binimetinib and Melanoma

Here, we summarize the 5-year results from part 1 of the COLUMBUS clinical study, which looked at the combination treatment of encorafenib plus binimetinib in people with a specific type of skin cancer called melanoma. Encorafenib (BRAFTOVI. In this 5-year update, more participants in the COMBO group were alive for longer without their disease getting worse after 5 years than those in the VEMU and ENCO groups. Patients in the COMBO group were alive for longer without their disease getting worse when they: Had less advanced cancer Were able to do more daily activities Had normal lactate dehydrogenase (LDH) levels Had fewer organs with tumors before treatment After treatment, fewer participants in the COMBO group received additional anticancer treatment than participants in the VEMU and ENCO groups. The number of participants who reported severe side effects was similar for each treatment. The side effects caused by the drugs in the COMBO group decreased over time.. Overall, this 5-year update confirmed that people with BRAF V600-mutant melanoma that has spread to other parts of the body and who took encorafenib plus binimetinib were alive for longer without their disease getting worse than those who took vemurafenib or encorafenib alone.

Topics: Antineoplastic Combined Chemotherapy Protocols; Drug-Related Side Effects and Adverse Reactions; Humans; Melanoma; Mutation; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Skin Neoplasms; Vemurafenib

Despite the significant progress in the treatment of unresectable or metastatic. Targeted therapy, including BRAF- and MEK-inhibitors, and immunotherapies have greatly contributed to advances in the treatment of

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Carbamates; Humans; Melanoma; Mutation; Neoplasms, Second Primary; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Randomized Controlled Trials as Topic; Skin Neoplasms; Sulfonamides

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

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

Approximately 50% of patients with metastatic melanoma have mutations in BRAF. Based on the results of prior phase III trials, the combination of a BRAF inhibitor (BRAFi) and a MEK inhibitor (MEKi) is the standard of care in patients with BRAF-mutant metastatic melanoma.. The author summarizes the available data on binimetinib, a reversible inhibitor of the kinase activity of MEK1 and MEK2, in BRAF- and NRAS-mutated melanoma.. With the advent of binimetinib and encorafenib, clinicians can choose between three BRAFi/MEKi combinations. Indirect comparison and a network meta-analysis suggest that binimetinib plus encorafenib is at least as active as the other two BRAFi/MEKi combinations and that safety is similar. The choice should be guided by the slightly different toxicity profile, local availability, and product experience. The optimal sequence of immunotherapy and BRAFi/MEKi in patients with BRAF-mutated tumors is unclear. As the response to BRAF/MEK inhibition is usually prompt and response to immunotherapy can be delayed, clinicians often choose a BRAFi/MEKi combination as first-line therapy in patients with rapidly evolving and threatening disease. Single-agent binimetinib almost doubled median progression-free survival when compared to dacarbazine in patients with NRAS-mutated melanoma.

Topics: Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Carbamates; Clinical Trials as Topic; GTP Phosphohydrolases; Humans; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Melanoma; Membrane Proteins; Molecular Targeted Therapy; Mutation; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Sulfonamides

Approximately 40-50% of patients with cutaneous melanoma harbor point mutations in. Encorafenib, a highly selective BRAF inhibitor, was developed in combination with binimetinib, a potent, selective allosteric MEK1/2 inhibitor, to improve efficacy and tolerability over other approved combo-targeted therapies. This novel combination shows peculiar pharmacodynamic properties which translate in a higher on-target potency and paradox index. Consistent survival improvements for encorafenib and binimetinib in. the favorable survival results and the attractive toxicity profile suggest that encorafenib and binimetinib combination is an intriguing standard option when targeted therapies are considered as first line treatment in BRAF mutated melanoma patients. In the near future, results from ongoing clinical trials will provide information on the use of this novel combination in specific situation, including as adjuvant treatment or as a combination strategy.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Carbamates; Humans; Melanoma; Point Mutation; Proto-Oncogene Proteins B-raf; Skin Neoplasms; Sulfonamides; Survival Rate

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

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

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Carbamates; Disease-Free Survival; Humans; Melanoma; Molecular Targeted Therapy; Mutation; Proto-Oncogene Proteins B-raf; Skin Neoplasms; Sulfonamides

BRAF is a constituent of the mitogen-activated protein kinase (MAPK) signaling pathway, which serves to activate downstream MEK, and is one of the most commonly mutated oncogenes in human tumors. Indeed, BRAF V600 mutations are present in approximately 40% of metastatic melanoma tumors. Encorafenib (LGX-818, Braftovi) and binimetinib (MEK-162, Mektovi) are small-molecule inhibitors of BRAF and MEK, respectively. BRAF and MEK inhibitors have been shown to improve overall and progression-free survival among patients with metastatic melanoma. Of these inhibitors, encorafenib and binimetinib are the newest combination, which received approval by the Food and Drug Administration (FDA) for the treatment of BRAF V600E/K-mutated melanoma in June 2018. This review will focus on the preclinical pharmacology, pharmacokinetics and clinical utility of encorafenib and binimetinib in BRAF V600-mutated melanoma.

Topics: Benzimidazoles; Carbamates; Humans; Melanoma; Mutation; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Sulfonamides

Encorafenib (Braftovi™), a BRAF inhibitor, and binimetinib (Mektovi

Topics: Benzimidazoles; Carbamates; Drug Approval; Humans; MAP Kinase Kinase Kinases; Melanoma; Molecular Structure; Mutation; Neoplasm Metastasis; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Sulfonamides; Treatment Outcome; United States

This year again, several breaking news were published in our field of oncodermatology, especially in the domain of immunotherapy. Many works have reported results on predictive biomarker identification. Concerning melanoma treatment, we were disappointed by the negative results of the phase III trial evaluating the IDO1 inhibitor epacadostat + pembrolizumab versus pembrolizumab. However, many promising preliminary results involving the combinations of anti-PD1 and innate immunity activators have been published. We also have a new anti-BRAF + anti-MEK combination: encorafenib + binimetinib with a good benefit/risk ratio and a particularly favorable safety profile as compared with existing similar combinations. Major steps forward were obtained for locally advanced Merkel cell carcinoma and squamous cell carcinoma with anti-PDL-1 avelumab and anti-PD1 cemiplimab respectively.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Immunological; Benzimidazoles; Biomarkers, Tumor; Carbamates; Carcinoma, Merkel Cell; Carcinoma, Squamous Cell; Clinical Trials as Topic; Dermatology; Humans; Melanoma; Skin Neoplasms; Sulfonamides; Survival Analysis

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

Although significant progress has been made in the treatment of unresectable or metastatic melanoma, at least half of all advanced melanoma patients eventually progress and pass away due to their disease. In particular, patients with NRAS-mutated melanoma still face limited therapeutic options, with immunotherapy being the current treatment type of choice. Binimetinib is a selective inhibitor of MEK, a central kinase in the tumor-promoting MAPK pathway. The results of a recent Phase III trial rendered binimetinib the first targeted therapy agent to significantly improve progression-free survival in NRAS-mutated melanoma. This review will summarize the development and clinical data of binimetinib in melanoma in general and also explore the potential future role of this substance as single agent or combination therapy.

Topics: Animals; Antineoplastic Agents; Benzimidazoles; Biomarkers, Tumor; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; GTP Phosphohydrolases; Humans; MAP Kinase Signaling System; Melanoma; Melanoma, Cutaneous Malignant; Membrane Proteins; Mutation; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Skin Neoplasms; Survival Analysis; Treatment Outcome

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

Activating NRAS mutations occur in approximately 15-20% of melanomas and are the second most common oncogenic driver mutation in this disease, after BRAF mutations. There is an unmet medical need for new targeted therapy opportunities in metastatic patients whose tumors harbor an NRAS mutation. Binimetinib, a mitogen-activated protein kinase kinase (MEK) inhibitor, has shown clinical activity in this group of patients. Areas covered: The purpose of this paper was to review the safety, activity and efficacy of the MEK inhibitor binimetinib for the treatment of NRAS-mutant melanoma, as well as to discuss future therapeutic perspectives such as multiple pathways, targeted therapy, and combinations with immunotherapy. Expert commentary: Only a modest progression-free survival (PFS) benefit was observed in NRAS-mutated patients who received binimetinib compared with dacarbazine in a randomized phase 3 clinical trial, with no improvement in overall survival. Nevertheless, binimetinib represents another promising treatment option for advanced melanoma and the first molecularly targeted therapy for the NRAS-mutant population. Binimetinib may also have a role in treating NRAS-mutated melanoma patients after failure of immunotherapy.

Topics: Antineoplastic Agents; Benzimidazoles; Disease-Free Survival; GTP Phosphohydrolases; Humans; Immunotherapy; Melanoma; Membrane Proteins; Mitogen-Activated Protein Kinase Kinases; Molecular Targeted Therapy; Mutation; Protein Kinase Inhibitors; Randomized Controlled Trials as Topic; Survival Rate

Historically, there were few effective and durable treatments for metastatic melanoma. Recently, mutation based targeted therapies have revolutionized treatment and outcomes for patients with metastatic melanoma. Specifically, inhibitors aimed at BRAF, NRAS, and C-KIT mutations are now commonly used in treatment for patients harboring the specific mutations. Areas covered: A brief review of current BRAF, NRAS, and C-KIT inhibitors provides background for a thorough review of newly developed agents namely binimetinib, a MEK inhibitor, encorafenib a BRAF inhibitor, and masitinib which inhibits C-KIT. Expert opinion: While the 3 novel agents reviewed here have potential for use in melanoma, optimal utilization will occur once a more personalized approach incorporating genomic, proteomic, and immunologic data guides therapeutic decisions.

Topics: Benzamides; Benzimidazoles; Carbamates; Humans; Melanoma; Mutation; Piperidines; Protein Kinase Inhibitors; Proteomics; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins c-kit; Pyridines; Skin Neoplasms; Sulfonamides; Thiazoles

Limited prospective data are available on sequential immunotherapy and BRAF/MEK inhibition for. A total of 209 patients were randomly assigned (69 in arm A, 71 in arm B, and 69 in arm C). At a median follow-up of 32.2 (interquartile range, 27.9-41.6) months, median OS was not reached in any arm and more than 30 patients were alive in all arms. Assuming a null hypothesis of median OS of ≤ 15 months, the OS end point was met for all arms. The 2-year and 3-year OS rates were 65% (95% CI, 54 to 76) and 54% (95% CI, 41 to 67) in arm A, 73% (95% CI, 62 to 84) and 62% (95% CI, 48 to 76) in arm B, and 69% (95% CI, 59 to 80) and 60% (95% CI, 58 to 72) in arm C. No new safety signals emerged.. Sequential immunotherapy and targeted therapy provide clinically meaningful survival benefits for patients with

Topics: Antineoplastic Combined Chemotherapy Protocols; Humans; Immunotherapy; Ipilimumab; Melanoma; Nivolumab; Prospective Studies; Proto-Oncogene Proteins B-raf; Skin Neoplasms

The combination of encorafenib (BRAF inhibitor) plus binimetinib (MEK inhibitor) has demonstrated clinical efficacy with an acceptable safety profile in patients with. In this ongoing, open-label, single-arm, phase II study, patients with. For patients with treatment-naïve and previously treated

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

Combination treatment with BRAF and MEK inhibitors has demonstrated benefits on progression-free survival (PFS) and overall survival (OS) and is a standard of care for the treatment of advanced. Patients with locally advanced unresectable or metastatic. Five hundred seventy-seven patients were randomly assigned: 192 to encorafenib plus binimetinib, 191 to vemurafenib, and 194 to encorafenib. The 5-year PFS and OS rates with encorafenib plus binimetinib were 23% and 35% overall and 31% and 45% in those with normal lactate dehydrogenase levels, respectively. In comparison, the 5-year PFS and OS rates with vemurafenib were 10% and 21% overall and 12% and 28% in those with normal lactate dehydrogenase levels, respectively. The median duration of response with encorafenib plus binimetinib was 18.6 months, with disease control achieved in 92.2% of patients. In comparison, the median duration of response with vemurafenib was 12.3 months, with disease control achieved in 81.2% of patients. Long-term follow-up showed no new safety concerns, and results were consistent with the known tolerability profile of encorafenib plus binimetinib. Interactive visualization of the data presented in this article is available at COLUMBUS dashboard.. In this 5-year update of part 1 of the COLUMBUS trial, encorafenib plus binimetinib treatment demonstrated continued long-term benefits and a consistent safety profile in patients with

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

Although combination BRAF and MEK inhibitors are highly effective for the 40-50% of cutaneous metastatic melanomas harboring BRAFV600 mutations, targeted agents have been ineffective for BRAFV600wild-type (wt) metastatic melanomas. The SU2C Genomics-Enabled Medicine for Melanoma Trial utilized a Simon two-stage optimal design to assess whether comprehensive genomic profiling improves selection of molecular-based therapies for BRAFV600wt metastatic melanoma patients who had progressed on standard-of-care therapy, which may include immunotherapy. Of the response-evaluable patients, binimetinib was selected for 20 patients randomized to the genomics-enabled arm, and nine were treated on the alternate treatment arm. Response rates for 27 patients treated with targeted recommendations included one (4%) partial response, 18 (67%) with stable disease, and eight (30%) with progressive disease. Post-trial genomic and protein pathway activation mapping identified additional drug classes that may be considered for future studies. Our results highlight the complexity and heterogeneity of metastatic melanomas, as well as how the lack of response in this trial may be associated with limitations including monotherapy drug selection and the dearth of available single and combination molecularly-driven therapies to treat BRAFV600wt metastatic melanomas.

Topics: Adult; Aged; Benzimidazoles; Female; Genomics; Humans; Male; Melanoma; Melanoma, Cutaneous Malignant; Middle Aged; Neoplasm Metastasis; Pilot Projects; Prospective Studies; Proto-Oncogene Proteins B-raf; Skin Neoplasms

In COLUMBUS, treatment with encorafenib plus binimetinib in patients with advanced BRAF-mutant melanoma showed improved progression-free and overall survival with favourable tolerability compared to vemurafenib treatment. Here, results on health-related quality of life (HRQoL) are presented.. COLUMBUS was a two-part, open-label, randomised, phase III study in patients with BRAF-mutant melanoma. In PART-I, 577 patients were randomised (1:1:1) to encorafenib plus binimetinib, encorafenib or vemurafenib. The primary objective was to assess progression-free survival. As a secondary objective, HRQoL was assessed by the EQ-5D, the EORTC QLQ-C30 and the FACT-M questionnaires. Furthermore, time to definitive 10% deterioration was estimated with a Kaplan-Meier analysis and differences in mean scores between groups were calculated with a mixed-effect model for repeated measures. Hospitalisation rate and the impact of hospitalisation on HRQoL were also assessed.. Patients receiving the combination treatment showed improvement of their FACT-M and EORTC QLQ-C30 global health status scores, compared to those receiving vemurafenib (post-baseline score differences: 3.03 [p < 0.0001] for FACT M and 5.28 [p = 0.0042] for EORTC QLQ-C30), indicative of a meaningful change in patient's status. Furthermore, a delay in the deterioration of QoL was observed in non-hospitalised patients compared to hospitalised patients (hazard ratio [95% CI]: 1.16 [0.80; 1.68] for EORTC QLQ-C30 and 1.27 [0.81; 1.99] for FACT-M) and a risk reduction of 10% deterioration, favoured the combination in both groups.. The improved efficacy of encorafenib plus binimetinib compared to vemurafenib, translates into a positive impact on the perceived health status as assessed by the HRQoL questionnaires. The study is registered with ClinicalTrials.gov, number NCT01909453 and EudraCT number 2013-001176-38.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Carbamates; Female; Humans; Male; Melanoma; Middle Aged; Mutation; Progression-Free Survival; Proto-Oncogene Proteins B-raf; Quality of Life; Skin Neoplasms; Sulfonamides; Vemurafenib; Young Adult

BRAF/MEK inhibitor combinations are established treatments for BRAF V600-mutant melanoma based on demonstrated benefits on progression-free survival (PFS) and overall survival (OS). Here, we report an updated analysis of the COLUMBUS (COmbined LGX818 [encorafenib] Used with MEK162 [binimetinib] in BRAF mutant Unresectable Skin cancer) trial with long-term follow-up.. In part 1 of the COLUMBUS trial, 577 patients with advanced/metastatic BRAF V600-mutant melanoma, untreated or progressed after first-line immunotherapy, were randomised 1:1:1 to 450 mg of encorafenib QD + 45 mg of binimetinib BID (COMBO450) vs 960 mg of vemurafenib BID (VEM) or 300 mg of encorafenib ENCO QD (ENCO300). An updated analysis was conducted that included PFS, OS, objective response rate, safety and tolerability and analyses of results by prognostic subgroups.. At data cutoff, there were 116, 113 and 138 deaths in the COMBO450, ENCO300 and VEM treatment arms, respectively. The median OS was 33.6 months (95% confidence interval [CI], 24.4-39.2) for COMBO450, 23.5 months (95% CI, 19.6-33.6) for ENCO300 and 16.9 months (95% CI, 14.0-24.5) for VEM. Compared with VEM, COMBO450 decreased the risk of death by 39% (hazard ratio [HR], 0.61; 95% CI, 0.48-0.79). The updated median PFS for COMBO450 was 14.9 months (95% CI, 11.0-20.2), ENCO300 was 9.6 months (95% CI, 7.4-14.8) and VEM was 7.3 months (95% CI, 5.6-7.9). PFS was longer for COMBO450 vs VEM (HR, 0.51; 95% CI, 0.39-0.67). Landmark OS and PFS results show consistent results for each year analysed. Subgroups all favoured COMBO450 vs VEM.. Updated PFS and OS results for COMBO450 from the COLUMBUS trial demonstrate a long-term benefit in patients with advanced BRAF V600-mutated melanoma.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Carbamates; Diarrhea; Disease-Free Survival; Female; Humans; Male; Melanoma; Middle Aged; Mutation; Nausea; Outcome Assessment, Health Care; Prognosis; Proto-Oncogene Proteins B-raf; Skin Neoplasms; Sulfonamides; Vemurafenib; Vomiting

This open-label, dose-finding phase Ib/II study reports the safety and activity of the first combination use with BRAF inhibitor (BRAFi) encorafenib plus MEK inhibitor (MEKi) binimetinib in patients with. In phase I, the recommended phase 2 doses (RP2D) were established (primary objective). In phase II, the clinical activity of the combination at the RP2D was assessed (primary objective) in patients with. The combination of encorafenib (450 mg) plus binimetinib (45 mg) showed acceptable tolerability and encouraging activity in patients with

Topics: Adult; Aged; Alanine Transaminase; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Carbamates; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Male; Melanoma; Middle Aged; Mitogen-Activated Protein Kinase Kinases; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Sulfonamides

Dual inhibition of the mitogen-activated protein kinase pathway with BRAF/MEK inhibitor (BRAFi/MEKi) therapy is a standard treatment for BRAFV600-mutant metastatic melanoma and has historically been associated with grade III pyrexia or photosensitivity depending on the combination used. The objective of this study was to fully describe adverse events from the COLUMBUS study evaluating the most recent BRAF/MEK inhibitor combination encorafenib+binimetinib.. Patients with locally advanced, unresectable or metastatic BRAFV600-mutant melanoma were randomised to receive encorafenib 450 mg once daily plus binimetinib 45 mg twice daily, encorafenib 300 mg once daily or vemurafenib 960 mg twice daily. Adverse events that represent known effects of available BRAFi and/or MEKi were evaluated.. The safety population included a total of 570 patients (encorafenib+binimetinib = 192; encorafenib = 192; vemurafenib = 186). Median duration of exposure was longer with encorafenib+binimetinib (51 weeks) than with encorafenib (31 weeks) or vemurafenib (27 weeks). Common BRAFi/MEKi toxicities with encorafenib+binimetinib were generally manageable, reversible and infrequently associated with discontinuation. Pyrexia was less frequent with encorafenib+binimetinib (18%) and encorafenib (16%) than with vemurafenib (30%) and occurred later in the course of therapy with encorafenib+binimetinib (median time to first onset: 85 days versus 2.5 days and 19 days, respectively). The incidence of photosensitivity was lower with encorafenib+binimetinib (5%) and encorafenib (4%) than with vemurafenib (30%). The incidence of serous retinopathy was higher with encorafenib+binimetinib (20%) than with encorafenib (2%) or vemurafenib (2%), but no patients discontinued encorafenib+binimetinib because of this event.. Encorafenib+binimetinib is generally well tolerated and has a low discontinuation rate in patients with BRAFV600-mutant melanoma, with a distinct safety profile as compared with other anti-BRAF/MEK targeted therapies.. ClinicalTrials.gov (Identifier: NCT01909453) and with EudraCT (number 2013-001176-38).

Topics: Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Carbamates; Fatigue; Female; Humans; Incidence; Male; Melanoma; Middle Aged; Mitogen-Activated Protein Kinases; Mutation; Nausea; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Skin Neoplasms; Sulfonamides; Vemurafenib; Vomiting

Combined BRAF-MEK inhibitor therapy is the standard of care for BRAF. COLUMBUS was conducted as a two-part, randomised, open-label phase 3 study at 162 hospitals in 28 countries. Eligible patients were aged 18 years or older and had histologically confirmed locally advanced (American Joint Committee on Cancer [AJCC] stage IIIB, IIIC, or IV), unresectable or metastatic cutaneous melanoma, or unknown primary melanoma; a BRAF. Between Dec 30, 2013, and April 10, 2015, 577 of 1345 screened patients were randomly assigned to either the encorafenib plus binimetinib group (n=192), the encorafenib group (n=194), or the vemurafenib group (n=191). With a median follow-up of 16·6 months (95% CI 14·8-16·9), median progression-free survival was 14·9 months (95% CI 11·0-18·5) in the encorafenib plus binimetinib group and 7·3 months (5·6-8·2) in the vemurafenib group (hazard ratio [HR] 0·54, 95% CI 0·41-0·71; two-sided p<0·0001). The most common grade 3-4 adverse events seen in more than 5% of patients in the encorafenib plus binimetinib group were increased γ-glutamyltransferase (18 [9%] of 192 patients), increased creatine phosphokinase (13 [7%]), and hypertension (11 [6%]); in the encorafenib group they were palmoplantar erythrodysaesthesia syndrome (26 [14%] of 192 patients), myalgia (19 [10%]), and arthralgia (18 [9%]); and in the vemurafenib group it was arthralgia (11 [6%] of 186 patients). There were no treatment-related deaths except for one death in the combination group, which was considered possibly related to treatment by the investigator.. Encorafenib plus binimetinib and encorafenib monotherapy showed favourable efficacy compared with vemurafenib. Overall, encorafenib plus binimetinib appears to have an improved tolerability profile compared with encorafenib or vemurafenib. Encorafenib plus binimetinib could represent a new treatment option for patients with BRAF-mutant melanoma.. Array BioPharma, Novartis.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Biomarkers, Tumor; Carbamates; Female; Humans; Male; Melanoma; Middle Aged; Molecular Targeted Therapy; Mutation; Progression-Free Survival; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Skin Neoplasms; Sulfonamides; Time Factors; Vemurafenib; Young Adult

Encorafenib plus binimetinib and encorafenib alone improved progression-free survival compared with vemurafenib in patients with BRAF. COLUMBUS was a two-part, randomised, open-label, phase 3 study done at 162 hospitals in 28 countries. Eligible patients were aged at least 18 years with histologically confirmed, locally advanced, unresectable, or metastatic cutaneous melanoma, or unknown primary melanoma, BRAF. Between Dec 30, 2013, and April 10, 2015, 577 of 1345 screened patients were randomly assigned to receive encorafenib plus binimetinib (n=192), encorafenib (n=194), or vemurafenib (n=191). Median follow-up for overall survival was 36·8 months (95% CI 35·9-37·5). Median overall survival was 33·6 months (95% CI 24·4-39·2) with encorafenib plus binimetinib and 16·9 months (14·0-24·5) with vemurafenib (hazard ratio 0·61 [95% CI 0·47-0·79]; two-sided p<0·0001). The most common grade 3 or 4 adverse events did not change substantially from the first report; those seen in more than 5% of patients treated with encorafenib plus binimetinib were increased γ-glutamyltransferase (18 [9%] of 192 patients), increased blood creatine phosphokinase (14 [7%]), and hypertension (12 [6%]); those seen with encorafenib alone were palmar-plantar erythrodysaesthesia syndrome (26 [14%] of 192 patients), myalgia (19 [10%]), and arthralgia (18 [9%]); and with vemurafenib the most common grade 3 or 4 adverse event was arthralgia (11 [6%] of 186 patients). One death in the combination treatment group was considered by the investigator to be possibly related to treatment.. The combination of encorafenib plus binimetinib provided clinically meaningful efficacy with good tolerability as shown by improvements in both progression-free survival and overall survival compared with vemurafenib. These data suggest that the combination of encorafenib plus binimetinib is likely to become an important therapeutic option in patients with BRAF. Array BioPharma, Novartis.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Biomarkers, Tumor; Carbamates; Disease Progression; Female; Genetic Predisposition to Disease; Humans; Male; Melanoma; Middle Aged; Mutation; Phenotype; Progression-Free Survival; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Skin Neoplasms; Sulfonamides; Time Factors; Vemurafenib; Young Adult

There are no established therapies specific for NRAS-mutant melanoma despite the emergence of immunotherapy. We aimed to assess the efficacy and safety of the MEK inhibitor binimetinib versus that of dacarbazine in patients with advanced NRAS-mutant melanoma.. NEMO is an ongoing, randomised, open-label phase 3 study done at 118 hospitals in 26 countries. Patients with advanced, unresectable, American Joint Committee on Cancer stage IIIC or stage IV NRAS-mutant melanoma who were previously untreated or had progressed on or after previous immunotherapy were randomised (2:1) to receive either binimetinib 45 mg orally twice daily or dacarbazine 1000 mg/m. Between Aug 19, 2013, and April 28, 2015, 402 patients were enrolled and randomly assigned, 269 to binimetinib and 133 to dacarbazine. Median follow-up was 1·7 months (IQR 1·4-4·1). Median progression-free survival was 2·8 months (95% CI 2·8-3·6) in the binimetinib group and 1·5 months (1·5-1·7) in the dacarbazine group (hazard ratio 0·62 [95% CI 0·47-0·80]; one-sided p<0·001). Grade 3-4 adverse events seen in at least 5% of patients the safety population in either group were increased creatine phosphokinase (52 [19%] of 269 patients in the binimetinib group vs none of 114 in the dacarbazine group), hypertension (20 [7%] vs two [2%]), anaemia (five [2%] vs six [5%]), and neutropenia (two [1%] vs ten [9%]). Serious adverse events (all grades) occurred in 91 (34%) patients in the binimetinib group and 25 (22%) patients in the dacarbazine group.. Binimetinib improved progression-free survival compared with dacarbazine and was tolerable. Binimetinib might represent a new treatment option for patients with NRAS-mutant melanoma after failure of immunotherapy.. Array BioPharma and Novartis Pharmaceuticals Corporation.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Dacarbazine; Female; Follow-Up Studies; GTP Phosphohydrolases; Humans; Male; Melanoma; Membrane Proteins; Middle Aged; Mutation; Neoplasm Staging; Prognosis; Survival Rate

To analyze the clinical characteristics of a serous retinopathy associated with mitogen-activated protein kinase kinase (MEK) inhibition with binimetinib treatment for metastatic cutaneous melanoma (CM) and uveal melanoma (UM), and to determine possible pathogenetic mechanisms that may lead to this retinopathy.. Prospective observational, cohort-based, cross-sectional study.. Thirty CM patients and 5 UM patients treated with the MEK inhibitor binimetinib (CM) or a combination of binimetinib and the protein kinase C inhibitor sotrastaurin (UM).. Extensive ophthalmic examination was performed, including Early Treatment of Diabetic Retinopathy Study best-corrected visual acuity, applanation tonometry, slit-lamp examination, indirect ophthalmoscopy, digital color fundus photography, and optical coherence tomography (OCT). In selected cases, additional examinations were performed, including visual field testing and electro-oculography (EOG). Blood samples were obtained from 3 CM patients and 3 UM patients to analyze the presence of autoantibodies against retinal and retinal pigment epithelium (RPE) proteins.. Visual symptoms, visual acuity, fundus appearance, characteristics on OCT, fundus autofluorescence (FAF), and EOG.. Six CM patients (20%) and 2 UM patients (40%) reported visual symptoms during the study. The median time to the onset of symptoms, which were all mild and transient, was 3.5 days (range, <1 hour to 3 weeks). On OCT, subretinal fluid (SRF) was detected in 77% of CM patients and 60% of UM patients. In the 26 patients with SRF, the fovea was affected in 85%. After the start of the medication, an EOG was performed in 19 eyes of 11 patients; 16 of these eyes (84%) developed SRF on OCT. Fifteen of these eyes (94%) showed an abnormal Arden ratio (<1.65). A broad pattern of anti-retinal antibodies was found in 3 CM patients and 2 UM patients tested, whereas anti-RPE antibodies were detected in all 6 tested patients.. A time-dependent and reversible serous retinopathy can develop both in patients with metastatic CM and UM treated with binimetinib. A minority of patients develop visual symptoms, which are generally mild and transient. A cause of binimetinib-associated serous retinopathy may be toxicity of medication, but autoantibodies also may be involved.

Topics: Adult; Aged; Autoantibodies; Benzimidazoles; Central Serous Chorioretinopathy; Cross-Sectional Studies; Drug Combinations; Electrooculography; Electroretinography; Eye Proteins; Female; Fluorescein Angiography; Humans; Male; Melanoma; Melanoma, Cutaneous Malignant; Middle Aged; Mitogen-Activated Protein Kinase Kinases; Prospective Studies; Protein Kinase C; Pyrroles; Quinazolines; Skin Neoplasms; Subretinal Fluid; Tomography, Optical Coherence; Uveal Neoplasms; Visual Acuity

Patients with melanoma harbouring Val600 BRAF mutations benefit from treatment with BRAF inhibitors. However, no targeted treatments exist for patients with BRAF wild-type tumours, including those with NRAS mutations. We aimed to assess the use of MEK162, a small-molecule MEK1/2 inhibitor, in patients with NRAS-mutated or Val600 BRAF-mutated advanced melanoma.. In our open-label, non-randomised, phase 2 study, we assigned patients with NRAS-mutated or BRAF-mutated advanced melanoma to one of three treatment arms on the basis of mutation status. Patients were enrolled at university hospitals or private cancer centres in Europe and the USA. The three arms were: twice-daily MEK162 45 mg for NRAS-mutated melanoma, twice-daily MEK162 45 mg for BRAF-mutated melanoma, and twice-daily MEK162 60 mg for BRAF-mutated melanoma. Previous treatment with BRAF inhibitors was permitted, but previous MEK inhibitor therapy was not allowed. The primary endpoint was the proportion of patients who had an objective response (ie, a complete response or confirmed partial response). We report data for the 45 mg groups. We assessed clinical activity in all patients who received at least one dose of MEK162 and in patients assessable for response (with two available CT scans). This study is registered with ClinicalTrials.gov, number NCT01320085, and is currently recruiting additional patients with NRAS mutations (based on a protocol amendment).. Between March 31, 2011, and Jan 17, 2012, we enrolled 71 patients who received at least one dose of MEK162 45 mg. By Feb 29, 2012 (data cutoff), median follow-up was 3·3 months (range 0·6-8·7; IQR 2·2-5·0). No patients had a complete response. Six (20%) of 30 patients with NRAS-mutated melanoma had a partial response (three confirmed) as did eight (20%) of 41 patients with BRAF-mutated melanoma (two confirmed). The most frequent adverse events were acneiform dermatitis (18 [60%] patients with NRAS -mutated melanoma and 15 [37%] patients with the BRAF-mutated melanoma), rash (six [20%] and 16 [39%]), peripheral oedema (ten [33%] and 14 [34%]), facial oedema (nine [30%] and seven [17%]), diarrhoea (eight [27%] and 15 [37%]), and creatine phosphokinase increases (11 [37%] and nine [22%]). Increased creatine phosphokinase was the most common grade 3-4 adverse event (seven [23%] and seven [17%]). Four patients had serious adverse events (two per arm), which included diarrhoea, dehydration, acneiform dermatitis, general physical deterioration, irregular heart rate, malaise, and small intestinal perforation. No deaths occurred from treatment-related causes.. To our knowledge, MEK162 is the first targeted therapy to show activity in patients with NRAS -mutated melanoma and might offer a new option for a cancer with few effective treatments.. Novartis Pharmaceuticals.

Topics: Aged; Benzimidazoles; Disease-Free Survival; Drug Administration Schedule; Europe; Female; Humans; Kaplan-Meier Estimate; Male; Melanoma; Middle Aged; Mutation; Neoplasm Staging; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins p21(ras); Treatment Outcome; United States

For patients with locally advanced or metastatic melanoma who have BRAF V600 activating mutations, combination therapy with BRAF and MEK inhibitors is now the standard of care. The combination of encorafenib, a highly selective adenosine triphosphate-competitive BRAF inhibitor, plus binimetinib, a potent, selective, allosteric, non-adenosine triphosphate-competitive MEK1/2 inhibitor, was approved by the US Food and Drug Administration for unresectable or metastatic melanoma with BRAF V600E or V600K mutations based on data from the phase III COLUMBUS study (NCT01909453). Clinical data evaluating BRAF and MEK inhibitor combinations in advanced melanoma indicate a specific profile of adverse events that includes serious retinopathy, skin disorders, and cardiovascular toxicities. Here we provide an overview of the rationale for combining BRAF and MEK inhibitors for the treatment of melanoma, long-term safety results from COLUMBUS, and guidance on managing the most common adverse events associated with this combination based on clinical experience. Proactive and appropriate management of adverse events can allow for longer treatment durations and may result in better treatment outcomes.

Topics: Antineoplastic Combined Chemotherapy Protocols; Humans; Melanoma; Mitogen-Activated Protein Kinase Kinases; Mutation; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Skin Neoplasms

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

Enhanced MAPK pathway signaling and cell-cycle checkpoint dysregulation are frequent in NRAS-mutant melanoma and, as such, the regimen of the MEK inhibitor binimetinib and the selective CDK4/6 inhibitor ribociclib is a rational combination.. This is a phase Ib/II, open-label study of ribociclib + binimetinib in patients with NRAS-mutant melanoma (NCT01781572). Primary objectives were to estimate the MTD/recommended phase II dose (RP2D) of the combination (phase Ib) and to characterize combination antitumor activity at the RP2D (phase II). Tumor genomic characterization and pharmacokinetics/pharmacodynamics were also evaluated.. Ten patients (16.4%) experienced dose-limiting toxicities in cycle 1 of phase Ib. Overall response rate in the phase II cohort (n = 41) for the selected RP2D (binimetinib 45 mg twice daily + ribociclib 200 mg once daily, 21 days on/7 days off) was 19.5% [8/41; 95% confidence interval (CI), 8.8-34.9]. The response rate was 32.5% (13/40; 95% CI, 20.1-48.0) in patients with NRAS mutation with concurrent alterations of CDKN2A, CDK4, or CCND1. Median progression-free survival was 3.7 months (95% CI, 3.5-5.6) and median overall survival was 11.3 months (95% CI, 9.3-14.2) for all patients. Common treatment-related toxicities included creatine phosphokinase elevation, rash, edema, anemia, nausea, diarrhea, and fatigue. Pharmacokinetics and safety were consistent with single-agent data, supporting a lack of drug-drug interaction.. Ribociclib + binimetinib can be safely administered and is clinically active in patients with NRAS-mutant melanoma. Co-mutations of cell-cycle genes may define a population with greater likelihood of treatment benefit. See related commentary by Moschos, p. 2977.

Topics: Aminopyridines; Benzimidazoles; GTP Phosphohydrolases; Humans; Melanoma; Membrane Proteins; Purines

Topics: Benzimidazoles; Carbamates; Humans; Melanoma; Proto-Oncogene Proteins B-raf; Sulfonamides

In the search for targeting MAPK plus other pathways in NRAS-mutant melanoma, a phase Ib/II trial tested binimetinib plus ribociclib in metastatic melanoma. The response rate in the phase II trial was 19.5%, and the median progression-free survival was 3.7 months. See related article by Schuler et al., p. 3002.

Topics: Aminopyridines; Benzimidazoles; GTP Phosphohydrolases; Humans; Melanoma; Membrane Proteins; Mutation; Protein Kinase Inhibitors; Purines

Malignant melanoma is a malignant tumor with a poor prognosis. From 2010 the discovery of mutation of BRAF and the development of drugs against this target significantly improved the survival of these patients. The best results were achieved with the double inhibition of the MAPK pathway. There are 3 approved targeted therapies: vemurafenib and cobimetinib, dabrafenib and trametinib, encorafenib and binimetinib. They have similar efficacy, but different toxicity profiles. In this article, is critically review the case of a patient with metastatic melanoma treated with the combination encorafenib and binimetinib.

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

Absolute quantification measurements (copies per cell) of peptide major histocompatibility complex (pMHC) antigens are necessary to inform targeted immunotherapy drug design; however, existing methods for absolute quantification have critical limitations. Here, we present a platform termed SureQuant-IsoMHC, utilizing a series of pMHC isotopologues and internal standard-triggered targeted mass spectrometry to generate an embedded multipoint calibration curve to determine endogenous pMHC concentrations for a panel of 18 tumor antigens. We apply SureQuant-IsoMHC to measure changes in expression of our target panel in a melanoma cell line treated with a MEK inhibitor and translate this approach to estimate antigen concentrations in melanoma tumor biopsies.

Topics: Antigen Presentation; Antigens, Neoplasm; Benzimidazoles; Histocompatibility Antigens Class I; Humans; Immunotherapy; MAP Kinase Kinase 1; Melanoma; Tumor Cells, Cultured

The treatment options for patients with metastatic melanoma (MM) have been dramatically expanded in recent years with the approval of new drugs. The MEK (mitogen-acitvated protein kinase kinase) and BRAF (serine/threonine-protein kinase B-Raf coding gene) inhibitor combination therapy is currently part of the standard of care for stage IIIC/IV of BRAF mutant melanoma. The MEK inhibitor-associated retinopathy (MEKAR) is observed in patients with MM who are treated (or have been treated) with such a combination therapy. This article reports the case of a 72-year-old male patient, who suffered from such a pathological condition under treatment with binimetinib in combination with nivolumab. This case study illustrates the importance of interdisciplinary collaboration in the treatment of MM patients.. Die Behandlungsmöglichkeiten für Patienten mit metastasierendem Melanom (MM) wurden in den letzten Jahren mit der Zulassung von neuen Medikamenten dramatisch erweitert. Die MEK(mitogen-aktivierte Proteinkinase-Kinasen)- und BRAF(Serin/Threonin-Kinase B-Raf kodierendes Gen)-Hemmer-Kombinationstherapie gehört aktuell zum Versorgungsstandard für das Stadium IIIC/IV des BRAF-mutierten Melanoms. MEKAR (MEK-Inhibitor-assoziierte Retinopathie) werden bei Patienten mit metastasierendem Melanom beobachtet, die mit einer solchen Kombinationstherapie behandelt werden bzw. wurden. Wir berichten über den Fall eines 72-jährigen Patienten, der eine solche Pathologie unter der Therapie mit Binimetinib in Kombination mit Nivolumab erlitt. Diese Kasuistik verdeutlicht die Wichtigkeit einer interdisziplinären Zusammenarbeit bei der Behandlung von MM-Patienten.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Humans; Male; Melanoma; Mitogen-Activated Protein Kinase Kinases; Mutation; Retinal Diseases

The efficacy of encorafenib plus binimetinib (E + B) combination therapy for BRAF-mutated advanced melanoma as second-line therapy and beyond is still unknown. In this report, we investigated 22 cases of BRAF-mutated advanced melanoma treated with E + B combination therapy. The objective response rate (ORR) for the total cohort was 68.4%. Notably, the ORR for the second-line and beyond cohort was 73.3%, suggesting that the therapeutic effect of E + B combination therapy is comparable with that of first-line targeted therapy. In contrast, overall survival and progress-free survival in our present cohort was worse than that in a previous clinical trial. Notably, although the incidence rate of severe adverse events was higher than that in a previous report, our present study suggested that E + B combination therapy is a well-tolerated antimelanoma regimen. Our present study suggested that the efficacy and safety profile of E + B combination therapy as a second-line therapy and beyond is comparable with that of first-line targeted therapy.

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

Encorafenib (Braftovi) is indicated for the treatment of adult patients with unresectable or metastatic melanoma with a BRAF V600 mutation, in combination with binimetinib (Mektovi). According to the product label of encorafenib, there are no specific treatment recommendations in case of an overdose. We report on a 63-year-old man who ingested a double dose (900 mg) of encorafenib for 16 days. He developed overall minor chronic overdose symptoms such as nausea and vomiting grade 1 and muscle pain. Based on the most occurring adverse events of encorafenib, liver values, kidney function parameters and QTc interval were measured. Kidney function parameters were normal, whereas liver values were slightly increased (grade 1) and QTc slightly prolonged. The plasma concentration 3 h after the last dose was 2110 ng/mL. We describe the course of a case with a chronic overdose during 16 days of the double dose of encorafenib as well as the followed approach, which could be taken into account when observing an encorafenib overdose. Providing information in times of Covid-19 is challenging, but remains necessary for good clinical care.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Carbamates; Communicable Disease Control; COVID-19; Dose-Response Relationship, Drug; Drug Monitoring; Drug Overdose; Humans; Liver Function Tests; Long QT Syndrome; Male; Medication Therapy Management; Melanoma; Middle Aged; Mutation; Proto-Oncogene Proteins B-raf; Skin Neoplasms; Sulfonamides; Vomiting

Objective The problem of drug resistance to BRAF-targeted therapy often occurs in melanoma treatment. Activation of PI3K/AKT/mTOR signaling pathway is one of the mechanisms of acquired resistance and a potential target for treatment. In the current research, we investigated that dual inhibition of mTOR and MEK synergistically reduced the viability of melanoma cells in vitro. Methods A combination of rapamycin (a macrolide immunosuppressant, mTOR inhibitor) and binimetinib (an anti-cancer small molecule, selective inhibitor of MEK) was studied using a panel of melanoma cell lines, including patient-derived cells. Results It was found, that combinatorial therapy of rapamycin (250 nM) and binimetinib (2 μM) resulted in 25% of cell viability compared to either rapamycin (85%) or binimetinib alone (50%) for A375 and vemurafenib-resistant Mel IL/R cells. The suppressed activation of mTOR and MEK by combined rapamycin and binimetinib treatment was confirmed using Western blot assay. Cell death occured via the apoptosis pathway; however, the combination treatment significantly increased the apoptosis only for Mel IL/R cells. The enhanced cytotoxic effect was also associated with enhanced cell cycle arrest in the G0/G1 phase. Conclusion In general, we provide the evidence that dual inhibition of mTOR and MEK could be promising for further preclinical investigations.

Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Benzimidazoles; Cell Line, Tumor; Drug Resistance, Neoplasm; Drug Synergism; Humans; Melanoma; Mitogen-Activated Protein Kinase Kinases; Phosphatidylinositol 3-Kinase; Proto-Oncogene Proteins c-akt; Sirolimus; TOR Serine-Threonine Kinases; Vemurafenib

Combination treatment with BRAF plus MEK inhibitors is a standard of care in patients with BRAF-mutant advanced melanoma. In addition to dabrafenib+trametinib and vemurafenib+cobimetinib, a new combination of BRAF and MEK inhibitors, encorafenib and binimetinib, was recently introduced into clinical practice. Encorafenib plus binimetinib achieved similar efficacy to that observed with previously available combinations, but incidence of some toxicities such as pyrexia and photosensitivity, which have a relevant impact on patients quality of life, is lower. In this article, the case of a patient who received encorafenib and binimetinib within the phase 3 trial COLUMBUS is presented and discussed, with a focus on the clinical management during the pandemic caused by SARS-CoV-2 virus.

Topics: Aged; Benzimidazoles; Carbamates; COVID-19; Drug Combinations; Female; Humans; Melanoma; Skin Neoplasms; Sulfonamides; Time Factors; Treatment Outcome

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

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

Metastatic melanoma is often accompanied by the development of brain metastases, at presentation or during the course of therapy. Local therapies such as surgery and radiation have been considered standard treatments for intracranial disease. However, the emergence of systemic therapies has been changing the treatment paradigm for the management of brain metastases. In patients with BRAF-mutated melanoma, combined BRAF and MEK inhibition has been found to elicit significant clinical responses. Patients who develop resistance to MAP kinase (MAPK) targeted therapy can achieve significant responses upon rechallenge. In this case, a 68-year-old woman with metastatic melanoma who had received multiple treatment courses including combination immunotherapy and combination MAPK-targeted therapy presented with a brainstem metastasis and demonstrated a complete response upon initiation of encorafenib and binimetinib, thereby obviating the need for stereotactic radiosurgery.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Brain Neoplasms; Carbamates; Female; Humans; Melanoma; Proto-Oncogene Proteins B-raf; Radiosurgery; Skin Neoplasms; Sulfonamides

Topics: Benzimidazoles; Brain Neoplasms; GTP Phosphohydrolases; Humans; Melanoma; Membrane Proteins; Mutation; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf

Sixty percent of patients with stage IV melanoma may develop brain metastases, which result in significantly increased morbidity and a poor overall prognosis. Phase 3 studies of melanoma usually exclude patients with untreated brain metastases; therefore, clinical data for intracranial responses to treatments are limited.. A multicenter, retrospective case series investigation of consecutive BRAF-mutant patients with melanoma brain metastases (MBMs) treated with a combination of BRAF inhibitor encorafenib and MEK inhibitor binimetinib was conducted to evaluate the antitumor response. Assessments included the intracranial, extracranial, and global objective response rates (according to the modified Response Evaluation Criteria in Solid Tumors, version 1.1); the clinical benefit rate; the time to response; the duration of response; and safety.. A total of 24 patients with stage IV BRAF-mutant MBMs treated with encorafenib plus binimetinib in 3 centers in the United States were included. Patients had received a median of 2.5 prior lines of treatment, and 88% had prior treatment with BRAF/MEK inhibitors. The intracranial objective response rate was 33%, and the clinical benefit rate was 63%. The median time to a response was 6 weeks, and the median duration of response was 22 weeks. Among the 21 patients with MBMs and prior BRAF/MEK inhibitor treatment, the intracranial objective response rate was 24%, and the clinical benefit rate was 57%. Similar outcomes were observed for extracranial and global responses. The safety profile for encorafenib plus binimetinib was similar to that observed in patients with melanoma without brain metastases.. Combination therapy with encorafenib plus binimetinib elicited intracranial activity in patients with BRAF-mutant MBMs, including patients previously treated with BRAF/MEK inhibitors. Further prospective studies are warranted and ongoing.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Brain Neoplasms; Carbamates; Female; Humans; Male; MAP Kinase Kinase Kinases; Melanoma; Middle Aged; Neoplasm Metastasis; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Sulfonamides

Topics: Aged; Androstadienes; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Breast Neoplasms; Carbamates; Female; Humans; Mastectomy; Mastectomy, Segmental; Melanoma; Neoplasms, Radiation-Induced; Neoplasms, Second Primary; Neoplasms, Unknown Primary; Radiotherapy; Skin Neoplasms; Sulfonamides

Various serious adverse events (AE) have been reported to occur at a high rate in patients treated with BRAF plus mitogen-activated protein kinase kinase (MEK) inhibitor combination therapy, but their subtypes differ among the BRAF/MEK inhibitors. Pyrexia or a spike of fever are well-known AE of BRAF inhibitors, with or without MEK inhibitors, and have been reported to have a high incidence after dabrafenib/trametinib, but not after encorafenib/binimetinib. In this report, we describe three cases of severe pyrexia in nivolumab-resistant advanced melanoma after successful combined therapy with encorafenib plus binimetinib. Interestingly, in all cases, the serum levels of soluble CD163 C-X-C motif chemokine (CXCL)9, CXCL10 and CXCL11, which are known biomarkers for adult-onset Still's disease (AOSD), increased in parallel with the development of pyrexia. Our present cases suggest that pyrexia caused by BRAF/MEK inhibitors may possess a similar pathophysiology as that of AOSD.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Carbamates; Drug Resistance, Neoplasm; Female; Fever; Humans; Lymph Nodes; Lymphatic Metastasis; Male; Melanoma; Middle Aged; Mitogen-Activated Protein Kinase Kinases; Nivolumab; Positron Emission Tomography Computed Tomography; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Skin Neoplasms; Sulfonamides; Treatment Outcome

Topics: Antineoplastic Combined Chemotherapy Protocols; Arthritis; Benzimidazoles; Carbamates; Humans; Melanoma; Mutation; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Sulfonamides

Topics: Benzimidazoles; Carbamates; Humans; Melanoma; Stevens-Johnson Syndrome; Sulfonamides

Melanoma can be classified based on the detection of relevant oncogenic driver mutations. These mutations partially determine a patient's treatment options. MEK inhibitors have demonstrated little efficacy in patients with NRAS-mutated melanoma owing to primary and secondary resistance. We report two patients with NRAS-mutant metastatic melanoma with long-term response to intermittent MEK-inhibitor binimetinib therapy. Intermittent dosing schedules could play a key role in preventing resistance to targeted therapy. This article highlights the efficacy of an intermittent dosing schedule, toxicities associated with binimetinib, and possible mechanisms preventing resistance in targeted therapy. Intermittent MEK-inhibitor therapy may be considered in patients with NRAS-mutated melanoma that have failed all standard therapies. KEY POINTS: Melanomas harbor NRAS mutations in 10%-30% of the cases. These mutations promote hyperactivation of the MAPK pathway, leading to proliferation and prolonged survival of tumor cells. Currently, drugs directly targeting NRAS are not available. Downstream inhibition of the MAPK pathway can be considered as a therapeutic option after immunotherapeutic failure. Intermittent administration of kinase inhibitors might be the way to partially overcome the development of drug resistance by (a) inducing a fitness deficit for drug-resistant cells on treatment break, (b) increasing the immunogenicity, and (c) inducing apoptosis and cell cycle arrest. It also enhances expression of numerous immunomodulating molecules, and reduction of immunosuppressive factors, which suggests better access of the immune system to the tumor.

Topics: Aged; Benzimidazoles; Cell Line, Tumor; Female; GTP Phosphohydrolases; Humans; Male; Melanoma; Membrane Proteins; Mutation; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Skin Neoplasms

Topics: Acute Disease; Benzimidazoles; Carbamates; Female; Humans; Melanoma; Middle Aged; Mutation; Proto-Oncogene Proteins B-raf; Skin Neoplasms; Sulfonamides; Tumor Lysis Syndrome

The advent of BRAF and MEK inhibitors changed the landscape of the management of BRAF mutated melanoma patients. In this article, we report the case of a 51-year-old man with BRAF mutated locally advanced cutaneous melanoma of the head who demonstrated a limited response to initial anti-BRAF monotherapy followed by extensive surgery. Anti-PD1 therapy failed to reverse the disease progression. However, subsequent double inhibition of the BRAF and MEK pathways induced a fast and remarkable tumour response.

Topics: Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Carbamates; Drug Resistance, Neoplasm; Humans; Lymph Node Excision; Male; MAP Kinase Kinase 1; Margins of Excision; Melanoma; Melanoma, Cutaneous Malignant; Middle Aged; Mutation; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Skin Neoplasms; Sulfonamides; Vemurafenib

Inhibitors of BRAF, a gene coding a protein called B-raf, with or without inhibitors of MEK (MAPK/extracellular signal-regulated kinase) are often used as palliative treatment in BRAF-mutated metastatic melanoma. Recent data show improved progression-free survival with encorafenib with binimetinib, a newer BRAF/MEK inhibitor combination, compared with older agents, but there have been no reports of this treatment in the setting of renal and liver failure. We report a patient with disease-induced transaminitis and renal failure requiring dialysis who was successfully treated with encorafenib and binimetinib. His transaminitis improved and he was able to stop dialysis without any significant adverse effects during treatment, suggesting encorafenib with binimetinib may be used safely and effectively even in patients with end organ damage.

Topics: Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Carbamates; Humans; Liver Neoplasms; Male; Melanoma; Middle Aged; Proto-Oncogene Proteins B-raf; Renal Insufficiency; Skin Neoplasms; Sulfonamides

B-rapidly accelerated fibrosarcoma (BRAF) inhibitor encorafenib alone and in combination with MEK inhibitor binimetinib improves survival in BRAF-mutated melanoma patients. So far, the range of cutaneous adverse events has been characterized only for established BRAF inhibitors (vemurafenib, dabrafenib) and MEK inhibitors (trametinib, cobimetinib).. The aim of this study was to investigate cutaneous adverse events emerging in melanoma patients treated with encorafenib and binimetinib.. Patients treated with BRAF and MEK inhibitors in clinical trials at the University Hospital of Zurich were identified. Frequency and features of cutaneous adverse events as well as their management were assessed based on the prospectively collected clinical and histopathological data. The events emerging during encorafenib and/or binimetinib therapy were compared to other BRAF and MEK inhibitors at the institution and in the literature.. The most frequent cutaneous adverse events observed in patients treated with encorafenib alone (n = 24) were palmoplantar hyperkeratosis (54%), palmoplantar erythrodysesthesia (58%) and alopecia (46%). Drug-induced papulopustular eruptions prevailed in patients with binimetinib monotherapy (n = 25). The most frequent cutaneous adverse events in patients treated with encorafenib/binimetinib (n = 49) were palmoplantar hyperkeratosis (10%).. Compared to data published for established BRAFi, encorafenib monotherapy showed less hyperproliferative cutaneous adverse events. In contrast, palmoplantar hyperkeratosis and palmoplantar erythrodysesthesia seem to occur more often. The combination of encorafenib and binimetinib is well tolerated and induces few cutaneous adverse events.

Topics: Aged; Alopecia; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Carbamates; Drug Eruptions; Female; Hand-Foot Syndrome; Humans; Keratosis; Male; Melanoma; Middle Aged; Mutation; Proto-Oncogene Proteins B-raf; Skin Neoplasms; Sulfonamides

Melanoma is one of the most aggressive and treatment-resistant tumors that responsible for majority of skin-cancer related deaths. Here we propose a combination of MEK inhibitor binimetinib with metformin as a promising therapy against human melanoma cells in vitro, including BRAF -mutated A375, Mel Z, and Mel IL cells, and NRAS-mutated Mel MTP and Mel Me cells. Additionally, we obtained two close to clinical practice models of melanoma progression. The first one was vemurafenib-resistant Mel IL/R melanoma cells with acquired resistance to BRAF inhibition-targeted therapy, and the second one was tumor spheroids, which are 3D in vitro model of small-size solid tumors in vivo. The cytotoxicity of binimetinib and metformin was synergistic in both 2D and 3D melanoma culture and mediated through apoptotic pathway. The combination reduced the number of melanoma-formed colonies, inhibited cell invasion and migration, and led to G0/G1 cell cycle arrest through cyclin D/CDK4/CDK6 pathway. The mechanism of metformin and binimetinib synergy in melanoma cells was associated with increased activation of p-AMPKα and decreased p-ERK, but not with alterations in p-mTOR. In summary, the combination of metformin and binimetinib resulted in stronger anti-proliferative effects on melanoma cells compared to binimetinib alone, and therefore could be promising for clinical applications.

Topics: Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Cell Line, Tumor; Dose-Response Relationship, Drug; Drug Synergism; Humans; Hypoglycemic Agents; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Melanoma; Metformin; Protein Kinase Inhibitors

Topics: Benzimidazoles; Carbamates; Fibrosarcoma; Humans; Melanoma; Sulfonamides

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

Topics: Antineoplastic Agents; Benzimidazoles; Chemotherapy, Adjuvant; GTP Phosphohydrolases; Humans; Male; MAP Kinase Kinase Kinases; Melanoma; Membrane Proteins; Middle Aged; Mutation; Neck Muscles; Neuromuscular Diseases; Protein Kinase Inhibitors; Skin Neoplasms; Syndrome; Treatment Outcome

Topics: Benzimidazoles; Carbamates; Humans; Melanoma; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Sulfonamides; Vemurafenib

Topics: Benzimidazoles; Carbamates; Humans; Melanoma; Proto-Oncogene Proteins B-raf; Sulfonamides; Vemurafenib

Ophthalmological complications constitute a class effect of treatment with BRAF inhibitors. Encorafenib is a new BRAF inhibitor currently being tested in phase 3 clinical trials for advanced or metastatic melanoma as monotherapy or in combination with the MEK-inhibitor binimetinib. In this study, we present a case of severe bilateral panuveitis and neurosensory hearing loss in an elderly patient treated with encorafenib and binimetinib for metastatic BRAF-mutant melanoma. This constellation of findings is compatible with incomplete Vogt-Koyanagi-Harada (VKH) disease. VKH disease is a rare multisystem disease characterized by granulomatous panuveitis, serous retinal detachments, and neurologic and dermatologic manifestations. In patients with melanoma, its emergence has been correlated to a favorable prognosis of the underlying melanoma by several authors. The patient reported here had a severe panuveitis and bilateral retinal detachments causing permanent visual impairment. She was treated with a long course of systemic corticosteroids, but at the same time, she achieved complete remission of the melanoma lasting for 26 months after permanent encorafenib and binimetinib discontinuation, without further antineoplastic treatment. VKH disease is a rare entity and the need for interdisciplinary cooperation for its diagnosis in patients with melanoma and uveitis is emphasized.

Topics: Aged, 80 and over; Benzimidazoles; Carbamates; Female; Humans; Melanoma; Protein Kinase Inhibitors; Sulfonamides; Uveomeningoencephalitic Syndrome

Topics: Benzimidazoles; Carbamates; Embarrassment; Humans; Melanoma; Proto-Oncogene Proteins B-raf; Sulfonamides; Vemurafenib

To investigate αvβ3-integrin-targeted optoacoustic imaging and MRI for monitoring a BRAF/MEK inhibitor combination therapy in a murine model of human melanoma.. Human BRAF V600E-positive melanoma xenograft (A375)-bearing Balb/c nude mice (n = 10) were imaged before (day 0) and after (day 7) a BRAF/MEK inhibitor combination therapy (encorafenib, 1.3 mg/kg/d; binimetinib, 0.6 mg/kg/d, n = 5) or placebo (n = 5), respectively. Optoacoustic imaging was performed on a preclinical system unenhanced and 5 h after i. v. injection of an αvβ3-integrin-targeted fluorescent probe. The αvβ3-integrin-specific tumor signal was derived by spectral unmixing. For morphology-based tumor response assessments, T2w MRI data sets were acquired on a clinical 3 Tesla scanner. The imaging results were validated by multiparametric immunohistochemistry (ß3 -integrin expression, CD31 -microvascular density, Ki-67 -proliferation).. The αvβ3-integrin-specific tumor signal was significantly reduced under therapy, showing a unidirectional decline in all animals (from 7.98±2.22 to 1.67±1.30; p = 0.043). No significant signal change was observed in the control group (from 6.60±6.51 to 3.67±1.93; p = 0.500). Immunohistochemistry revealed a significantly lower integrin expression (ß3: 0.20±0.02 vs. 0.39±0.05; p = 0.008) and microvascular density (CD31: 119±15 vs. 292±49; p = 0.008) in the therapy group. Tumor volumes increased with no significant intergroup difference (therapy: +107±42 mm3; control +112±44mm3, p = 0.841). In vivo blocking studies with αvβ3-integrin antagonist cilengitide confirmed the target specificity of the fluorescent probe.. αvβ3-integrin-targeted optoacoustic imaging allowed for the early non-invasive monitoring of a BRAF/MEK inhibitor combination therapy in a murine model of human melanoma, adding molecular information on tumor receptor status to morphology-based tumor response criteria.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Carbamates; Cell Line, Tumor; Humans; Integrin alphaVbeta3; Magnetic Resonance Imaging; Melanoma; Mice; Mice, Nude; Molecular Imaging; Mutation; Photoacoustic Techniques; Proto-Oncogene Proteins B-raf; Sulfonamides; Treatment Outcome; Xenograft Model Antitumor Assays

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

B7-H3 (CD276) belongs to the B7 family of immunoregulatory proteins and has been implicated in cancer progression and metastasis. In this study, we found that metastatic melanoma cells with knockdown expression of B7-H3 showed modest decrease in proliferation and glycolytic capacity and were more sensitive to dacarbazine (DTIC) chemotherapy and small-molecule inhibitors targeting MAP kinase (MAPK) and AKT/mTOR pathways: vemurafenib (PLX4032; BRAF inhibitor), binimetinib (MEK-162; MEK inhibitor), everolimus (RAD001; mTOR inhibitor), and triciribidine (API-2; AKT inhibitor). Similar effects were observed in melanoma cells in the presence of an inhibitory B7-H3 monoclonal antibody, while the opposite was seen in B7-H3-overexpressing cells. Further, combining B7-H3 inhibition with small-molecule inhibitors resulted in significantly increased antiproliferative effect in melanoma cells, as well as in BRAF

Topics: B7 Antigens; Benzimidazoles; Cell Line, Tumor; Cell Proliferation; Dacarbazine; Everolimus; Gene Knockdown Techniques; Glycolysis; Humans; Indoles; Melanoma; Molecular Targeted Therapy; Mutation; Neoplasm Metastasis; Protein Kinase Inhibitors; Sulfonamides; Vemurafenib

BRAF and MEK inhibitors have significantly improved the prognosis of metastatic melanoma, by inhibiting both the mitogen-activated protein kinase (MAP-kinase) pathway. They are associated with infrequent adverse kidney events. Most of these are related to the use of BRAF inhibitors and involve interstitial nephritis with acute tubular necrosis.. We report a unique case of glomerulonephritis with renal granulomatous vasculitis in a patient diagnosed with metastatic melanoma treated with BRAF and MEK inhibitors. The patient was a 55-year old woman, who presented a melanoma of the right thigh with pulmonary metastasis. Treatment started in November 2015, with Encorafenib and Binimetinib, new BRAF and MEK inhibitors, respectively. Two months after the beginning of the treatment, there was a worsening of her renal function with significant proteinuria.. Kidney biopsy showed extracapillary proliferation in the glomeruli with a granulomatous reaction.. Renal function recovered completely after withdrawal of the chemotherapy.. All the reported kidney adverse events secondary to BRAF and MEK inhibitors in the literature are related to the use of BRAF inhibitors. Some previous reported mechanistic investigations also provide insight between BRAF inhibitors and podocytes injuries. Therefore, encorafenib most likely is the main responsible of the disease. However, evidence has emerged that inhibition of the MAP kinase pathway could also enhance autoimmunity. Thus, binimetinib may also have played a role and the combination of BRAF and MEK inhibitors may have facilitated this autoimmune kidney disease.

Topics: Antineoplastic Agents; Benzimidazoles; Carbamates; Female; Glomerulonephritis; Humans; Kidney; Lung Neoplasms; MAP Kinase Kinase Kinases; Melanoma; Middle Aged; Protein Kinase Inhibitors; Sulfonamides; Vasculitis

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

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

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

Neurocutaneous melanocytosis (NCM) is characterized by clonal nevomelanocytic proliferations in the CNS and skin. Given the scarcity of effective therapeutic targets, testing new drugs requires a reliable and reproducible in vitro cellular model of the disease.. We generated nevomelanocytic spheroids in vitro from lesions of the spinal cord, brain, and skin from 4 NCM patients. Nevomelanocytic cells were grown as monolayers or spheroids and their growth characteristics were evaluated. Cultured cell identity was confirmed by demonstration of the same NRAS mutation found in the original lesions and by immunophenotyping. Nevomelanocytic spheroids were treated with inhibitors of specific mediators of the NRAS signaling pathway (vemurafenib, MEK162, GDC0941, and GSK2126458). Drug sensitivity and cell viability were assessed.. Cultured cells were growth-factor dependent, grew as spheroids on Geltrex matrix, and maintained their clonogenicity in vitro over passages. Skin-derived cells formed more colonies than CNS-derived cells. Inhibitors of specific mediators of the NRAS signaling pathway reduced viability of NRAS mutated cells. The highest effect was obtained with GSK2126458, showing a viability reduction below 50%.. NRAS mutated cells derived from clinical NCM samples are capable of continuous growth as spheroid colonies in vitro and retain their genetic identity. Drugs targeting the NRAS signaling pathway reduce in vitro viability of NCM cells. NCM lesional spheroids represent a new and reliable experimental model of NCM for use in drug testing and mechanistic studies.

Topics: Apoptosis; Benzimidazoles; Blotting, Western; Brain Neoplasms; Cell Proliferation; Child; Child, Preschool; Fluorescent Antibody Technique; GTP Phosphohydrolases; Humans; Immunoenzyme Techniques; Infant; Male; Melanoma; Membrane Proteins; Mutation; Prospective Studies; Signal Transduction; Skin Neoplasms; Spheroids, Cellular; Tumor Cells, Cultured

Recently, treatment with MEK inhibitors has been shown to be an effective treatment option for metastatic melanoma. Treatment efficacy is dependent on inhibition of MAPK-related melanoma proliferation. However, targeting of MEK can be accompanied by a time-dependent and reversible serous retinopathy of unknown origin.We analyzed the molecular mechanism by which the MEK inhibitor binimetinib may lead to retinopathy, using neuroretina and cell models of retinal pigment epithelium (RPE).Binimetinib inhibited the MAPK pathway while discontinuation of treatment resulted in reactivation. However, cell proliferation was not inhibited correspondingly during binimetinib treatment of ARPE19 cells. Remarkably, post-mitotic neuroretinal tissue displayed a strong MAPK activation that was lost after binimetinib treatment.We propose that binimetinib-associated retinopathy is correlated with inhibition of the MAPK pathway in multiple retinal components. Retinal cells are able to regain the activation after binimetinib treatment, mimicking the reversibility of the retinopathy. As most retinal cells are nonregenerating, other mechanisms than stimulation of proliferation must be involved.

Topics: Antineoplastic Agents; Benzimidazoles; Cell Proliferation; Cells, Cultured; Humans; MAP Kinase Kinase Kinases; MAP Kinase Signaling System; Melanoma; Mitogen-Activated Protein Kinases; Neoplasm Metastasis; Retinal Diseases; Retinal Pigment Epithelium

Mitogen-activated protein kinase kinase (MEK) inhibitors have aroused considerable interest in oncology. Activity has been demonstrated in various types of cancer, especially melanoma. MEK inhibitors induce a transient retinopathy, considered to be a class effect. At present, only sparse data are available on retinal effects with long-term MEK inhibition.. In this prospective, observational study, patients with advanced melanoma participating in different phase 1/2 or phase 3 clinical trials were treated with the MEK inhibitor binimetinib, with a v-Raf murine sarcoma viral oncogene homolog B (BRAF) inhibitor, or with combination therapy. They underwent regular ophthalmological examinations including determination of visual function, biomicroscopy, dilated fundoscopy and optical coherence tomography (OCT) for a period of up to 2 years. Retinopathy was diagnosed on defined OCT criteria.. Sixty-two patients were investigated between 1st October 2011 and 31st July 2015: 13 were treated with the MEK inhibitor binimetinib alone, 10 with a selective BRAF inhibitor, and 39 with combination therapy. In 92% of patients on monotherapy and 100% of those on combination treatment, binimetinib caused dose-related lesions with serous neuroretinal detachments and oedema, strongly dependent on the time after medication. With continued treatment, retinal volume and thickness decreased to levels below baseline, without any apparent functional deficits or changes in structural integrity.. Binimetinib induces a specific retinopathy with daily fluctuations depending on the time interval after medication. The retinopathy partially recovers, but can still be detected many months later. Retinal thinning, possible first signs of retinal atrophy have been observed after long-term treatment, but, so far, without functional relevance.

Topics: Aged; Antineoplastic Agents; Benzimidazoles; Dose-Response Relationship, Drug; Female; Humans; Male; Melanoma; Middle Aged; Mitogen-Activated Protein Kinase Kinases; Prospective Studies; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Retinal Diseases; Skin Neoplasms

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

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

Uveal melanoma (UM) is a genetically and biologically distinct type of melanoma, and once metastatic there is no effective treatment currently available. Eighty percent of UMs harbor mutations in the Gαq family members GNAQ and GNA11. Understanding the effector pathways downstream of these oncoproteins is important to identify opportunities for targeted therapy. We report consistent activation of the protein kinase C (PKC) and MAPK pathways as a consequence of GNAQ or GNA11 mutation. PKC inhibition with AEB071 or AHT956 suppressed PKC and MAPK signalling and induced G1 arrest selectively in melanoma cell lines carrying GNAQ or GNA11 mutations. In contrast, treatment with two different MEK inhibitors, PD0325901 and MEK162, inhibited the proliferation of melanoma cell lines irrespective of their mutation status, indicating that in the context of GNAQ or GNA11 mutation MAPK activation can be attributed to activated PKC. AEB071 significantly slowed the growth of tumors in an allograft model of GNAQ(Q209L)-transduced melanocytes, but did not induce tumor shrinkage. In vivo and in vitro studies showed that PKC inhibitors alone were unable to induce sustained suppression of MAP-kinase signaling. However, combinations of PKC and MEK inhibition, using either PD0325901or MEK162, led to sustained MAP-kinase pathway inhibition and showed a strong synergistic effect in halting proliferation and in inducing apoptosis in vitro. Furthermore, combining PKC and MEK inhibition was efficacious in vivo, causing marked tumor regression in a UM xenograft model. Our data identify PKC as a rational therapeutic target for melanoma patients with GNAQ or GNA11 mutations and demonstrate that combined MEK and PKC inhibition is synergistic, with superior efficacy compared to treatment with either approach alone.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Benzimidazoles; Cell Line, Tumor; Cell Proliferation; Drug Synergism; Female; GTP-Binding Protein alpha Subunits; GTP-Binding Protein alpha Subunits, Gq-G11; Humans; Inhibitory Concentration 50; MAP Kinase Kinase Kinases; Melanoma; Mice; Mice, Inbred C57BL; Mice, Nude; Mutation, Missense; Protein Kinase C; Protein Kinase Inhibitors; Pyrroles; Quinazolines; Signal Transduction; Tumor Burden; Uveal Neoplasms; Xenograft Model Antitumor Assays

Gain of function mutations in B-RAF and N-RAS occur frequently in melanoma, leading to mitogen activating protein kinase (MAPK) pathway activation, and this pathway is the target of drugs in development. Our purpose was to study clinical characteristics of patients with mutations in this pathway and to determine activity of inhibitors of B-RAF and MEK in short term cultures grown from tumors of some of these patients.. Clinical and pathologic data were collected retrospectively on melanoma patients tested for B-RAF and N-RAS mutations at the Yale Cancer Center and associations with survival were determined. We studied in vitro activity of the pan-RAF inhibitor, RAF265, and the MEK inhibitor, MEK162, in 22 melanoma short term cultures. We further characterized the effect of MEK inhibition on apoptosis and growth of melanoma cultures.. In a cohort of 144 metastatic melanoma patients we found that patients with N-RAS mutant melanoma had a worse prognosis. These patients were more likely to have brain metastases at the time of presentation with metastatic disease than their N-RAS-wild-type counterparts. All N-RAS mutant melanoma cultures tested in our study (n = 7) were sensitive to MEK inhibition 162. Exposure to MEK162 reduced ERK1/2 phosphorylation, and induced apoptosis. Clonogenic survival was significantly reduced in sensitive melanoma cell cultures.. The prognosis of patients with melanoma expressing constitutively active N-RAS is poor, consistent with studies performed at other institutions. N-RAS mutant melanoma cultures appear to be particularly sensitive to MEK162, supporting ongoing clinical trials with MEK162 in N-RAS mutated melanoma.

Topics: Aged; Benzimidazoles; Blotting, Western; Female; Genes, ras; Humans; Kaplan-Meier Estimate; Male; MAP Kinase Kinase Kinases; Melanoma; Middle Aged; Mutation; Neoplasm Metastasis; Proportional Hazards Models; Protein Kinase Inhibitors; Tumor Cells, Cultured

Topics: Aminopyridines; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Benzimidazoles; Cell Proliferation; GTP Phosphohydrolases; Melanoma; Membrane Proteins; Mutation; Purines

Topics: Benzimidazoles; Female; Humans; Male; Melanoma; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf