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Plexxikon, Roche File Rx/Dx Application for PLX4032, Cobas Mutation Test in Metastatic Melanoma

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Originally published May 16.

Plexxikon has submitted applications to the US Food and Drug Administration and the European Medical Agency for the regulatory approval of its pharmacogenomically guided melanoma drug PLX4032, the company announced this week.

Plexxikon is seeking marketing approval for PLX4032, or vemurafenib, for the treatment of metastatic melanoma in patients harboring the BRAF V600 mutation. Since identifying best responders for the drug will require a companion genetic test, Roche Molecular Diagnostics has simultaneously submitted a premarket approval application to the FDA for its Cobas 4800 BRAF V600 Mutation Test and is also planning to register the test in Europe.

PLX4032 is an oral kinase inhibitor that was initially discovered by Plexxikon in 2005. The Daiichi Sankyo subsidiary is co-developing the drug with Genentech under a 2006 license and collaboration agreement with Genentech parent company Roche.

According to Plexxikon, approximately half of all melanoma patients and eight percent of patients with solid tumor cancers have the BRAF V600 mutation. If the drug is approved by the FDA, the labeling for PLX4032 will likely recommend that only patients with BRAF mutations should receive the treatment, since early studies have shown that this subset of patients will likely have better outcomes than those without this mutations.

Regulatory submissions for the drug and the test are based on results from Phase II and Phase III trials, called BRIM2 and BRIM3, respectively. The studies evaluated PLX4032 in patients with BRAF V600 mutation-positive melanoma; mutation status was determined in clinical trials by the Cobas 4800 BRAF V600 Mutation Test (PGx Reporter 01/19/2011).

In the BRIM2 study, which was a 100-patient, single-arm study in previously treated melanoma patients, researchers reported a 52 percent response rate and tumor shrinkage in the majority of patients receiving the drug.

The BRIM3 study, which began in early 2010 and is scheduled to run through 2014, is a randomized, multicenter, Phase III study evaluating PLX4032 compared to the standard of care, dacarbazine, in nearly 700 patients with previously untreated, BRAF V600 mutation-positive metastatic melanoma. According to interim results reported earlier this year, participants who received RG7204 showed better overall survival and progression-free survival compared to participants who received dacarbazine.

The most frequent Grade 3 adverse event observed in clinical trials of PLX4032 was cutaneous squamous cell carcinoma, a common skin cancer treated by local excision. Other common adverse events seen in trials were rash, increased sun sensitivity, joint pain, hair loss, and fatigue. Possible serious side effects of PLX4032 include liver issues, abnormal heartbeats, and allergic reactions.

Updated BRIM2 data and comprehensive BRIM3 data will be presented at a plenary session at the annual meeting of the American Society of Clinical Oncology in June. The Rx/Dx development partners plan to continue to study the drug in combination with other treatments and in other cancer indications.

In addition to their co-development agreement, Plexxikon 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 PLX4032 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.

While the drug is undergoing regulatory approval, Genentech and Plexxikon are making PLX4032 available to patients with BRAF V600 mutation-positive melanoma through a global patient access program.

Approximately 70,000 people in the US and 160,000 people worldwide are diagnosed with melanoma annually. The American Cancer Society estimates that the five-year survival rate for people with Stage IV melanoma is 15 percent.

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