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Genentech Says PGx-Guided Melanoma Drug Meets Primary Endpoints in Phase III Trial

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Genentech said this week that BRIM3, a Phase III clinical trial of a targeted melanoma treatment, has met its co-primary endpoints, showing a "significant" survival benefit in patients with previously untreated metastatic melanoma who are positive for the BRAF V600E mutation.

The drug, RG7204, is an oral kinase inhibitor that targets the oncogenic BRAF V600E mutation. It was initially discovered by Plexxikon, which is co-developing the drug with Genentech under a 2006 license and collaboration agreement with Genentech parent Roche. RG7204 is being co-developed with an investigational diagnostic test, the PCR-based Cobas 4800 BRAF V600 Mutation Test from Roche Molecular Diagnostics, to identify patients whose tumors carry the mutated BRAF V600 gene (PGx Reporter 9/1/2010).

Mutations in residue 600 of the BRAF protein are found in about half of all melanomas and it is estimated that approximately eight percent of all solid tumors contain BRAF V600 mutations.

The BRIM3 study, which began in early 2010 and is scheduled to run through 2014, is a randomized, multicenter, Phase III study evaluating RG7204 compared to the standard of care, dacarbazine, in patients with previously untreated, BRAF V600 mutation-positive metastatic melanoma. Mutation status of the 675 enrolled patients is being determined by the Cobas companion diagnostic assay.

Study participants were randomized to receive either 960 mg of RG7204 orally twice daily or 1,000 mg/m2 of dacarbazine intravenously every three weeks. Patients continued dosing until their disease progressed or there was unacceptable toxicity.

Participants who received RG7204 showed better overall survival and progression-free survival compared to participants who received dacarbazine, Genentech said. The interim Phase III results follow positive data that Plexxikon released last November from a Phase II trial of previously treated metastatic melanoma patients that showed a 52 percent response rate and tumor shrinkage in the majority of patients.

"For the first time, a personalized investigational medicine, RG7204, has shown a significant survival benefit in metastatic melanoma," said Hal Barron, chief medical officer and head of global product development at Genentech, in a statement. "This is an important advance for people with the BRAF V600 mutation-positive form of the disease who have had extremely limited treatment options."

Based on the interim results, patients on the control arm of the study will now have the option to cross over to receive RG7204, Genentech said.

The most common adverse events were rash, photosensitivity, joint pain, hair loss, and fatigue. The most frequent Grade 3 adverse events were skin related, and included cutaneous squamous cell carcinoma, a common skin cancer treated by local excision. Additionally, "generally mild and reversible" increases in liver enzymes were observed in some patients, Genentech said.

Genentech said it expects to present full data from the study at a medical meeting later this year.

The company said it is also working with global health authorities to expand the RG7204 Patient Access Program to include people with previously untreated, BRAF V600 mutation-positive metastatic melanoma.

In addition to their co-development agreement, Plexxicon and Genentech signed an additional agreement earlier this year covering co-promotion of the drug.

Under the agreement, Plexxikon will provide a sales force to co-promote RG7204 in the US and will reimburse Genentech for certain marketing and promotion costs. In exchange, Plexxikon said it will be entitled to "enhanced royalties" on product sales.

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