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FDA Extends Cobimetinib Review Period in Advanced Melanoma

The FDA has extended the review period for the MEK inhibitor cobimetinib in combination with the BRAF inhibitor vemurafenib (Zelboraf) for patients with BRAFV600 mutation-positive advanced melanoma by 3 months, making the new decision date November 11, 2015.

The extension in the review timeline follows the submission of updated data from the pivotal phase III coBRIM study, which were presented at the 2015 ASCO Annual Meeting.1 In the initial data submitted to the FDA the median progression-free survival (PFS) seen with the combination was 9.9 months compared with 6.2 months for vemurafenib and placebo (HR = 0.51; 95% CI, 0.39-0.68).2 However, for the updated analysis the median PFS with the combination was extended to 12.25 versus 7.20 months with vemurafenib plus placebo (HR = 0.58; 95% CI, 0.46-0.72).

“Updated coBRIM efficacy data, now with a median follow-up of 14.2 months, confirmed the clear and definitive clinical benefit of adding cobimetinib to vemurafenib in BRAFV600-mutated melanoma,” lead investigator James Larkin, MD, PhD, medical oncologist at the Royal Marsden Hospital, said during a presentation of the results at the ASCO meeting. “This study continues to follow patients for overall survival. We hope and expect that the final overall survival analysis will occur near the end of this year.”

The international phase III coBRIM trial randomized 495 patients to 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. More than half of patients had stage IV, M1c melanoma.

PFS was the primary endpoint of the study. Secondary outcome measures included overall survival (OS), objective response rate (ORR), duration of response, and safety.

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.

Genentech, the developer of vemurafenib, submitted the new drug application for the combination, which initially received a priority review designation from the FDA in February 2015. Exelixis, the developer of cobimetinib, announced the extension to the regulatory timeline.

"The combination of cobimetinib and Zelboraf extended the time people lived without their disease getting worse to a year," Sandra Horning, MD, chief medical officer and head of Global Product Development at Genentech, said in a statement when the coBRIM data were presented. "These results are exciting because they underscore the importance of combining medicines that target the signals, which cause about half of all melanomas to grow." - See more at: