Patients Respond to Oral BRAF Inhibitor

In patients with stage IV melanoma with distant metastases, what is the response rate to an oral inhibitor of the protein kinase BRAF?

Background: There are few effective therapies for patients with stage IV metastatic melanoma. Response rates to standard therapy (interleukin-2 or dacarbazine) are 10 to 20 percent, and complete responses are exceedingly rare. The activating V600E mutation in the BRAF gene is found in 40 to 60 percent of melanomas. The oral agent PLX4032 is a potent inhibitor of mutated BRAF signaling.

Study design: Phase I dose-escalation trial followed by extension phase. The dose-escalation phase included 55 patients. The recommended phase II dose was then administered to 32 patients with metastatic melanoma testing positive for the V600E mutation in the BRAF gene.

Setting: Multi-center trial.

Synopsis: An oral dose of 960 mg twice daily was selected as the recommended phase II dose. The most common toxicities were rash, arthralgia, nausea, photosensitivity, cutaneous squamous cell carcinoma and pruritus, 89 percent of which were grade 1-2. Cutaneous squamous cell carcinomas developed in 31 percent of patients; these were resected and did not lead to treatment discontinuation.

Response rate in the extension cohort of V600E mutant melanomas was 26 of 32 patients (81 percent). Dramatic tumor responses were observed in the lungs, lymph nodes, visceral organs and bone metastases. The median progression-free survival was greater than seven months, and median overall survival had not been reached at the time of data analysis.

Bottom line: An unprecedented 81 percent response rate was observed in patients with metastatic melanoma carrying a mutated, activated BRAF gene and treated with an oral BRAF inhibitor. This mutation is found in 40 to 60 percent of melanomas, a similar percentage of papillary and anaplastic thyroid cancers and a smaller percentage of other cancers. A phase III trial is currently underway to determine whether PLX4032 improves overall survival.

Citation: Flaherty KT, Puzanov I, Kim KB, et al. Inhibition of mutated, activated BRAF in metastatic melanoma. New Engl J Med. 2010;363(9):809-819.

—Reviewed by Dennis H. Kraus, MD, and Luc Morris, MD