Assessing patient risk, benefit, and outcomes in drug development: a decade of vemurafenib clinical trials

Background: Vemurafenib (Zelboraf^®, Roche), approved by the FDA in 2011 for unresectable and metastatic melanoma and Erdheim-Chester Disease, has been explored in trials for other BRAF-mutated cancers. Despite 12 years of clinical use, the risk-benefit profile for off-label indications remain unclear. Research Design and Methods: This study systematically reviewed clinical trials utilizing vemurafenib in adult malignancies, with responses assessed using RECIST or similar criteria. On May 25, 2023, we searched PubMed/MEDLINE, Embase, Cochrane CENTRAL, and ClinicalTrials.gov. Screening and data extraction were performed in a masked, duplicate fashion, collecting data on trial characteristics, adverse events, progression-free survival, overall survival, and objective response rates. Results: Vemurafenib was tested in 15 cancers beyond its FDA-approved indications. A 0% complete response rate was observed in colorectal cancer, non-small cell lung cancer, and papillary thyroid cancer. Adverse events were more frequent in non-melanoma cancers, with 5,205 grade 3–5 events reported, equating to two severe events for every three participants. Only metastatic melanoma consistently demonstrated efficacy, aligning with its FDA approval. Conclusions: Although vemurafenib showed efficacy in metastatic melanoma, off-label use resulted in limited benefit and increased adverse events. Unclear endpoints and underreported adverse events highlight the need for improved clinical trial design.