The approval was based on an extension in progression-free survival in the phase 3 coBRIM study.
The FDA has approved the combination of Zelboraf (vemurafenib) and Cotellic (cobimetinib) as a treatment for patients with metastatic or unresectable BRAF V600E/K mutation-positive melanoma, based on an extension in progression-free survival in the phase 3 coBRIM study.
In the data submitted to the FDA, the median progression-free survival with the combination was 12.3 versus 7.2 months with Zelboraf plus placebo, representing a 44 percent reduction in the risk of disease progression or death. Additionally, the companies manufacturing the drugs, Genentech and Exelixis, announced that the combination had improved overall survival. These data will be presented later this month and were not part of the FDA review.
“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 Zelboraf, demonstrates greater benefit than Zelboraf alone in patients with BRAF mutation-positive melanoma.”
The phase 3 coBRIM study compared the MEK inhibitor Cotellic plus the BRAF inhibitor Zelboraf to single-agent Zelboraf in previously untreated BRAFV600 mutation-positive patients with unresectable locally advanced or metastatic melanoma. In the study, 495 patients were randomized to continuous Zelboraf at 960 mg twice daily plus placebo (248 patients) or Cotellic at 60 mg once daily on days 1-21 of a 28-day cycle (247 patients).
Patient demographics were well balanced across the two arms for age, ECOG performance status, geographic region, and disease stage. More than half of patients had stage 4, M1c melanoma and BRAF mutations were detected by the Cobas 4800 BRAF V600 Mutation Test. The primary endpoint for the study was progression-free survival, with secondary endpoints focused on overall survival, objective response rate, and duration of response.
In an analysis presented at the 2015 annual meeting of the American Society of Clincal Oncology, the objective response rate was 69.6 percent versus 50 percent, for Cotellic and placebo, respectively. The absolute difference in objective response rate between the two arms was 19.64 percent. The complete response rate in the combination arm was 15.8 percent versus 10.5 percent with Zelboraf and placebo. The median duration of response was 12.98 months versus 9.23 months, with Cotellic and placebo, respectively.
In a biomarker analysis from the study, 11 percent 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 progression-free survival or objective response rate 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 Cotellic arm versus the control arm included diarrhea (57 percent vs 28 percent), nausea (39 percent vs 24 percent), photosensitivity (28 percent vs 16 percent), increased ALT (24 percent vs 18 percent), increased AST (22 percent vs 13 percent), increased CPK (30 percent vs 3 percent), vomiting (21 percent vs 12 percent) and serous retinopathy (20 percent vs less than 1 percent).
Some AEs occurred at lower rates in the combination group, including hair loss (14 percent vs 29 percent), hyperkeratosis (10 percent vs 29 percent), joint pain (33 percent vs 40 percent), cutaneous squamous cell carcinomas (3 percent vs 11 percent) and keratoacanthomas (less than 1 percent vs 8 percent).
Treatment-related discontinuation rates in the combination and control groups were similar at 13 percent and 12 percent, respectively. There were six deaths related to AEs in the Cotellic arm and three in the control arm.