dermatitis induced 3 months after initiation of vemurafenib and cobimetinib therapy.. Radiation recall dermatitis is a cutaneous reaction that must be known and which in rare cases such as ours may occur a long time after the end of radiotherapy.

Topics: Adrenal Gland Neoplasms; Antineoplastic Agents; Azetidines; Ear Auricle; Ear Neoplasms; Facial Dermatoses; Humans; Male; MAP Kinase Kinase 1; Melanoma; Middle Aged; Piperidines; Radiodermatitis; Skin Neoplasms; Vemurafenib

Topics: Azetidines; Erythema Multiforme; Female; Humans; MAP Kinase Kinase 1; Melanoma; Middle Aged; Mutation; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Skin Neoplasms; Vemurafenib

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

We conducted a retrospective analysis to evaluate the impact of concomitant acid-reducing agents (ARAs) and vemurafenib dose on the efficacy of vemurafenib in patients with BRAF. Data were pooled for patients treated with vemurafenib or cobimetinib plus vemurafenib in the BRIM-2, BRIM-3, BRIM-7, and coBRIM studies. The primary end-points were progression-free survival and overall survival across patient subgroups defined by vemurafenib dose (full vs reduced) and concomitant ARA use (yes vs no). Objective response rate (ORR) was also analysed. Steady-state vemurafenib concentrations were evaluated according to vemurafenib dosing and concomitant ARA use across treatment cohorts in a subset of patients from BRIM-7 and coBRIM with available concentration data.. Efficacy analyses included 920 patients: 641 in the vemurafenib cohort and 279 in the cobimetinib plus vemurafenib cohort. Overall, no significant differences in survival outcomes were observed across subgroups according to vemurafenib dose and ARA use, with or without adjustment for known prognostic covariates, in both treatment cohorts. ORR was also similar across subgroups in both treatment cohorts. Steady-state vemurafenib concentrations were analysed in 389 patients (193 in the vemurafenib cohort and 196 in the cobimetinib plus vemurafenib cohort) and were generally similar across vemurafenib dose subgroups, regardless of ARA use in both treatment cohorts.. Results of this retrospective pooled analysis suggest that ARAs can be used concomitantly with vemurafenib, alone or in combination with cobimetinib, without compromising the efficacy of vemurafenib.

Topics: Adult; Aged; Antacids; Antineoplastic Combined Chemotherapy Protocols; Azetidines; Female; Humans; Male; Melanoma; Melanoma, Cutaneous Malignant; Middle Aged; Mutation; Piperidines; Progression-Free Survival; Proto-Oncogene Proteins B-raf; Retrospective Studies; Skin Neoplasms; Treatment Outcome; Vemurafenib

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

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

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Azetidines; Humans; Melanoma; Piperidines; Proto-Oncogene Proteins B-raf; Vemurafenib

Three clinical cases are presented of MEK retinopathy associated with the combination of cobimetinib and vemurafenib characterised by alteration of the retinal pigment epithelium and neurosensory detachment. Two of the cases conserved the vision of the unit, and the third developed a large bilateral neurosensory detachment with final visual acuity of 0.6 for the right eye and 0.1 for the left one.. The new therapeutic strategies against metastatic cutaneous melanoma condition the appearance of alterations of the pigmentary epithelium of the retina with serous detachments, leading to close monitoring with macular optical coherence tomography.

Topics: Antineoplastic Agents; Azetidines; Female; Humans; Male; Melanoma; Middle Aged; Mitogen-Activated Protein Kinases; Piperidines; Retinal Diseases; Vemurafenib

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

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

Prognostic models may provide insight into clinical trial results and inform the clinical management of patients with BRAF V600-mutated metastatic melanoma.. To identify subgroups with distinct survival outcomes based on clinical and genomic characteristics and to assess survival in identified prognostic subgroups across cohorts treated with dacarbazine, vemurafenib, or cobimetinib plus vemurafenib.. This retrospective and exploratory recursive partitioning analysis (RPA) modeled associations between prespecified covariates and survival outcomes using pooled data from the BRIM-2, BRIM-3, BRIM-7, and coBRIM studies.. Dacarbazine, vemurafenib, or cobimetinib plus vemurafenib.. Progression-free survival (PFS) and overall survival (OS), estimated using the Kaplan-Meier method.. The RPA included 1365 patients (783 men; 57.4%). Of these, 1032 (75.6%) were older than 65 years; 310 received cobimetinib plus vemurafenib; 717, vemurafenib alone; and 338, dacarbazine. Median follow-up was 14.1 months (interquartile range, 6.3-28.3 months). In the RPA that included all patients, baseline lactate dehydrogenase (LDH) level, Eastern Cooperative Oncology Group performance status (ECOG PS), presence or absence of liver metastases, and baseline sum of longest diameters of target lesions (SLDs) were significant prognostic factors for PFS: Median PFS was longest in patients with lower LDH (≤2 × upper limit of normal [ULN]), ECOG PS 0, and shorter SLD (≤44 mm) (11.1 months; 95% CI, 7.0-18.4 months), and shortest in those with elevated LDH (>2 × ULN) (3.5 months; 95% CI, 3.0-3.8 months). The subgroup with normal baseline LDH and no liver metastases had the longest median OS (22.7 months; 95% CI, 20.3-27.2 months). Similar PFS trends were observed when these prognostic subgroups were applied to the cobimetinib plus vemurafenib, vemurafenib alone, and dacarbazine cohorts. Baseline LDH, ECOG PS, and SLD were significant prognostic factors for OS: Median OS was longest in patients with normal LDH and shorter SLD (≤45 mm) (27.2 months; 95% CI, 22.1-32.1 months) and shortest in those with elevated LDH (>2 × ULN) (6.0 months; 95% CI, 5.3-6.8 months). Among patients in the most favorable subgroup (normal LDH and SLD ≤45 mm), 3-year OS rates were 53.3% (95% CI, 39.5%-67.1%) in the cobimetinib plus vemurafenib cohort, 35.6% (95% CI, 27.4%-43.8%) in the vemurafenib cohort, and 35.6% (95% CI, 24.8%-46.4%) in the dacarbazine cohort. Among patients with available gene expression data, RPA identified gene signature as a significant prognostic factor for PFS in those with normal LDH; 3-year PFS rates were 21.9%, (95% CI, 15.4%-28.4%) and 8.8% (95% CI, 3.6%-14.1%) in immune and cell cycle signature, respectively. The RPA for OS did not identify gene signature as a significant factor.. Baseline LDH, ECOG PS, disease burden, and gene signature appear to be key determinants of survival outcomes in patients with BRAF V600-mutated metastatic melanoma treated with BRAF and/or MEK inhibitors. These results are consistent with survival benefits of cobimetinib plus vemurafenib over vemurafenib alone observed in the coBRIM study.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Azetidines; Dacarbazine; Female; Humans; Kaplan-Meier Estimate; Male; Melanoma; Middle Aged; Mutation; Neoplasm Metastasis; Piperidines; Prognosis; Proto-Oncogene Proteins B-raf; Randomized Controlled Trials as Topic; Retrospective Studies; Skin Neoplasms; Treatment Outcome; Vemurafenib

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

Combined treatment with BRAF-V600 and MEK inhibitors has significantly improved progression-free and overall survival of patients with BRAF-mutated melanoma. Pattern of disease progression and outcomes in patients have not been fully characterized.. We conducted a single-center, retrospective, descriptive analysis of a cohort of 52 patients treated with BRAF-V600 + MEK inhibitors for advanced melanoma over a 12-month period. The aim of this study was to characterize disease progression, defined as metastatic pattern, disease kinetics, and response to subsequent therapies, in melanoma patients treated with BRAF-V600 + MEK inhibitors.. Disease progression was observed in 31/52 (59.6%) patients treated with BRAF-V600 + MEK inhibitors. Relapse of melanoma involved the CNS for 22/31 (70.9%) patients with disease progression, including 18/31 (58%) patients who had exclusive intracranial metastases. Sixteen patients died from disease progression. Among the 31 patients who had disease progression, the median time until a relapse was 8 months, and the median survival time after disease progression was 2 months.. Our study shows that, for patients treated with BRAF-V600 + MEK inhibitors who lose response, disease progression was aggressive and had poor outcomes. Most patients had CNS metastases and low rates of therapeutic response to any subsequent therapy.

Topics: Acrylonitrile; Aged; Aniline Compounds; Antineoplastic Combined Chemotherapy Protocols; Azetidines; Disease Progression; Female; Humans; Male; MAP Kinase Kinase 1; Melanoma; Middle Aged; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Retrospective Studies; Skin Neoplasms; Treatment Outcome; Vemurafenib

We present a case report of an early-onset drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) induced by vemurafenib (BRAF inhibitor) in a middle-age man affected by a metastatic, BRAF mutant melanoma who was started on first-line metastatic treatment with vemurafenib and cobimetinib.After initiating the treatment, the patient presented an extensive cutaneous rash with eosinophilia and renal impairment. Due the constellation of signs and symptoms, a diagnosis of DRESS syndrome was made which strongly contraindicated the reintroduction of vemurafenib due to its hypersensibility reaction. Thus, vemurafenib was stopped immediately, and we started corticoid treatment with clinical improvement.Due to the contraindication to start vemurafenib again, after multidisciplinary view of the case and having balanced the risks and benefits, we successfully performed a switch to another BRAF inhibitor in a progressively ascending pattern, without any skin toxicity and with a good response of the metastatic melanoma.

Topics: Acute Kidney Injury; Adrenal Cortex Hormones; Azetidines; Drug Hypersensitivity Syndrome; Eosinophilia; Exanthema; Humans; Male; MAP Kinase Kinase 1; Melanoma; Middle Aged; Piperidines; Protein Kinase Inhibitors; Skin Neoplasms; Treatment Outcome; Vemurafenib

A combined therapy MEK inhibitor, Cobimetinib (CB) and BRAF inhibitor, Vemurafenib (VMF), results in an improvement in progression-free survival among patients with BRAF V600-mutated metastatic melanoma. VMF skin adverse effects attributed to ERK paradoxical activation are decreased by the adjunction of CB. The aim of this study was to determine if this combination also improved the renal side effects of VMF.. To investigate the incidence of acute kidney injury (AKI), we conducted a retrospective observational monocentric study in Lyon Sud University Hospital in France. We included 38 patients with metastatic BRAF-mutated melanomas treated by VMF and CB between March 2015 and June 2016. According to the NCI-CTCAE classification, AKI was defined as an increase in serum creatinine exceeding the baseline concentration by 1.5-fold. Serum creatinine was measured before treatment, then on a monthly basis during treatment, and 1 month after treatment discontinuation. Patients were divided into two main groups: AKI-positive (AKI+) and AKI-negative (AKI-), and further subdivided into three groups according to AKI severity (stage 1-5).. Of 38 patients, 29 (76%) were AKI-, and all 9 AKI+ patients (24%) were diagnosed within the first trimester of treatment. Three-quarters of AKI (n = 7, 77%) had stage 1 AKI and the remaining 23% stage 2 AKI. Pre-treatment renal function was significantly better in AKI+ group: 105 vs. 80 ml/min/1.73m² AKI-, p = 0.009. Compared to previous results, the AKI incidence under the combined VMF-CB vs. VMF monotherapy was reduced by 60%.. We reported a reduced incidence and severity of nephrotoxicity of the association inhibitors of BRAF and MEK compared to a BRAF inhibitor monotherapy.

Topics: Acute Kidney Injury; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Azetidines; Creatinine; Disease-Free Survival; Enzyme Inhibitors; Extracellular Signal-Regulated MAP Kinases; Female; Humans; Incidence; Indoles; Male; Melanoma; Middle Aged; Piperidines; Proto-Oncogene Proteins B-raf; Retrospective Studies; Skin Neoplasms; Sulfonamides; Vemurafenib

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

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

Topics: Antineoplastic Combined Chemotherapy Protocols; Azetidines; Brain Neoplasms; Demyelinating Diseases; Female; Guillain-Barre Syndrome; Humans; Indoles; Liver Neoplasms; Lung Neoplasms; Lymphatic Metastasis; MAP Kinase Kinase Kinases; Melanoma; Middle Aged; Piperidines; Polyradiculoneuropathy; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Skin Neoplasms; Sulfonamides; Vemurafenib

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Azetidines; Female; Humans; Indoles; Melanoma; Middle Aged; Piperidines; Programmed Cell Death 1 Receptor; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Sulfonamides; Systemic Inflammatory Response Syndrome; Vemurafenib

Therapeutic advances derived from targeted therapy and immune checkpoint inhibitors can improve melanoma prognosis. Since 2015, cobimetinib has been approved in combination with vemurafenib in the first-line treatment for BRAF-mutated melanoma. For NRAS-mutated melanomas, MEK inhibition seems to be a therapeutic target, and association with checkpoint inhibitor provides a further therapeutic perspective. Infraclinical creatine phosphokinase (CPK) elevation is an MEK inhibitor side effect. We describe a case of focal necrotizing myopathy with 'dropped-head syndrome' induced by cobimetinib, 1 month after its introduction. The clinical presentation comprised interscapular pain, axial fatigue with cervical hypotonia, CPK elevation, intense fluorine-18-fluorodeoxyglucose uptake in cervical muscles, and necrotizing myopathy was confirmed by muscle biopsy. Cobimetinib was temporarily discontinued, resulting in CPK normalization. Re-evaluation showed partial response, motivating continuation of combination therapy with a reduced dose of cobimetinib (40 mg/day). Because prescription of targeted therapies is likely to increase, this adverse event should be known.

Topics: Aged; Azetidines; Humans; Male; MAP Kinase Kinase 1; Melanoma; Muscular Diseases; Piperidines; Skin Neoplasms

Vemurafenib ha probado ser una herramienta útil en el tratamiento de melanoma metastásico con mutación BRAF-V600E. Los efectos adversos incluyen artralgias, fatiga y toxicidad cutánea, siendo infrecuente la paniculitis. Presentamos el caso de una paciente de 43 años con melanoma metastásico que desarrolla lesiones subcutáneas dolorosas en miembros inferiores y superiores, asociadas a clínica sistémica después de 2 semanas de inicio de tratamiento con Vemurafenib + Cobimetinib. La histología demostró paniculitis linfocitaria septal y lobulillar. La paciente tuvo mala tolerancia al tratamiento anti diana a dosis plenas, requiriendo su ajuste, generando una corticodependencia para controlar sintomatología, y que finalmente obligó a la descontinuación de la terapia dirigida contra melanoma.  A la fecha, se han descrito 29 casos en la literatura de paniculitis asociada a vemurafenib, siendo la mayoría paniculitis neutrofílicas con adecuado control de sintomatología asociando antiinflamatorios no esteroidales y/o corticoides orales sin requerir en su mayoría modificación de la terapia contra melanoma; sin embargo hay que tener presente que pueden haber casos con mala evolución que obligan a la reducción de dosis de vemurafenib y descontinuar el tratamiento, como ha ocurrido en nuestro reporte.Vemurafenib has proven to be a useful tool in the treatment of metastatic melanoma with BRAF-V600E mutation. Adverse effects include arthralgia, fatigue, and skin toxicity; panniculitis is a rare complication. We present the case of a 43-year-old patient with metastatic melanoma who developed painful subcutaneous nodules of the lower and upper limbs and associated systemic clinical symptoms after 2 weeks of treatment with vemurafenib plus cobimetinib. Histology showed a septal and lobular lymphocytic panniculitis.The patient had poor tolerance of the full-dose treatment, requiring its adjustment. Systemic corticosteroids were required to control symptomatology, which finally forced the discontinuation of the medication.To date, 29 cases have been described in the literature of panniculitis associated with vemurafenib. Most of these have been neutrophilic panniculitis, but adequate control of symptoms is usually achieved with nonsteroidal anti-inflammatory drugs and/or oral corticosteroids without requiring modification of melanoma therapy. However, it must be borne in mind that there may be cases that force the reduction and discontinuation ofvemurafenib treatment. We beli

Topics: Adult; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Azetidines; Female; Humans; Indoles; Melanoma; Panniculitis; Piperidines; Skin Neoplasms; Sulfonamides; Vemurafenib

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Azetidines; Brain; Disease Progression; Humans; Indoles; Lymphatic Metastasis; Magnetic Resonance Imaging; Male; Melanoma; Piperidines; Posterior Leukoencephalopathy Syndrome; Proto-Oncogene Proteins B-raf; Skin Neoplasms; Sulfonamides; Vemurafenib

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

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

The development of BRAF V600 and MEK inhibitors constitutes a breakthrough in the treatment of patients with BRAF-mutated metastatic melanoma. However, although there is an increase in overall survival, these patients generally confront recurrence, and several resistance mechanisms have already been described. In the present study we describe a different resistance mechanism. After several weeks of long‑term in vitro treatment of two different V600E BRAF‑mutated melanoma cell lines with MARK inhibitors, PLX4032 and/or GDC-0973, the majority of the cells died whereas some remained viable and quiescent (SUR). Markedly, discontinuing treatment of SUR cells with MAPK inhibitors allowed the population to regrow and these cells retained drug sensitivity equal to that of the parental cells. SUR cells had increased expression levels of CD271 and ABCB5 and presented senescence-associated characteristics. Notably, SUR cells were efficiently lysed by cytotoxic T lymphocytes recognizing MART-1 and gp100 melanoma differentiation antigens. We propose quiescent plasticity as a mechanism of resistance to BRAF and MEK inhibitors while retaining sensitivity to immune effectors.

Topics: Animals; Apoptosis; Azetidines; Blotting, Western; CD8-Positive T-Lymphocytes; Cell Cycle; Cell Proliferation; Drug Resistance, Neoplasm; Enzyme Inhibitors; Flow Cytometry; gp100 Melanoma Antigen; Humans; Immunoenzyme Techniques; In Vitro Techniques; Indoles; MAP Kinase Signaling System; MART-1 Antigen; Melanoma; Mice; Mice, Inbred NOD; Mice, SCID; Mitogen-Activated Protein Kinases; Piperidines; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sulfonamides; T-Lymphocytes, Cytotoxic; Tumor Cells, Cultured; Vemurafenib; Xenograft Model Antitumor Assays

Previously, a BRAF-V600E-mutant melanoma obtained from the right chest wall of a patient was grown orthotopically in the right chest wall of nude mice to establish a patient-derived orthotopic xenograft (PDOX) model. Trametinib (TRA), an MEK inhibitor, caused tumor regression. In contrast, another MEK inhibitor, cobimetinib (COB) could slow but not arrest growth or cause regression of the melanoma PDOX. First-line therapy temozolomide (TEM) could slow but not arrest tumor growth or cause regression. In addition, vemurafenib (VEM) was not effective even though VEM is supposed to target the BRAF-V600E mutation. We also previously demonstrated that tumor-targeting with S. typhimurium A1-R combined with TEM was significantly more effective than either S. typhimurium A1-R alone or TEM alone on the melanoma PDOX with the BRAF-V600E mutation. The present study used this PDOX model of melanoma to test its sensitivity to VEM combined with S. typhimurium A1-R compared to VEM alone and VEM combined with COB. VEM combined with S. typhimurium A1-R was significantly more effective than VEM alone or VEM combined with COB (P = 0.0216) which is currently first line therapy for advanced melanoma with a BRAF-V600E mutation. J. Cell. Biochem. 118: 2314-2319, 2017. © 2017 Wiley Periodicals, Inc.

Topics: Aged; Animals; Azetidines; Cell Line, Tumor; Disease Models, Animal; Female; Humans; Indoles; Melanoma; Mice; Mice, Nude; Microscopy, Confocal; Microscopy, Electron, Transmission; Mutation; Piperidines; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Salmonella typhimurium; Sulfonamides; Vemurafenib; Xenograft Model Antitumor Assays

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Azetidines; Humans; Iris Neoplasms; Male; Melanoma; Piperidines; Protein Kinase Inhibitors; Remission Induction; Skin Neoplasms; Vemurafenib

Topics: Azetidines; Drug Interactions; Humans; MAP Kinase Kinase 1; Melanoma; Neoplasm Metastasis; Piperidines; Skin Neoplasms; Survival Rate

Topics: Antineoplastic Agents; Azetidines; Drug Interactions; Female; Humans; Male; Melanoma; Mitogen-Activated Protein Kinase Kinases; Piperidines; Pregnancy; Protein Kinase Inhibitors; Risk Factors; Signal Transduction; Skin Neoplasms; Treatment Outcome

Topics: Antineoplastic Agents; Azetidines; Central Serous Chorioretinopathy; Drug Therapy, Combination; Humans; Indoles; Male; Melanoma; Middle Aged; Piperidines; Recurrence; Skin Neoplasms; Sulfonamides; Treatment Outcome; Vemurafenib

Although MAPK pathway inhibitors are becoming a promising anticancer strategy, they are insufficient to fully eliminate cancer cells and their long-term efficacy is strikingly limited in patients with BRAF-mutant melanomas. It is well established that BRAF inhibitors (BRAFi) hamper glucose uptake before the apparition of cell death. Here, we show that BRAFi induce an extensive restructuring of mitochondria including an increase in mitochondrial activity and biogenesis associated with mitochondrial network remodeling. Furthermore, we report a close interaction between ER and mitochondria in melanoma exposed to BRAFi. This physical connection facilitates mitochondrial Ca2+ uptake after its release from the ER. Interestingly, Mfn2 silencing disrupts the ER-mitochondria interface, intensifies ER stress and exacerbates ER stress-induced apoptosis in cells exposed to BRAFi in vitro and in vivo. This mitochondrial control of ER stress-mediated cell death is similar in both BRAF- and NRAS-mutant melanoma cells exposed to MEK inhibitors. This evidence reinforces the relevance in combining MAPK pathway inhibitors with mitochondriotropic drugs to improve targeted therapies.

Topics: Animals; Antineoplastic Agents; Apoptosis; Azetidines; Calcium; Cell Death; Cell Line, Tumor; Drug Resistance, Neoplasm; Endoplasmic Reticulum; Female; Gene Silencing; GTP Phosphohydrolases; Humans; Indoles; MAP Kinase Signaling System; Melanoma; Mice; Mice, SCID; Mitochondria; Mitochondrial Proteins; Neoplasms; Oxidative Phosphorylation; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; RNA Interference; Sulfonamides; Treatment Outcome; Vemurafenib

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Azetidines; Cell Transformation, Neoplastic; Dermoscopy; Female; Humans; Indoles; Male; Melanoma; Middle Aged; Mitogen-Activated Protein Kinases; Nevus, Pigmented; Piperidines; Signal Transduction; Skin Neoplasms; Sulfonamides; Vemurafenib

Melanoma is a recalcitrant disease. The present study used a patient-derived orthotopic xenograft (PDOX) model of melanoma to test sensitivity to three molecularly-targeted drugs and one standard chemotherapeutic. A BRAF-V600E-mutant melanoma obtained from the right chest wall of a patient was grown orthotopically in the right chest wall of nude mice to establish a PDOX model. Two weeks after implantation, 50 PDOX nude mice were divided into 5 groups: G1, control without treatment; G2, vemurafenib (VEM) (30 mg/kg); G3; temozolomide (TEM) (25 mg/kg); G4, trametinib (TRA) (0.3 mg/kg); and G5, cobimetinib (COB) (5 mg/kg). Each drug was administered orally, daily for 14 consecutive days. Tumor sizes were measured with calipers twice a week. On day 14 from initiation of treatment, TRA, an MEK inhibitor, was the only agent of the 4 tested that caused tumor regression (P < 0.001 at day 14). In contrast, another MEK inhibitor, COB, could slow but not arrest growth or cause regression of the melanoma. First-line therapy TEM could slow but not arrest tumor growth or cause regression. The patient in this study had a BRAF-V600E-mutant melanoma and would be considered to be a strong candidate for VEM as first-line therapy, since VEM targets this mutation. However, VEM was not effective. The PDOX model thus helped identify the very-high efficacy of TRA against the melanoma PDOX and is a promising drug for this patient. These results demonstrate the powerful precision of the PDOX model for cancer therapy, not achievable by genomic analysis alone.

Topics: Aged; Animals; Antineoplastic Agents; Azetidines; Drug Resistance, Neoplasm; Female; Humans; Indoles; Melanoma; Mice; Mitogen-Activated Protein Kinase Kinases; Mutation; Piperidines; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Sulfonamides; Vemurafenib; Xenograft Model Antitumor Assays

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

Medications in dermatology are used in a variety of different methods and dosages and for numerous different diseases entities that are not approved by the US Food and Drug Administration (FDA); however, there are medications that have only recently hit the market that require our attention, as they are either FDA approved for the intended dermatologic use or could be effective in treating conditions that previously have been poorly managed.

Topics: Aminolevulinic Acid; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Arthritis, Psoriatic; Azetidines; Biphenyl Compounds; Carcinoma, Basal Cell; Cosmetic Techniques; Deoxycholic Acid; Dermatologic Agents; Drug Approval; Facial Dermatoses; Humans; Keratosis, Actinic; Melanoma; Oncolytic Virotherapy; Piperidines; Psoriasis; Pyridines; Scalp Dermatoses; Skin Neoplasms; United States; United States Food and Drug Administration

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

Vemurafenib, a RAF inhibitor, extends survival in patients with BRAF(V600)-mutant melanoma but activates extracellular signal-regulated kinase (ERK) signaling in RAS-mutant cells. In a patient with a BRAF(V600K)-mutant melanoma responding to vemurafenib, we observed accelerated progression of a previously unrecognized NRAS-mutant leukemia. We hypothesized that combining vemurafenib with a MAP-ERK kinase (MEK) inhibitor would inhibit ERK activation in the melanoma and prevent ERK activation by vemurafenib in the leukemia, and thus suppress both malignancies. We demonstrate that intermittent administration of vemurafenib led to a near-complete remission of the melanoma, and the addition of the MEK inhibitor cobimetinib (GDC-0973) caused suppression of vemurafenib-induced leukemic proliferation and ERK activation. Antimelanoma and antileukemia responses have been maintained for nearly 20 months, as documented by serial measurements of tumor-derived DNA in plasma in addition to conventional radiographic and clinical assessments of response. These data support testing of intermittent ERK pathway inhibition in the therapy for both RAS-mutant leukemia and BRAF-mutant melanoma.

Topics: Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Azetidines; Cell Line, Tumor; Cell Proliferation; DNA, Neoplasm; Drug Administration Schedule; GTP Phosphohydrolases; Humans; Indoles; Leukemia; Male; MAP Kinase Signaling System; Melanoma; Membrane Proteins; Mutation; Neoplastic Cells, Circulating; Piperidines; Proto-Oncogene Proteins B-raf; Sulfonamides; Vemurafenib

Topics: Azetidines; Female; Humans; Indoles; Male; Melanoma; Piperidines; Proto-Oncogene Proteins B-raf; Skin Neoplasms; Sulfonamides; Vemurafenib

Eruptive melanocytic nevi (EMN) are characterized by the sudden onset of numerous melanocytic nevi and have been traditionally described in the setting of immunosuppression. Selective BRAF inhibitors such as vemurafenib cause multiple cutaneous adverse effects, including the formation of cutaneous squamous cell carcinoma, as well as EMN. We describe the first reported case, to our knowledge, of involution of BRAF inhibitor-induced EMN following the concomitant addition of a MEK inhibitor, cobimetinib.. A woman in her 20s with a history of metastatic melanoma developed EMN while receiving therapy with vemurafenib, a selective BRAF inhibitor. After disease progression, the patient was placed on a clinical trial that combined vemurafenib with a MEK inhibitor, cobimetinib. Within months, we noted clinical involution of many of her EMN. In addition, numerous preexisting nevi were noted to fade in color on the dual regimen. Over a year after initiating this combination therapy, most of the patient's EMN were no longer clinically evident.. Our case report describing the involution of EMN supports data from previous clinical trials indicating that combination BRAF and MEK inhibition may reduce cutaneous proliferative effects that arise on BRAF inhibitor monotherapy. Further studies are necessary to characterize the biological mechanisms underlying this phenomenon.

Topics: Antineoplastic Combined Chemotherapy Protocols; Azetidines; Drug Interactions; Female; Humans; Indoles; MAP Kinase Kinase 1; Melanoma; Nevus, Pigmented; Piperidines; Proto-Oncogene Proteins B-raf; Skin Neoplasms; Sulfonamides; Vemurafenib; Young Adult

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

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

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

Topics: Azetidines; Humans; Indoles; Melanoma; Mutation; Piperidines; Proto-Oncogene Proteins B-raf; Sulfonamides; Vemurafenib

Targeted therapeutics that block signal transduction through the RAS-RAF-MEK and PI3K-AKT-mTOR pathways offer significant promise for the treatment of human malignancies. Dual inhibition of MAP/ERK kinase (MEK) and phosphatidylinositol 3-kinase (PI3K) with the potent and selective small-molecule inhibitors GDC-0973 and GDC-0941 has been shown to trigger tumor cell death in preclinical models. Here we have used phosphomotif antibodies and mass spectrometry (MS) to investigate the effects of MEK/PI3K dual inhibition during the period immediately preceding cell death. Upon treatment, melanoma cell lines responded by dramatically increasing phosphorylation on proteins containing a canonical DNA damage-response (DDR) motif, as defined by a phosphorylated serine or threonine residue adjacent to glutamine, [s/t]Q. In total, >2,000 [s/t]Q phosphorylation sites on >850 proteins were identified by LC-MS/MS, including an extensive network of DDR proteins. Linear mixed-effects modeling revealed 101 proteins in which [s/t]Q phosphorylation was altered significantly in response to GDC-0973/GDC-0941. Among the most dramatic changes, we observed rapid and sustained phosphorylation of sites within the ABCDE cluster of DNA-dependent protein kinase. Preincubation of cells with the inhibitors of the DDR kinases DNA-dependent protein kinase or ataxia-telangiectasia mutated enhanced GDC-0973/GDC-0941-mediated cell death. Network analysis revealed specific enrichment of proteins involved in RNA metabolism along with canonical DDR proteins and suggested a prominent role for this pathway in the response to MEK/PI3K dual inhibition.

Topics: Azetidines; Blotting, Western; Cell Line, Tumor; Chromatography, Liquid; DNA Damage; Humans; Indazoles; Linear Models; Melanoma; Mitogen-Activated Protein Kinase Kinases; Phosphoinositide-3 Kinase Inhibitors; Phosphoproteins; Phosphorylation; Piperidines; Proteomics; Signal Transduction; Sulfonamides; Tandem Mass Spectrometry

Mutations and activations of the MEK and PI3K pathways are associated with the development of many cancers. GDC-0973 and GDC-0941 are inhibitors of MEK and PI3K, respectively, currently being evaluated clinically in combination as anti-cancer treatment. The objective of these studies was to characterize the relationship between the plasma concentrations of GDC-0973 and GDC-0941 administered in combination and efficacy in A2058 melanoma xenograft.. GDC-0973 and GDC-0941 were administered to A2058 tumor-bearing mice daily (QD) or every third day (Q3D) either as single agents or in combination. A semi-mechanistic population anti-cancer model was developed to simultaneously describe the tumor growth following QD/Q3D single-agent and QD combination treatments. The interaction terms ψ included in the model were used to assess whether the combination was additive. Using this model, data from the Q3D combination regimen were simulated and compared with the observed tumor volumes.. The model consisting of saturable tumor growth provided the best fit of the data. The estimates for ψ were not significantly different from 1, suggesting an additive effect of GDC-0973 and GDC-0941 on tumor growth inhibition. The population rate constants associated with tumor growth inhibition for GDC-0973 and GDC-0941 were 0.00102 and 0000651 μM(-1) h(-1), respectively. Using the model based on single-agent and QD combination efficacy data, simulations adequately described the tumor growth from the Q3D combination regimen.. These findings suggest that, based on minimal data, it is possible to predict the effects of various combinations preclinically and also assess the potential clinical efficacy of combinations using human pharmacokinetic inputs.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Azetidines; Female; Indazoles; MAP Kinase Kinase 1; Melanoma; Mice; Mice, Nude; Models, Biological; Phosphoinositide-3 Kinase Inhibitors; Piperidines; Sulfonamides; Xenograft Model Antitumor Assays