Exelixis, Inc, a biopharmaceutical company, announced positive top-line results from coBRIM, the phase 3 pivotal trial evaluating cobimetinib, a specific MEK inhibitor discovered by Exelixis, in combination with vemurafenib in previously untreated patients with unresectable locally advanced or metastatic melanoma harboring the BRAFV600 mutation.

Exelixis’ collaborator Genentech, a member of the Roche Group, informed the company that coBRIM met its primary endpoint, delivering a statistically significant increase in progression-free survival (PFS) for the combination of cobimetinib plus vemurafenib as compared to vemurafenib alone. Adverse events were consistent with those observed in a previous study of the combination. Genentech will present these coBRIM data at an upcoming medical meeting and plans to initiate regulatory filings before year end.

“These positive top-line results from coBRIM represent an important milestone for melanoma patients and their physicians, and are the first of four anticipated phase 3 pivotal trial read-outs for Exelixis-discovered compounds in 2014,” said Michael M. Morrissey, Ph.D., president and chief executive officer of Exelixis. “Despite recent therapeutic innovations, BRAFV600 mutation-positive advanced melanoma can be difficult to treat due to the emergence of resistance. We look forward to the full presentation of the data later this year. If ultimately approved, we will execute on our collaborative US co-promotion effort with Genentech and work alongside our partner to bring this important new therapeutic option to melanoma patients in need.”

In addition to the coBRIM results just announced, Exelixis anticipates delivering on the following key clinical development initiatives before the end of 2014:

Top-line results from pivotal phase 3 studies COMET-1 (overall survival endpoint) and COMET-2 (pain palliation endpoint) of cabozantinib in metastatic castration-resistant prostate cancer; Top-line results from the overall survival analysis of EXAM, the phase 3 pivotal trial of cabozantinib in progressive, metastatic medullary thyroid cancer; and Completing enrollment in METEOR, the phase 3 pivotal trial of cabozantinib in metastatic renal cell cancer.

coBRIM is an international, randomised, double-blind, placebo-controlled phase 3 study evaluating the safety and efficacy of cobimetinib in combination with vemurafenib, compared to vemurafenib alone, in 495 patients with BRAFV600 mutation-positive unresectable locally advanced or metastatic melanoma, previously untreated in the metastatic setting. The primary endpoint for coBRIM is progression-free survival. Secondary endpoints include overall survival, objective response rate, duration of response, and other safety, pharmacokinetic and quality of life measures.

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.

In November 2013, Exelixis exercised its option to co-promote cobimetinib, if approved, in the United States. Exelixis is entitled to an initial equal share of US profits and losses, which will decrease as sales increase, and will share equally in the US marketing and commercialisation costs. Exelixis is eligible to receive royalties on any sales of the product outside the United States.

Cobimetinib is a selective inhibitor that blocks the activity of MEK, a protein kinase that is part of a key pathway (the RAS-RAF-MEK-ERK pathway) that promotes cell division and survival. This pathway is frequently activated in human cancers including melanoma, where mutation of one of its components (BRAF) causes abnormal activation in about 50per cent of tumours. tumours with BRAF mutations may develop resistance and subsequently progress after treatment with a BRAF inhibitor. In preclinical melanoma models, co-treatment with vemurafenib and the MEK inhibitor cobimetinib may delay the emergence of resistant tumours. In addition to the combination with vemurafenib in melanoma, cobimetinib is also being investigated in combination with several investigational medicines, including an immunotherapy, in several tumour types, including non-small cell lung cancer and colorectal cancer.

Melanoma is the less common, but more serious category of skin cancer that starts in the skin’s pigment producing cells known as melanocytes. According to the American Cancer Society, approximately five percent of skin cancer diagnoses are melanoma, but melanoma accounts for a large majority of skin cancer deaths. Cases of melanoma have been increasing for at least 30 years, and in 2014, it is estimated that in the United States, more than 76,100 people will be diagnosed with melanoma and more than 9,700 people will die from the disease. It is thought that approximately half of all melanomas, and eight per cent of solid tumours, contain a mutation of the BRAF protein. BRAF is a key component of the RAS-RAF-MEK-ERK pathway involved in normal cell growth and survival. However, mutations that keep the BRAF protein in an active state may cause excessive signaling in the pathway, leading to uncontrolled cell growth and survival. The BRAFV600 mutation-positive form of melanoma is associated with high-risk characteristics of the disease, including early onset, the absence of chronic skin damage, and decreased survival.

Cabozantinib inhibits the activity of tyrosine kinases including MET, VEGFRs and RET. These receptor tyrosine kinases are involved in both normal cellular function and in pathologic processes such as oncogenesis, metastasis, tumour angiogenesis, and maintenance of the tumour microenvironment. Exelixis markets cabozantinib for the treatment of progressive, metastatic medullary thyroid cancer, and the compound is the subject of a broad clinical development Programme encompassing more than fifty clinical trials conducted either by Exelixis, independent investigators, or through the company’s collaboration with the National Cancer Institute’s Cancer Therapy Evaluation Programme (NCI-CTEP).