1. Tuma, Rabiya S. PHD

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It is already known that vemurafenib significantly improves response rates, progression-free survival, and six-month survival in advanced melanoma patients with BRAF-mutant tumors. So the report (NEJM 2012;366:707-714) that the drug improves overall survival, while not a surprise, is nonetheless good news.


Median overall survival for the 132 patients enrolled in the phase II BRIM2 trial was 15.9 months.


Because this was a single-arm study, there was no benchmark for comparison, but senior author Antoni Ribas, MD, PhD, Professor of Hematology/Oncology at Jonsson Cancer Center at UCLA, estimates that the expected survival for these patients with any other agent would be between six and nine months.


He noted in an email that because the phase III trial (BRIM3) was stopped so early-just one month after the last patient was enrolled-follow-up has been relatively short. And patients in the chemotherapy arm were allowed to cross over to vemurafenib at that early time point, meaning that even with longer follow-up, the phase III overall survival data will be seriously compromised, if not completely useless.


The good news, though, is that with such a large increase, it is clear that it is not just an artifact of the out-of-trial comparison, and although the exact magnitude of the benefit is not known, the benefit is clearly and dramatically there.


Also recently reported by Ribas and colleagues was that vemurafenib triggers squamous cell skin cancers in the presence of preexisting RAS mutations, and that a MEK-inhibitor combination mitigates the problem. It is known that approximately 25% of patients treated with vemurafenib develop cutaneous squamous cell carcinomas, but new data (NEJM 2012:366:207-215) show that the majority of the squamous cell cancers arise from cells that had a preexisting RAS mutation (13 out of 21 squamous tumors sampled). When vemurafenib blocks BRAF activity in RAS mutant cells, it activates the MAP kinase pathway and triggers out-of-control growth.


The paradoxical activation of the MAP kinase pathway by BRAF inhibitors in RAS mutant cells was previously known, Ribas noted, but what is new is the identification of RAS mutations in the affected skin of patients treated with vemurafenib.


He explained that patients who get squamous cell cancers tend to be a bit older than the average melanoma patient and frequently have chronic sun skin damage, and he suspects that the RAS mutations are the result of that sun exposure.


The team found that combining a BRAF inhibitor with a MEK inhibitor blocks activation of the MAP kinase pathway in RAS-mutant skin cells and prevents formation of squamous cell skin cancers in a mouse model.


The study, funded by Roche, the makers of vemurafenib, is important because it explains at a molecular level what was being seen in the clinic, said Jeff Weber, MD, PhD, Director of the Donald A. Adam Comprehensive Melanoma Research Center at Moffitt Cancer Center.


In phase I and II trials testing a combination of GlaxoSmithKline's BRAF and MEK inhibitors (GSK2118436 and GSK1120212, respectively), just 2% of patients developed squamous cell cancers, according to data presented at the Society for Melanoma Research meeting last fall in Tampa.


"The irony is that the guys from Roche proved that it would be a good idea to add [the MEK and BRAF inhibitors] together, but they have been badly beaten to the punch by GSK," Weber said.


GSK expects to launch a phase III registration trial for their combination sometime this year. By contrast, the Roche/Genentech MEK inhibitor is currently in phase I trials as a single agent.