The FDA ( Food and Drug Administration ) has granted Priority Review for the New Drug Application ( NDA ) for Cobimetinib in combination with Vemurafenib ( Zelboraf ) for the treatment of people with BRAF V600 mutation-positive advanced melanoma.
A Priority Review designation is granted to medicines that the FDA determines have the potential to provide significant improvements in the treatment, prevention or diagnosis of a disease.
The NDA is based on results of the coBRIM phase III study, which showed the MEK inhibitor Cobimetinib plus Vemurafenib reduced the risk of disease worsening or death by half in people who received the combination ( hazard ratio [ HR ]=0.51, 95% confidence interval [CI] 0.39-0.68; p less than 0.0001 ), with a median progression-free survival of 9.9 months for Cobimetinib plus Vemurafenib compared to 6.2 months with Vemurafenib alone.
The safety profile was consistent with a previous study of the combination. The most common Grade 3 or higher adverse events in the combination arm included liver lab value abnormalities, elevated creatine phosphokinase ( CPK, an enzyme released by muscles ) and diarrhea.
The most common adverse events seen in the combination arm included diarrhea, nausea, rash, photosensitivity and lab value abnormalities.
CoBRIM is an international, randomized, double-blind, placebo-controlled phase III study evaluating the safety and efficacy of 60 mg once daily of Cobimetinib in combination with 960 mg twice daily of Vemurafenib, compared to 960 mg twice daily of 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 randomized to receive Vemurafenib every day on a 28-day cycle plus either Cobimetinib or placebo on days 1-21.
Treatment was continued until disease progression, unacceptable toxicity or withdrawal of consent.
Investigator-assessed progression-free survival was the primary endpoint. Secondary endpoints include progression-free survival by independent review Committee, overall response rate, overall survival, 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 in the combination arm ( 65 vs 59% ), with close to half of these due to lab value abnormalities ( mainly increased blood levels of liver enzymes and CPK ).
Common adverse events ( occurring in more than 20% ) observed at a higher frequency ( all grades ) in the combination arm compared to the Vemurafenib arm included diarrhea ( 57 vs 28% ), nausea ( 39 vs 24% ), photosensitivity ( 28 vs 16% ), lab value abnormalities ( increased alanine aminotransferase [ ALT, 24 vs 18% ], increased aspartate aminotransferase [ AST, 22 vs 13% ], increased CPK [ 30 vs 3% ] ) and vomiting ( 21 vs 12% ).
Common adverse events observed at a lower frequency in the combination arm included hair loss ( 14 vs 29% ), thickening of the outer layer of the skin ( 10 vs 29% ) and joint pain ( 33 vs 40% ). Most instances of each common adverse event were grade 1 or 2 in severity.
Other select adverse events that were lower in the combination arm included cutaneous squamous cell carcinomas ( 3 vs. 11%; all grades ) and keratoacanthomas ( less than 1 vs 8%; all grades ). Serous retinopathy ( collection of fluid under the retina ) was observed at a higher frequency in the combination arm ( 20 vs less than 1% ) with most of these events either grade 1 or 2 and temporary in nature.
Specific adverse events leading to withdrawal from treatment were similar in both study arms, as was the overall discontinuation rate from treatment ( 13 vs 12% ).
Cobimetinib is designed to selectively block the activity of MEK, one of a series of proteins inside cells that make up 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 tumors to grow. ( Xagena )
Source: Genentech, 2015