The FDA has granted a priority review to the MEK inhibitor cobimetinib for use in combination with the BRAF inhibitor vemurafenib (Zelboraf) to treat patients with BRAF V600â€“positive advanced melanoma.
Sandra Horning, MD
The FDA has granted a priority review to the MEK inhibitor cobimetinib for use in combination with the BRAF inhibitor vemurafenib (Zelboraf) to treat patients with BRAF V600—positive advanced melanoma. A final approval decision will come from the FDA by August 11, 2015.
The priority review is based on data from the phase III coBRIM study, in which the cobimetinib/vemurafenib combination reduced the risk of disease progression by 49% versus vemurafenib alone. Median progression-free survival (PFS) was improved by 3.7 months with cobimetinib.
“We are pleased the FDA has accepted our application for cobimetinib in combination with Zelboraf and granted it priority review status,” said Sandra Horning, MD, chief medical officer and head of Global Product Development at Genentech, which is developing cobimetinib with Exelixis.
The international, double-blind, phase III coBRIM trial randomized 495 patients in a 1:1 ratio to continuous vemurafenib at 960 mg twice daily plus placebo or vemurafenib at the same dosage plus cobimetinib at 60 mg once daily on days 1-21 of a 28-day cycle. Treatment was administered until progression or unacceptable toxicity.
Patients had histologically confirmed unresectable, locally advanced stage IIIC or IV melanoma with a BRAF V600 mutation as detected by the Cobas 4800 BRAF V600 Mutation Test. The median patient age in both arms was about 55 years, and all patients had an ECOG performance status of 0 or 1.
PFS was the primary endpoint, with secondary endpoints including overall survival (OS), objective response rate (ORR), duration of response, and safety.
Median PFS was significantly improved in the cobimetinib arm, at 9.9 months compared with 6.2 months in patients receiving vemurafenib alone (HR = 0.51; 95% CI, 0.39-0.68; P <.0001). The PFS benefit was upheld among predetermined patient subgroups.
At the time of the final PFS analysis, there was an interim OS analysis conducted in the intent-to-treat population; however, it had not crossed the prespecified hazard-ratio boundary for significance (HR = 0.65; 95% CI, 0.42-1.00; P = .046), according to study results published in November 2014 in The New England Journal of Medicine.
ORR was 68% in the combination arm versus 45% with single-agent vemurafenib.
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%).
The overall incidence of grade ≥3 AEs was higher in the combination arm at 65% versus 59% in the control group. About half of these events involved elevated levels of ALT, AST, or CPK.
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.
Single-agent vemurafenib was approved by the FDA in 2011 for the treatment of patients with advanced melanoma who have a BRAF V600E mutation.
In her statement, Horning expressed her hope for a quick regulatory review of the cobimetinib combination.
“We look forward to working with the FDA to bring this new treatment option to people with BRAF mutation—positive advanced melanoma as soon as possible.”
Larkin J, Ascierto PA, Dréno B, et al. Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med. 2014;371(20):1867-1876.