Genentech, a member of the Roche Group, today announced the U.S. Food and Drug Administration (FDA) has accepted and granted Priority Review for the company’s New Drug Application (NDA) for cobimetinib in combination with Zelboraf® (vemurafenib) for the treatment of people with BRAF V600 mutation-positive advanced melanoma. The FDA will make a decision on approval by August 11, 2015.
"We are pleased the FDA has accepted our application for cobimetinib in combination with Zelboraf and granted it Priority Review status," said Sandra Horning, M.D., chief medical officer and head of Global Product Development. "We look forward to working with the FDA to bring this new treatment option to people with BRAF mutation-positive advanced melanoma as soon as possible."
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 Zelboraf reduced the risk of disease worsening or death by half in people who received the combination (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 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.
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 PFS 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 percent), 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 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 value 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).
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.
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, colorectal cancer, triple- negative breast cancer and melanoma.
Zelboraf (zelboraf.com) 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.
Important Safety Information
Zelboraf can cause serious side effects, including risk of cancers. Zelboraf may cause a type of skin cancer called cutaneous squamous cell carcinoma (cuSCC). New melanoma lesions have occurred in people who take Zelboraf. Zelboraf may also cause another type of cancer called non-cutaneous squamous cell carcinoma (SCC). Patients must talk with their healthcare provider about their risk for these cancers. Patients must check their skin and tell their doctor about skin changes including a new wart, a sore or bump that bleeds or does not heal, or a mole that changes size or color.
A patient’s healthcare provider should also check for cancers that may not occur on the skin. Patients must tell their healthcare provider about any new symptoms that they get while taking Zelboraf.
While taking Zelboraf, patients should avoid sunlight. When they go outside, patients must wear clothes that protect their skin, including their head, face, hands, arms and legs. Patients must use lip balm and a broad-spectrum sunscreen with SPF 30 or higher.
Possible serious side effects of Zelboraf include severe allergic reactions, severe skin reactions, potentially life-threatening changes in the electrical activity of the heart called QT prolongation, liver injury and eye problems. Patients must tell their doctor if they are pregnant or plan to become pregnant, as Zelboraf can harm a patient’s unborn baby.
Common side effects of Zelboraf include joint pain, rash, hair loss, tiredness, sunburn or sun sensitivity, nausea, itching or warts.
Patients must tell their doctor if they have any side effect that bothers them or does not go away. These are not all of the possible side effects of Zelboraf. For more information about side effects, patients should ask their doctor or pharmacist.
Report side effects to the FDA at (800) FDA-1088 or fda.gov/medwatch . Report side effects to Genentech at (888) 835-2555 .
Founded more than 35 years ago, Genentech (gene.com) 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.