On November 10, 2015, the U.S. Food and Drug Administration approved cobimetinib (COTELLIC Tablets, Genentech, Inc.) for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, in combination with vemurafenib.  Cobimetinib is not indicated for treatment of patients with wild-type BRAF melanoma.
The approval was based on the demonstration of improved progression-free survival (PFS) and overall survival (OS) in a multicenter, double-blind, randomized, active-controlled trial conducted in 495 patients with previously untreated, BRAF V600 mutation-positive, unresectable or metastatic melanoma as detected using the cobas 4800 BRAF V600 mutation test.  All patients received vemurafenib 960 mg orally twice daily and were randomized (1:1) to receive cobimetinib 60 mg (n=247) or matching placebo (n=248) orally once daily on days 1-21 of an every 28-day cycle.  The median age of the study population was 55 years (range 23 to 88 years), 58% of patients were male, 93% were White and 5% had no race reported, 60% had stage M1c disease, 72% had a baseline ECOG performance status of 0, 45% had an elevated baseline serum lactate dehydrogenase (LDH), 10% had received prior adjuvant therapy, and less than 1% had previously treated brain metastases.
The trial demonstrated a statistically significant improvement in PFS [HR: 0.56 (95% CI: 0.45, 0.70), p < 0.001]; the median PFS was 12.3 months (95% CI: 9.5, 13.4) and 7.2 months (95% CI: 5.6, 7.5) on the cobimetinib plus vemurafenib and single-agent vemurafenib arms, respectively.  The trial also demonstrated a statistically significant improvement in OS based on an interim analysis [HR: 0.63 (95% CI: 0.47, 0.85); stratified log-rank p-value=0.0019]; the  median OS was not reached (NR) (95% CI: 20.7, NR) and was 17 months (95% CI: 15.0, NR) on the cobimetinib plus vemurafenib and single-agent vemurafenib arms, respectively. The confirmed objective response rates were 70% (95% CI: 64, 75) and 50% (95% CI: 44, 56) on the cobimetinib plus vemurafenib and single-agent vemurafenib arms, respectively (p < 0.001).
Safety data was evaluated in 247 patients who received at least one dose of cobimetinib. The most common adverse reactions were diarrhea (60%), photosensitivity reaction (46%), nausea (41%), pyrexia (28%), and vomiting (24%).  The most common (greater than or equal to 5%) Grade 3-4 adverse reaction was diarrhea (6%).  The most common Grade 3-4 laboratory abnormalities with cobimetinib were increased GGT (21%), increased creatine phosphokinase (14%), hypophosphatemia (12%), increased alanine aminotransferase (11%), lymphopenia (10%), increased aspartate aminotransferase (8%), increased alkaline phosphatase (7%), hyponatremia (6%), and hypokalemia (5%).
The most serious risks in patients receiving cobimetinib were new primary malignancies, hemorrhage, cardiomyopathy, severe dermatologic reactions, serous retinopathy and retinal vein occlusion, hepatotoxicity, rhabdomyolysis, and severe photosensitivity reactions.
The recommended dose and schedule of cobimetinib is 60 mg orally once daily on days 1-21 of an every 28-day cycle.
The development program for cobimetinib for this indication was designated as a Fast Track development program for this indication and this application received Priority Review designation. A description of these expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics, available at: http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm358301.pdf.
Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).

Page Last Updated: 11/10/2015
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