Cobimetinib

Cobimetinib (formerly GDC-0973/XL518) is a selective inhibitor of MEK, also known as mitogen-activated protein kinase kinase. MEK is a dual specificity kinase that is a component of the RAS/RAF/MEK/ERK pathway. This pathway mediates signaling downstream of growth factor receptors, and is activated in a wide variety of human tumors. In preclinical studies, cobimetinib resulted in 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. Following the determination of the maximum tolerated dose in phase 1 by Exelixis, Genentech exercised its option to further develop cobimetinib.

Under the terms of the collaboration, Exelixis is entitled to an initial equal share of U.S. profits and losses, which will decrease as sales increase, and shares U.S. commercialization costs. In November 2013, Exelixis exercised its option to co-promote cobimetinib in the United States and fields 25 percent of the U.S. sales force, closely coordinating its efforts with Genentech. Outside of the United States, Exelixis is eligible to receive royalties on any sales.

Regulatory Approvals to Treat Advanced Melanoma

Cobimetinib is now approved in multiple countries, including the United States, European Union, Switzerland, Canada, Australia and Brazil, to treat specific forms of BRAF mutation-positive unresectable or metastatic melanoma, in combination with vemurafenib. The trade name for cobimetinib is COTELLIC®. For more information on COTELLIC, including important safety information, please click here.

Ongoing and Planned Pivotal Trials

Genentech (a member of the Roche Group) has been responsible for cobimetinib’s clinical development since it opted to further develop the compound following Exelixis’ determination of a maximum tolerated dose in phase 1 clinical trials. Since then, Genentech has undertaken a clinical development program aimed at evaluating cobimetinib’s potential in combination with a variety of investigational and approved therapies. Most notably, activity in phase 1b trials of cobimetinib in combination with atezolizumab, a PD-L1 inhibitor, has led to three ongoing or planned phase 3 studies of the combination.

Metastatic colorectal cancer (CRC). Phase 1b data for cobimetinib and atezolizumab in a cohort of patients with metastatic colorectal cancer (CRC) were first presented at the Annual Meeting of the American Society of Clinical Oncology in June 2016. The results – including antitumor activity in the microsatellite-stable form of CRC that has historically responded poorly to single-agent PD-L1 therapy – provide the rationale for IMblaze370, Genentech’s ongoing phase 3 pivotal trial of cobimetinib and atezolizumab in unresectable locally advanced or metastatic CRC. This trial is targeting an enrollment of 360 patients with unresectable metastatic colorectal cancer who have received at least two prior regimens of therapy in the metastatic setting. Patients are randomized 2:1:1 to cobimetinib plus atezolizumab, atezolizumab monotherapy, and regorafenib monotherapy. The primary endpoint of IMblaze370 is overall survival. For more information, please visit the trial’s page on ClinicalTrials.gov.

BRAF Wild-Type Melanoma. Results from the metastatic melanoma cohort of the same phase 1b dose escalation trial of cobimetinib and atezolizumab were the subject of a presentation at the Society for Melanoma Research Congress in November 2016. Among 20 non-ocular melanoma patients, the objective response rate (ORR) was 45 percent, with 9 partial responses, including 5 in BRAF wild-type patients. Based on these results, Genentech plans to initiate IMspire170, a phase 3 pivotal trial of cobimetinib plus atezolizumab versus pembrolizumab in patients with previously untreated BRAF wild-type advanced melanoma this year. More information on this trial will be available on ClinicalTrials.gov in 2017.

BRAF V600 mutation-positive advanced melanoma. A separate phase 1b trial is evaluating the triple combination of cobimetinib, vemurafenib and atezolizumab in patients with previously untreated BRAF V600 mutation-positive advanced melanoma. Data from this study were first presented at the European Society of Medical Oncology’s annual Congress in October 2016 and suggested that adding atezolizumab to the combination regimen of cobimetinib and vemurafenib is associated with a manageable safety profile and promising antitumor activity. Based on the results, Genentech has initiated IMspire150 TRILOGY, a pivotal placebo-controlled phase 3 trial of the triple combination in an estimated 500 patients with previously untreated BRAF V600 mutation-positive metastatic melanoma. The primary endpoint of IMspire 150 TRILOGY is progression-free survival. More information on the study is available on ClinicalTrials.gov.

Broad Development Program to Identify Future Clinical Opportunities

In addition to the ongoing IMblaze370 and IMspire150 TRILOGY phase 3 studies, and the IMspire170 pivotal trial planned for 2017, additional areas of focus for cobimetinib’s clinical development include:

  • Metastatic triple-negative breast cancer, including COLET, an ongoing multistage, phase 2 study evaluating the safety and efficacy of cobimetinib in combination with paclitaxel as first-line treatment. This study was recently amended to add cohorts evaluating the combination of cobimetinib, paclitaxel and atezolizumab and cobimetinib, nab-paclitaxel and atezolizumab.
  • A Phase 1/2 study evaluating the safety and activity of cobimetinib in combination with venatoclax in relapsed or refractory AML

For more information on cobimetinib clinical trials, please visit www.clinicaltrials.gov.

Cobimetinib is widely approved for the treatment specific forms of BRAF mutation-positive unresectable or metastatic melanoma, in combination with vemurafenib.  It is also the subject of investigation in combination with other agents in a variety of ongoing clinical trials; its safety and efficacy profile in these trials has not yet been established.