Experimental Melanoma Agent Shows Survival Benefit in Phase 3 Trial

Roxanne Nelson

January 21, 2011

January 21, 2011 — The experimental agent RG7204 (also known as PLX4032; Plexxicon/Roche) statistically significantly extends survival in patients with metastatic melanoma, according to the results of a phase 3 trial.

Interim data released from the BRIM3 trial demonstrated that patients treated with RG7204 had significantly longer overall and progression-free survival times, compared with patients treated with carbazine.

On the basis of these interim analyses, patients in the control group now have the option of crossing over to the RG7204 group. In addition, the expanded-access program for the agent will be open to previously untreated melanoma patients with the BRAF mutation.

The agent is being codeveloped by Roche Worldwide and Plexxikon Corporation, and at the beginning of this year, Plexxikon announced collaboration with Genentech to copromote the drug in the United States.

RG7204 is an oral small-molecule drug that selectively inhibits a mutated form of the BRAF protein. Mutations in residue 600 of the BRAF protein are found in about 50% of melanoma cases, according to Roche. It is estimated that approximately 8% of all solid tumors contain BRAF V600 mutations.

"For the first time, a personalized investigational medicine, RG7204, has shown a significant survival benefit in metastatic melanoma," said Hal Barron, MD, chief medical officer and head of Global Product Development at Roche, 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."

"A Major Breakthrough"

The results of a phase 1 trial presented last year drew praise and enthusiasm from the oncology community. In a phase 1 dose-escalation study, 81% of patients whose melanomas had an activating mutation in BRAF responded to the treatment (N Engl J Med. 2010;363:809-819). This represents "a major breakthrough," according to the authors of an editorial that accompanied the published study (N Engl J Med. 2010;363:876-879).

The results of an open-label phase 2 trial seemingly confirmed these early data. As reported by Medscape Medical News, of the 132 patients with advanced melanoma positive for the BRAF mutation, 82% experienced a response (52%) or stable disease (30%), and 52% experienced a decrease in their tumor size of 30% or more.

In the phase 2 trial, median progression-free survival was 6.2 months, which was much higher than the 2 months historically seen in this patient population. Overall survival is usually in the range of 6 to 9 months, but median overall survival had not yet been reached when the results were presented at the 7th International Melanoma Research Congress of the Society for Melanoma Research in Sydney, Australia in November 2010.

At that time, Antoni Ribas, MD, from the Jonsson Comprehensive Cancer Center at the University of California in Los Angeles, who was involved in both the phase 1 and phase 2 clinical trials, told Medscape Medical News that the responses were not durable. However, he speculated that response to RG7204 might lead to an improvement in survival by shifting the first part of the survival curve over by a few months.

No Data Yet

Now it appears that a survival benefit has been achieved, according to the manufacturer. However, the full study results have not yet been published and no actual data have been disclosed at this time. Instead, Roche says that the full data will be presented at a "medical meeting later this year."

Plexxikon notes that that the study "met the prespecified criteria for the coprimary end points of overall survival and progression-free survival."

BRIM3, a randomized open-label phase 3 trial that was conducted at more than 100 sites worldwide, was initiated in December 2009. The study enrolled 675 patients whose mutation status was determined with the cobas 4800 BRAF V600 Mutation Test (Roche Molecular Diagnostics), a companion diagnostic assay being codeveloped with RG7204.

Patients were randomized to receive either 960 mg of oral RG7204 twice daily or 1000 mg/m2 of intravenous dacarbazine every 3 weeks. The protocol continued until disease progression or unacceptable toxicity.

The safety profile was generally consistent with that seen in earlier trials. The most frequently observed grade 3 adverse events were skin related and included cutaneous squamous cell carcinoma. Other common adverse events were rash, photosensitivity, joint pain, hair loss, and fatigue.

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