Cobimetinib (formerly GDC-0973/XL518) is a potent highly selective inhibitor of MEK also known as activated mitogen protein kinase.

Cobimetinib (formerly GDC-0973/XL518) is a potent highly selective inhibitor of MEK also known as activated mitogen protein kinase. mEK is a serine/threonine kinase that is a component of the RAS/RAF/MEK/ERK pathway. This pathway mediates the flow of growth factor receptor signaling and is predominantly activated in a wide variety of cancers.

Cobimetinib is a drug that acts as an inhibitor of MEK, a protein involved in the MAP kinase signaling pathway. The MAP kinase pathway is an important cellular regulatory pathway involved in cell growth, differentiation and survival. Cobimetinib was developed for the treatment of specific forms of cancer, in particular for advanced or metastatic melanoma with the BRAF V600 mutation.

When the BRAF gene undergoes the V600E or V600K mutation, the BRAF protein becomes overactive, leading to uncontrolled proliferation of cancer cells. Cobimetinib works by inhibiting the MEK protein, which is located just downstream of BRAF in the signaling pathway. This MEK inhibitor prevents cancer cells from continuing to proliferate and divide uncontrollably, helping to slow the growth of the tumor and improving the patient’s prospects for survival.

Cobimetinib is administered in combination with other drugs, such as the BRAF inhibitor vemurafenib, to optimize therapeutic effects in the treatment of melanoma with a BRAF V600 mutation. Cobimetinib combination therapy demonstrated better outcomes than vemurafenib monotherapy, increasing overall survival and disease control.

As with many chemotherapy drugs, cobimetinib can cause side effects, including fatigue, skin rash, nausea, diarrhea, and gastrointestinal reactions. However, cobimetinib combination therapy continues to represent an important therapeutic option for patients with advanced melanoma with the BRAF V600 mutation, helping to improve the quality of life and survival prospects for this specific subpopulation of cancer patients.

In preclinical studies, oral doses of cobimetinib resulted in a potent and substantial reduction of MEK in RAS or BRAF mutant tumours. Cobimetinib was developed by iRoche and Genentech under a collaborative agreement with Exelixis.

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 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 co-development agreement to provide up to 25% of the total sales force in the United States, should cobimetinib be approved.

Metastatic Melanoma: In July 2014, 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. coBRIM met its primary endpoint, delivering a statistically significant increase in progression-free survival for the combination as compared to vemurafenib alone. Based on the results from coBRIM, Genentech announced plans to initiate regulatory filings before the end of 2014.

Additional Trials Involving Cobimetinib
Additional phase 1 trials are ongoing assessing the ability to combine cobimetinib 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