FDA Approves Vemurafenib for Treatment of Metastatic Melanoma

The US Food and Drug Administration (FDA) approved vemurafenib (Zelboraf) earlier this week for the treatment of metastatic or unresectable melanoma. The new drug, also known as PLX4032, specifically targets patients whose tumors express the BRAF V600E gene mutation. Coinciding with the approval of vemurafenib is a companion diagnostic test, named the cobas® 4800 BRAF V600 Mutation Test, that will determine whether a patient's cells have the gene mutation.

"[Vemurafenib] blocks a mutated protein in the cancer that's like a switch that's stuck on the on position, telling the cancer cell to be growing all the time," said Dr. Antoni Ribas of UCLA's Jonsson Comprehensive Cancer Center, referring to the BRAF V600E gene mutation that is found in 40% to 60% of melanoma patients. Dr. Ribas reported findings of the clinical trials involving vemurafenib at the American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago. "We get very reproducable responses," said Dr. Ribas. "Over 50% response rates in this type of melanoma."

In a phase I study, the use of the vemurafenib was associated with a response rate of 69% in melanoma patients with tumors that harbored the BRAF V600E mutation, and a phase II trial showed a confirmed response rate of 53%. The results of the phase III trial were published in June in the New England Journal of Medicine, coinciding with the ASCO annual meeting where the data were also presented. "It's a big step forward," said Dr. Ribas. "Any prior therapies, it was less than 10% responses. And up to 80% or 90% of the patients have some shrinkage, some of them do not have enough shrinkage to call it a response."

The phase III trial involved 2,107 patients and took place at 104 centers in 12 different countries. All of the patients, 675 after screening for the gene mutation, had unresectable, previously untreated stage IIIC or stage IV melanoma that tested positive for the BRAF V600E mutation. The study was designed to determine whether vemurafenib would prolong the rate of overall or progression-free survival, as compared with dacarbazine.

Prior to the approval of ipilimumab, and now vemurafenib, dacarbazine was the only chemotherapeutic agent approved by the FDA for the treatment of metastatic melanoma. Dacarbazine was associated with a response rate of 7% to 12% and a median overall survival of 5.6 to 7.8 months after the initiation of treatment.

The trial was stopped due to positive early results, and patients were given the option to begin taking vemurafenib. "This drug when compared to chemotherapy is so much more active that the study had to be closed within the first month of patient follow-up," said Dr. Ribas. "The benefit was so big for the new drug that it was not ethical to continue treating patients with chemotherapy. So the patients with chemotherapy were asked to switch to the active drug."

The median survival of patients receiving vemurafenib has not been reached (77% were still alive at 6 months, 58% at 12 months), while the median survival for those who received dacarbazine was 8 months (64% are still alive).

"This has been an important year for patients with late-stage melanoma. Zelboraf is the second new cancer drug approved that demonstrates an improvement in overall survival," said Richard Pazdur, MD, director of the Office of Oncology Drug Products in the FDA's Center for Drug Evaluation and Research. "In March, we approved Yervoy (ipilimumab), another new treatment for late-stage melanoma that also showed patients live longer after receiving the drug."

In June, the two makers of these newly approved drugs (Roche [vemurafenib] and Bristol-Meyers Squibb [ipilimumab]) announced that they would enter a collaboration to study vemurafenib and ipilimumab in metastatic melanoma. They will conduct a phase I/II study to determine the efficacy and safety of the combination therapy.

Vemurafenib was reviewed under the FDA's priority review program that provides for an expedited 6-month review of drugs that may offer major advances in treatment or that provide a treatment when no adequate therapy exists. Vemurafenib and the companion BRAF V600E test are being approved ahead of the drug's October 28, 2011 goal date and the companion diagnostics' November 12, 2011 goal date.

The most common side effects reported with vemurafenib include joint pain, rash, hair loss, fatigue, nausea, and skin sensitivity with sun exposure. About 26% of patients developed cutaneous squamous cell carcinoma, which was managed with surgery. Patients undergoing treatment with vemurafenib should be advised to limit sun exposure.