Roche's investigational combination of cobimetinib plus Zelboraf (vemurafenib) provided significant benefit to people with advanced melanoma over Zelboraf alone
• Cobimetinib plus Zelboraf reduced the risk of disease worsening by half compared to Zelboraf alone
• Phase III coBRIM study results will be presented today during the Presidential Symposium at the European Society of Medical Oncology (ESMO) 2014 Congress and published in the New England Journal of Medicine
• Roche has submitted an EU marketing authorisation application for the combination for the treatment of BRAF V600 mutation-positive advanced melanoma
Roche (SIX: RO, ROG; OTCQX: RHHBY) today announced positive data from the coBRIM Phase III study. The results showed that people with previously untreated BRAF V600 mutation-positive, advanced melanoma who received the MEK inhibitor cobimetinib plus Zelboraf (vemurafenib) lived significantly longer without their disease worsening or death (progression-free survival; PFS) compared to Zelboraf alone.
The combined therapy reduced the risk of disease worsening or death by half (hazard ratio [HR]=0.51, 95 percent confidence interval [CI] 0.39-0.68; p<0.0001), with a median PFS of 9.9 months for cobimetinib plus Zelboraf compared to 6.2 months with Zelboraf alone. The safety profile was consistent with a previous study of the combination. The most common adverse events seen in the combination arm included diarrhea, nausea, rash, photosensitivity, and lab abnormalities.
"We combined cobimetinib and Zelboraf in this study to better inhibit a major cancer growth pathway and hopefully improve clinical outcomes," said Sandra Horning, M.D., Chief Medical Officer and Head of Global Product Development. "The coBRIM results are exciting because they support the potential of the combination as a new treatment option for people with BRAF mutation-positive advanced melanoma."
The coBRIM results were statistically significant across multiple secondary endpoints. The median PFS by independent review committee (IRC) was 11.3 months for the combination arm compared to 6.0 months for the control arm (HR=0.60, 95 percent CI 0.45-0.79; p=0.0003). The objective response rate (ORR) was higher in the combination compared to the control arm (68 vs. 45 percent; p<0.0001). Overall survival (OS) data are not yet mature.1
The late-breaking coBRIM data will be presented at ESMO 2014 today during the Presidential Symposium by Professor Grant McArthur, Peter MacCallum Cancer Centre, Australia (Abstract #LBA5_PR, Monday, September 29, 2014, 16:00-17:20 CEST) and are also part of the official press programme. Additionally, the study was published online today in the New England Journal of Medicine.1
Roche has submitted the coBRIM data to the European Medicines Agency and plans to submit a new drug application to the U.S. Food and Drug Administration later this year.
About the coBRIM study
CoBRIM is an international, randomised, 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 Zelboraf, compared to 960 mg twice daily of Zelboraf 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 randomised to receive Zelboraf 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.1 Investigator-assessed PFS was the primary endpoint. In addition to PFS by IRC, ORR and OS, secondary endpoints included 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 percent), with close to half of these due to lab abnormalities. Common adverse events (occurring in more than 20 percent) observed at a higher frequency (all grades) in the combination arm compared to the Zelboraf arm included diarrhea (57 vs. 28 percent), nausea (39 vs. 24 percent), photosensitivity (28 vs. 16 percent), lab abnormalities (increased alanine aminotransferase [24 vs. 18 percent], increased aspartate aminotransferase [22 vs. 13 percent], increased creatine phosphokinase [an enzyme released by muscles, 30 vs. 3 percent]), and vomiting (21 vs. 12 percent). Common adverse events observed at a lower frequency in the combination arm included hair loss (14 vs. 29 percent), thickening of the outer layer of the skin (10 vs. 29 percent) and joint pain (33 vs. 40 percent). Most instances of each common adverse event were Grade 1 or 2 in severity.1
Other select adverse events that were lower in the combination arm included cutaneous squamous cell carcinomas (3 vs. 11 percent; all grades) and keratoacanthomas (<1 vs. 8 percent; all grades). Serous retinopathy (collection of fluid under the retina) was observed at a higher frequency in the combination arm (20 vs. <1 percent) 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 percent).1