FDA Extends Review Period for Cobimetinib Melanoma NDA

Sandra Horning, MD

Sandra Horning, MD

The FDA has extended the review timeline for the combination of cobimetinib and vemurafenib in advanced melanoma by 3 months, to allow ample time to review updated data that were presented at the 2015 ASCO Annual Meeting.¹

The progression-free survival (PFS) was found to be approximately 2.35 months longer in the combination arm in the updated analysis presented at ASCO compared with earlier findings. In the initial data submitted to the FDA from the phase III coBRIM study the median 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).²However, 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).

Genentech, the developer of vemurafenib, submitted the new drug application (NDA) for the combination, which was accepted by the FDA in February 2015. At this time, the agency assigned the NDA a priority review, which set an approval decision deadline of August 11. However, under the new timeline, the final review deadline is now November 11, 2015, per the Prescription Drug User Fee Act.

"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."

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 versus 9.23 months, with cobimetinib and placebo, respectively.

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%).

References

1. Larkin JMG, Yan Y, McArthur GA, et al. Update of progression-free survival (PFS) and correlative biomarker analysis from coBRIM: Phase III study of cobimetinib (cobi) plus vemurafenib (vem) in advanced BRAF-mutated melanoma. J Clin Oncol.2015;33 (suppl; abstr 9006).
2. Larkin JMG, Ascierto PA, Dr&eacute;no B, et al. Combined vemurafenib and cobimetinib in BRAF-mutated melanoma.N Engl J Med. 2014;371(20):1867-1876.