gdc-0973 and Cardiotoxicity

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

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