Roche and Exelixis said today they will submit regulatory filings before year’s end for a combination therapy of Cobimetinib—an MEK inhibitor being co-developed by the companies—and Roche’s Zelboraf (vemurafenib), based on positive Phase III results being trumpeted today by the companies.

Exelixis and Roche said the combination met its primary endpoint—a statistically significant increase in progression-free survival (PFS) compared to Zelboraf alone—in the coBRIM Phase III trial. The companies did not quantify the PFS improvement, with Roche saying it plans to present detailed data from coBRIM “at an upcoming medical meeting,” and Exelixis saying that regulatory filings seeking approval of the combination would be submitted before year end.

The pivotal trial assessed Cobimetinib plus Zelboraf in 495 patients with BRAFV600 mutation-positive unresectable locally advanced or metastatic melanoma, who were previously untreated for advanced disease. While PFS was primary endpoint, coBRIM had several secondary endpoints that included overall survival, objective response rate, duration of response, and other safety, pharmacokinetic and quality of life measures. Adverse events were consistent with those observed in a previous study of the combination, the companies said.

The positive results were widely expected, and lend credence to the view that cobimetinib could generate an estimated $150 million in peak annual sales—based on a 50-50 market split with another combination therapy for melanoma, GlaxoSmithKline (GSK)’s MEK-BRAF inhibitor combination of trapetinib and dabrafenib, Leerink Partners analysts Michael Schmidt, Ph.D., and Jonathan Chang, Ph.D., said in a note to investors.

The analysts noted, however, that GSK is already competing with Roche's vemurafenib on price, and that at least four MEK inhibitors are currently in development for melanoma. “In addition, an ongoing paradigm shift to broader utilization of immunotherapy upfront will decrease the addressable patient population for MEK and BRAF inhibitors longer term, in our view,” Drs. Schmidt and Chang added.

Cobimetinib is a selective inhibitor that blocks MEK, a protein kinase that is part of a key pathway that promotes cell division and survival, known as the RAS-RAF-MEK-ERK pathway. The pathway is frequently activated in human cancers including melanoma, where mutation of one of its components, BRAF, causes abnormal activation in about half of tumors.

In preclinical melanoma models, co-treatment with vemurafenib and cobimetinib appeared to delay the emergence of resistant tumors. According to Exelixis, Cobimetinib is also being studied in combination with several investigational medicines, including an immunotherapy, in several tumor types, including non-small cell lung cancer and colorectal cancer.

“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 III pivotal trial read-outs for Exelixis-discovered compounds in 2014,” Michael M. Morrissey, Ph.D., Exelixis’ president and CEO, said in a statement.

The other readouts include top-line results from two pivotal phase III studies of cabozantinib in metastatic castration-resistant prostate cancer, known as COMET-1 (overall survival endpoint) and COMET-2 (pain palliation endpoint); and top-line results from the overall survival analysis of EXAM, a phase III pivotal trial of cabozantinib in progressive, metastatic medullary thyroid cancer.

Exelixis discovered cobimetinib, then in 2006 agreed to co-develop the compound with Genentech in return for receiving upfront and milestone payments from Genentech. Exelixis oversaw development of cobimetinib through the end of phase I, at which point Genentech exercised its option to further develop the compound.

In November, Exelixis exercised its option to co-promote cobimetinib, if approved, in the U.S. 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 U.S.