Cobimetinib (formerly GDC-0973/XL518) is a potent, highly selective inhibitor of mitogen-activated protein kinase kinase, also known as MEK, 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 co-development 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 end of phase 1, at which point Genentech exercised its option to further develop the compound.
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 co-development agreement to co-promote in the United States.
Final data from BRIM7, a phase 1b dose escalation study conducted by Roche and Genentech, Exelixis’ collaboration partner, of cobimetinib in combination with the BRAF inhibitor vemurafenib in patients with locally advanced/unresectable or metastatic melanoma carrying a BRAFV600 mutation, were presented in May 2014 at the 10th European Association of Dermato-Oncology Congress. For more details on the data, please see the accompanying press release.
coBRIM, a multicenter, randomized, double-blind, placebo-controlled phase 3 clinical trial evaluating the combination of vemurafenib with cobimetinib versus vemurafenib in previously untreated BRAFV600 mutation positive patients with unresectable locally advanced or metastatic melanoma is currently ongoing. Roche and Genentech have announced that they expect top-line results from this trial and, if the data are positive, to file a NDA with the FDA in 2014.
Five phase 1 trials are now ongoing assessing the ability to combine cobimetinib with other agents. These novel combinations are being studied in patients with advanced solid tumors and in some trials entry is restricted to patients whose tumors carry specific genetic mutations. The agents being studied in combination with cobimetinib are:
- GDC-0941, a PI3K inhibitor
- GDC-0068, an AKT inhibitor
- Onartuzumab, a MET targeting antibody
- MPDL3280A, an antibody against the immune checkpoint regulator PD-L1
- MEHD7945A, a biotherapeutic targeting EGFR and HER3.