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New Drug Application Submitted to FDA for Cobimetinib/Vemurafenib in Advanced Melanoma
A new drug application (NDA) has been submitted to the FDA for the investigational MEK inhibitor cobimetinib (Genentech/Roche), in combination with vemurafenib (Zelboraf, Genentech/Daiichi Sankyo), for the treatment of patients with BRAF V600 mutation-positive advanced melanoma.
The submission was based on results from the phase III coBRIM trial, which showed that patients who received cobimetinib plus vemurafenib had significantly longer progression-free survival (PFS) compared with those treated with vemurafenib alone.
In the coBRIM study, cobimetinib and vemurafenib reduced the risk of disease worsening or death by half (hazard ratio, 0.51; P < 0.0001), with median PFS of 9.9 months for cobimetinib/vemurafenib compared with 6.2 months for vemurafenib alone.
The results were published in the New England Journal of Medicine.
The CoBRIM trial was an international, randomized, double-blind, placebo-controlled study evaluating the safety and efficacy of cobimetinib (60 mg once daily) in combination with vemurafenib (960 mg twice daily) compared with vemurafenib alone. In the study, 495 patients with BRAF V600 mutation-positive unresectable locally advanced or metastatic melanoma (detected by the Cobas 4800 BRAF mutation test) and previously untreated for advanced disease were randomly assigned to receive vemurafenib every day on a 28-day cycle plus either cobimetinib or placebo on days 1 to 21. Treatment was continued until disease progression, unacceptable toxicity, or withdrawal of consent occurred.
Investigator-assessed PFS was the primary endpoint. Secondary endpoints included the duration of response and other safety, pharmacokinetic, and quality-of-life measures.
There was a higher overall frequency of grade-3 or higher adverse events (AEs) in the combination arm compared with the monotherapy arm (65% vs. 59%, respectively), with nearly half of these due to laboratory abnormalities (mainly increased blood levels of liver enzymes and creatine phosphokinase [CPK]). Common adverse events observed at a higher frequency (all grades) in the combination arm compared with the monotherapy arm included diarrhea (57% vs. 28%, respectively), nausea (39% vs. 24%), photosensitivity (28% vs. 16%), laboratory abnormalities (i.e., increased alanine aminotransferase [ALT], 24% vs. 18%; increased aspartate aminotransferase [AST], 22% vs. 13%; and increased CPK, 30% vs. 3% percent), and vomiting (21% vs. 12%). Common adverse events observed at a lower frequency in the combination arm than in the monotherapy arm included hair loss (14% vs. 29%, respectively), thickening of the outer layer of the skin (10% vs. 29%), and joint pain (33% vs. 40%).
Cobimetinib is designed to selectively block the activity of MEK, one of a series of intracellular proteins that comprise a signaling pathway that helps regulate cell division and survival. Cobimetinib binds to MEK while vemurafenib binds to mutant BRAF, another protein on the pathway, to interrupt abnormal signaling that can cause tumor growth.
In addition to treatment with vemurafenib in advanced melanoma, cobimetinib is being studied in combination with other investigational medications, including immunotherapy, in several tumor types, including non–small-cell lung cancer, colorectal cancer, and triple-negative breast cancer.
Source: Genentech; December 14, 2014.