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From the moment that the BRAF V600E mutation was first associated with melanoma, nearly 10 years ago, this large, phase 3 trial of vemurafenib (PLX4032), a potent inhibitor of mutated BRAF, has been in the making. The brisk march of this drug from benchside to bedside was marked by positive indicators along the way: A phase 1 trial established the maximum tolerated dose and found consistent tumor responses, and a phase 2 trial (BRIM-2; J Clin Oncol 2011; 29:S8509) showed a response rate of 53% and a median response duration of 6.7 months.
Investigators conducted an open-label, multicenter clinical trial in patients with untreated, unresectable stage IIIc or IV melanoma and a BRAF V600E mutation. Patients were randomly assigned to vemurafenib (960 mg orally, twice daily) or dacarbazine (the only FDA-approved chemotherapeutic for metastatic melanoma). In 672 evaluable patients, overall survival at 6 months was 84% with vemurafenib and 64% with dacarbazine — high survival rates that reflect the short follow-up. In fact, the trial was terminated early after an interim analysis showed a significant survival difference. The hazard ratio for tumor progression with vemurafenib was 0.26. The estimated median progression-free survival was 5.3 months in vemurafenib recipients and 1.6 months with dacarbazine. Nearly half of vemurafenib recipients met RECIST criteria for tumor response, versus <10% of dacarbazine recipients. Cutaneous squamous cell carcinomas and keratoacanthomas were among the most common adverse effects.
Chapman PB et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 2011 Jun 5; [e-pub ahead of print]. (http://dx.doi.org/10.1056/NEJMoa1103782)
Comment
This landmark study may well prompt FDA activity. Wider access to vemurafenib would enlarge the melanoma medicine cabinet for late-stage disease. Despite the excitement, several points are worth noting: First, follow-up in the interim analysis was short, so longer-term data are needed. Second, for the many patients without BRAF V600E mutations, immunologic treatments and targets further downstream (e.g., MEK) may be an answer, but truly personalized medicine depends on having options for every genotype. Additionally, even some patients with BRAF V600E mutations will not respond, so markers of likely response would be beneficial. Most importantly, many patients with an initial response soon relapse: Vemurafenib delivers a concussive but not a lethal blow. Studies of vemurafenib resistance mechanisms have been published, and the pipeline for future analysis is open. If approved, vemurafenib will become the first-choice drug for many, but unmet needs will leave us all wanting more than the drug can deliver.