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Cotellic

Treatment for Melanoma -- Metastatic

Update: Cotellic (cobimetinib) Now FDA Approved - November 10, 2015

Genentech Submits NDA to FDA for Investigational Cobimetinib Used in Combination with Zelboraf (vemurafenib) in Advanced Melanoma

South San Francisco, Calif. -- December 14, 2014 -- Genentech, a member of the Roche Group (SIX: RO, ROG; OTCQX: RHHBY), today announced the company has submitted a New Drug Application (NDA) for cobimetinib to the U.S. Food and Drug Administration (FDA) for treatment, in combination with Zelboraf® (vemurafenib), for people with BRAF V600 mutation-positive advanced melanoma. The submission is based on results of the coBRIM Phase III study, which showed people who received the MEK inhibitor cobimetinib plus Zelboraf lived significantly longer without their disease worsening or death (progression-free survival; PFS) compared to Zelboraf alone.

"In the past several years we have made significant progress in treating advanced melanoma, but it remains a serious and difficult to treat cancer that affects more people each year,” said Sandra Horning, M.D., chief medical officer and head of Global Product Development. “We look forward to working with the FDA as they review the NDA and hope the combination of cobimetinib and Zelboraf will soon become a new option for people with BRAF mutation-positive advanced melanoma."

In the coBRIM study, cobimetinib and Zelboraf 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 Grade 3 or higher adverse events in the combination arm included liver lab 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 abnormalities. The most common Grade 3 or higher adverse events in the combination arm included liver lab abnormalities, elevated creatine phosphokinase (CPK, an enzyme released by muscles) and diarrhea.

The results were presented at the European Society of Medical Oncology (ESMO) 2014 Congress and published in the New England Journal of Medicine. Roche has already submitted the coBRIM data to the European Medicines Agency.

About the coBRIM study

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 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 randomized 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. Investigator-assessed PFS was the primary endpoint. Secondary endpoints include In addition to PFS by IRCindependent review committee, ORR overall response rate, and overall survivalOS, 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 (mainly increased blood levels of liver enzymes and CPK). 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 [ALT, 24 vs. 18 percent], increased aspartate aminotransferase [AST, 22 vs. 13 percent], increased CPK [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.

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).

About melanoma

Melanoma is less common, but more aggressive and deadlier than other forms of skin cancer. When melanoma is diagnosed early, it is generally a curable disease, but most people with advanced melanoma have a poor prognosis. The American Cancer Society estimates there will be more than 76,100 new cases of melanoma and approximately 9,700 melanoma deaths this year in the United States. In recent years, there have been significant advances in treatment for metastatic melanoma and people with the disease have more options. However, it continues to be a serious health issue with a high unmet need and a steadily increasing incidence over the past 30 years.

About the cobimetinib and Zelboraf combination

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 Zelboraf binds to mutant BRAF, another protein on the pathway, to interrupt abnormal signaling that can cause tumors to grow.

About cobimetinib

Cobimetinib (GDC-0973, XL518) was discovered by Exelixis Inc. and is being developed in collaboration with Exelixis. Cobimetinib is also being investigated in combination with several investigational medicines, including an immunotherapy, in several tumor types such as non-small cell lung cancer, and colorectal cancer, triple- negative breast cancer and melanoma.

About Zelboraf

Zelboraf is a prescription medicine used to treat a type of skin cancer called melanoma that has spread to other parts of the body or cannot be removed by surgery, and has a certain type of abnormal “BRAF” gene. BRAF is mutated in approximately half of melanomas. A patient’s healthcare provider will perform a test to make sure that Zelboraf is right for the patient. Zelboraf is not used to treat melanoma with a normal BRAF gene. It is not known if Zelboraf is safe and effective in children under 18 years of age.

Zelboraf is now approved in more than 80 countries and has been used to treat more than 11,000 patients worldwide. Zelboraf was co-developed under a 2006 license and collaboration agreement between Roche and Plexxikon, now a member of the Daiichi Sankyo Group.

About Genentech


Founded more than 35 years ago, Genentech is a leading biotechnology company that discovers, develops, manufactures and commercializes medicines to treat patients with serious or life-threatening medical conditions. The company, a member of the Roche Group, has headquarters in South San Francisco, California. For additional information about the company, please visit http://www.gene.com.

Source: Genentech

Posted: December 2014

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