A randomized, international Phase III trial showed that vemurafenib (also known as PLX4032), which targets the V600E mutations in the BRAF gene, is the first drug to improve overall survival when compared to standard chemotherapy in patients with advanced melanoma. It is also the first drug to improve progression-free survival (PFS) and response proportion in these patients. If approved by the U.S. Food and Drug Administration, vemurafenib could become a new standard treatment for patients with melanoma who have this gene mutation. The drug has received extensive attention as a result of striking results from earlier-stage trials. This study is the first to demonstrate conclusively that the drug significantly improves survival better than the current standard.

"This is really a huge step toward personalized care in melanoma," said lead author Paul Chapman, M.D., attending physician in the melanoma/sarcoma service at Memorial Sloan-Kettering Cancer Center in New York. "This is the first successful melanoma treatment tailored to patients who carry a specific gene mutation in their tumor, and could eventually become one of only two drugs available that improves overall survival in advanced cancers." The other drug, ipilumumab, is an immune therapy also featured in ASCO's 2011 Annual Meeting plenary session.

Approximately half of all melanomas harbor a V600E mutation in the BRAF gene. The trial compared the effectiveness - overall survival and progression-free survival - of treatment with vemurafenib to the chemotherapy drug dacarbazine in 675 patients with previously untreated, inoperable stage IIIC or stage IV metastatic melanoma and a V600E mutation in the BRAF gene.

At the planned interim analysis at median three months, patients receiving vemurafenib had a 63 percent reduction in risk of death compared to those receiving dacarbazine. Those who received vemurafenib also had a 74 percent reduction in the risk of progression (or death) compared to dacarbazine. In addition, the researchers found that those receiving vemurafenib had a 48.4 percent response rate compared to 5.5 percent for the dacarbazine group. At the first trial interim analysis, it was recommended that those patients receiving dacarbazine switch to vemurafenib.

The most common side effects of vemurafenib were skin rashes, photosensitivity, elevated liver enzymes, and joint pain. Fewer than 10 percent of these side effects were grade three or worse. In addition, 18 percent of patients developed a low-grade non-melanoma skin tumor.

Dr. Chapman said that because the study findings showed improvements in PFS and response rate along with greater overall survival, PFS may now become a validated study endpoint for future trials with similarly targeted therapies in melanoma.

The researchers plan to next test vemurafenib in combination with other agents in patients with advanced melanoma. A Phase I trial has already begun with vemurafenib and ipilimumab, which received approval from the U.S. Food and Drug Administration earlier this year.

The study was sponsored by Hoffman-La Roche.