Cobimetinib (formerly GDC-0973/XL518) is a selective inhibitor of MEK, also known as mitogen-activated protein kinase kinase. MEK is a serine/threonine kinase that is a component of the RAS/RAF/MEK/ERK pathway. This pathway mediates signaling downstream of growth factor receptors, and is prominently activated in a wide variety of human tumors. In preclinical studies, oral dosing of cobimetinib resulted in potent and sustained inhibition of MEK in RAS- or BRAF-mutant tumor models. Cobimetinib is being developed by Roche and Genentech (a member of the Roche Group) under a collaboration agreement with Exelixis.
Collaboration with Genentech
Exelixis discovered cobimetinib internally and advanced the compound to investigational new drug (IND) status. In late 2006, Exelixis entered into a worldwide collaboration agreement with Genentech, under which Exelixis received initial upfront and milestone payments for signing the agreement and submitting the IND. Exelixis was responsible for development of cobimetinib through the initial phase 1 study, and Genentech exercised its option to develop the compound further.
Exelixis is entitled to an initial equal share of U.S. profits and losses, which will decrease as sales increase, and will share equally in the U.S. marketing and commercialization costs. Exelixis is eligible to receive royalties on any sales of the product outside the United States. In November 2013, Exelixis exercised its option under the collaboration agreement to provide up to 25% of the total sales force in the United States, should cobimetinib be approved.
Genentech and Exelixis announced positive top-line results from coBRIM, the phase 3 pivotal trial evaluating cobimetinib in combination with vemurafenib in previously untreated patients with unresectable locally advanced or metastatic melanoma harboring a BRAFV600 mutation, in July 2014. Updated results were most recently presented at the Annual Meeting of the American Society of Clinical Oncology in June 2015. coBRIM met its primary endpoint, demonstrating a statistically significant increase in progression-free survival for the combination as compared to vemurafenib alone. Based on the results from coBRIM, Roche filed a Marketing Authorization Application for the combination with the European Medicines Agency in September 2014, and in December 2014, Genentech completed its New Drug Application with the U.S. Food & Drug Administration (FDA). The FDA granted Priority Review to the application, and the PDUFA action date is now November 11, 2015.
Additional Trials Involving Cobimetinib
Additional phase 1 and 2 trials are assessing the ability to combine cobimetinib with vemurafenib in other settings, as well as with other agents. These novel combinations are being studied in patients with advanced solid tumors. In some of these trials, entry is restricted to patients whose tumors carry specific genetic mutations. For more information on cobimetinib clinical trials, please visit www.ClinicalTrials.gov.
Cobimetinib is the subject of investigation in a variety of ongoing clinical trials; its safety and efficacy profile has not yet been established.