Mutation to Medicine

Improved Survival with Vemurafenib in Melanoma

Hensin Tsao, MD, PhD


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In This Article

Abstract and Introduction


Patients with unresectable melanoma and the BRAF V600E mutation saw rapid response and improved rates of overall and progression-free survival.


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.


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