The side effect profile was manageable, according to the investigators. Only about 10% of patients on active therapy had grade 3 or higher toxicity. Joint pain, photosensitivity, and skin rashes were the most common. About 20% of patients developed cutaneous squamous cell carcinoma, but it was benign and easily removed by dermatologists. Only 6% of patients on vemurafenib and 4% on dacarbazine discontinued because of adverse events.
The investigators also looked at patients who had BRAF mutations other than V600E, and were encouraged to find that 6 of 10 responded to vemurafenib, Dr. Chapman said in an interview. While more analysis is need, he was encouraged that it would be effective in these patients as well. Other studies are looking at efficacy in other malignancies such as thyroid cancer in which a subset of patients are known to have these mutations.
As for the pressing question of how and when to use vemurafenib in clinical practice, the quick action of vemurafenib in relieving symptom burden would make it the first choice in patients who have BRAF mutations and are very sick, according to Dr. Kim Allyson Margolin of the University of Washington Fred Hutchinson Cancer Research Center in Seattle.
In an invited discussion of BRIM-3 and the new ipilimumab data, she said rapid response is likely in patients treated with vemurafenib, and their tumor burden would be lower if they switched later to ipilimumab. Other subsequent therapies and combinations need to be explored, she said.
In contrast, Dr. Margolin suggested slower-working ipilimumab might be the first choice in patients with low tumor burden and minimal symptoms. If they progress, however, she would switch them to vemurafenib. "Both agents require experience and commitment by the M.D., and patient to management of unique toxicities," she advised.
As for the studies to come next, she cited single-agent questions about biomarkers of resistance, predictors of toxicity, and patient management issues. Among agents to be studied in combination with vemurafenib, she proposed MEK inhibitors, PI3K and mTOR inhibitors, IGFR inhibitors, immunomodulators, and cytotoxic agents.
Genentech sponsored the BRIM-2 and BRIM-3 trials. Dr. Chapman reported consultant/advisory roles and research funding from its parent company Roche. Some coauthors were Roche employees, and others reported similar relationships with Genentech. Dr. Ribas and several of his co-authors reported similar consulting and advisory relationships with Roche/Genentech. Dr. Schuchter had no disclosures. Dr. Ernstoff made no relevant financial conflicts of interest.