gdc-0973 and encorafenib

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

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

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