Vemurafenib/Cobimetinib Combo for Melanoma Approved by FDA

November 10, 2015

The FDA has approved a combination of vemurafenib (Zelboraf) and cobimetinib (Cotellic) to treat patients with metastatic or unresectable BRAF V600E/K mutation-positive melanoma.

Richard Pazdur, MD

The FDA has approved a combination of vemurafenib (Zelboraf) and cobimetinib (Cotellic) to treat patients with metastatic or unresectable BRAF V600E/K mutation-positive melanoma. The approval was based on based on an extension in progression-free survival (PFS) in the phase III coBRIM study.

In the data submitted to the FDA, the median PFS with the combination was 12.3 versus 7.2 months with vemurafenib plus placebo (HR, 0.58; 95% CI, 0.46-0.72). PFS was the primary endpoint of the study with secondary outcome measures including overall survival (OS), objective response rate (ORR), duration of response, and safety.

“As we continue to advance our knowledge of tumor biology, we have learned that cancer cells have a remarkable ability to adapt and become resistant to targeted therapies. Combining two or more treatments addressing different cancer-causing targets may help to address this challenge,” Richard Pazdur, MD, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, said in an interview. “Today’s approval provides a new targeted treatment that, when added to vemurafenib, demonstrates greater benefit than vemurafenib alone in patients with BRAF mutation-positive melanoma.”

In early October, the manufacturers of the drugs, Genentech and Exelixis, announced the combination had improved overall survival. These data will be presented later this month and were not part of the FDA review.

The international phase III coBRIM trial randomized 495 patients to receive continuous vemurafenib at 960 mg twice daily plus placebo (n = 248) or cobimetinib at 60 mg once daily on days 1-21 of a 28-day cycle (n = 247). Patient demographics were well balanced across the two arms for age, ECOG performance status, geographic region, and disease stage. Over half of patients taking part in the trial had stage IV, M1c melanoma.

In the ASCO analysis, the ORR was 69.6% versus 50%, for cobimetinib and placebo, respectively. The absolute difference in ORR between the two arms was 19.64% (95% CI, 10.95-28.32). The complete response rate in the combination arm was 15.8% versus 10.5% with vemurafenib and placebo. The median duration of response was 12.98 months versus 9.23 months, with cobimetinib and placebo, respectively.

In a biomarker analysis from the study, 11% of patients in the coBRIM study were found to have a co-existing baseline mutation in RAS/RAF/RTK. However, these alterations were not found to impact PFS or ORR in patients who received the combination.

In an earlier analysis of the study published in The New England Journal of Medicine, the most frequently reported adverse events (AEs) of all grades reported in the cobimetinib arm versus the control arm included diarrhea (57% vs 28%), nausea (39% vs 24%), photosensitivity (28% vs 16%), increased ALT (24% vs 18%), increased AST (22% vs 13%), increased CPK (30% vs 3%), vomiting (21% vs 12%), and serous retinopathy (20% vs <1%).

Some AEs occurred at lower rates in the combination group, including hair loss (14% vs 29%), hyperkeratosis (10% vs 29%), joint pain (33% vs 40%), cutaneous squamous cell carcinomas (3% vs 11%), and keratoacanthomas (<1% vs 8%).

Treatment-related discontinuation rates in the combination and control groups were similar at 13% and 12%, respectively. There were six deaths related to AEs in the cobimetinib arm and three in the control arm.