Vemurafenib, which targets a mutated gene in cancer cells, significantly increased survival for metastatic melanoma patients in a phase 2 trial.
Vemurafenib (Zelboraf), recently approved by the FDA to treat metastatic melanoma patients with a specific protein mutation, nearly doubles survival, according to results of a phase 2 trial published in the February 23, 2012, edition of the New England Journal of Medicine
Few metastatic melanoma patients have responded to previously available treatments, and average survival for the disease has ranged from 6 to 10 months. In the new trial, the average overall survival was 15.9 months.
Vemurafenib targets a mutated BRAF gene in cancer cells, which is present for about half of all metastatic melanomas. The trial enrolled 132 metastatic melanoma patients with the mutated gene who had previously received systemic treatment between October 2009 and March 2010. Participants received 960 mg of vemurafenib orally twice a day. The median follow-up for efficacy was 12.9 months and for safety it was 10.4 months.
The results found that complete response was achieved in 8 patients (6%) and partial response in 62 patients (47%), for an overall response rate of 53%. The overall survival rate was 77% at 6 months, 58% at 12 months, and was estimated to be 43% at 18 months. The researchers note that these are impressive numbers given that patients in the trial did not have favorable baseline characteristics: In 61%, cancer had spread to internal organs, and 49% had an elevated lactate dehydrogenase level. In addition, the BRAF mutation is associated with shorter survival in patients with metastatic melanoma.
Most patients had at least 1 adverse event related to the drug, although these side effects were not severe or life threatening in most cases. The most common adverse events were joint pain, rash, photosensitivity reaction, fatigue, and hair loss. Dosage was reduced for 59 patients (45%), and dose interruptions were required for 85 patients (64%). Nonetheless, participants received on average 91% of the intended dose of 1920 mg per day.
"This study shows that Zelboraf changes the natural history of this disease," said co-principal investigator Antoni Ribas, MD, PhD, of UCLA’s Jonsson Comprehensive Cancer Center. "We're seeing a significant number of patients with durable responses to the drug, and that the whole group of treated patients is living longer."
The primary limitation of vemurafenib is that tumors eventually become resistant to it, and researchers are investigating ways to combat this resistance. FDA approval
of the drug in August 2011 was based on results
of a phase 3 trial published after the current trial was completed. The phase 3 trial found a significant improvement in survival using vemurafenib over chemotherapy, but could not address long-term outcomes, as it had a much shorter follow-up period than the current trial.
To read the study, which was sponsored by the Roche, the manufacturer of Zelboraf, click here
. (Registration required to access full text.)