Combined targeted therapy demonstrates anti-tumor activity in advanced melanoma

2011 ASCO Annual Meeting

CHICAGO — Combining a MEK inhibitor and a BRAF inhibitor was safe and resulted in preliminary anti-tumor activity in patients with advanced melanoma, according to data from a phase 1 trial presented here.

“With new therapies that target mutations in melanoma, we can now potentially select the right patients to receive them,” Jeffrey Infante, MD, director of drug development at the Sarah Cannon Research Institute in Nashville, Tennessee, said in a press release. “Individually, BRAF inhibitors are active and have good response rates, but low durability. We’re receiving favorable responses so far and hope that the benefits of the combination will last longer with less resistance and improved tolerability.”

Infante and colleagues are conducting a three-part trial among patients with BRAF V600 mutation-positive solid tumors. Part one was a pharmacokinetic drug-drug interaction study; part two was a dose-escalation study that included continuous daily dosing followed by expansion cohorts; and the final, third part of the study is a randomized phase 2 trial in patients with untreated stage IV melanoma.

One hundred and nine patients were treated with both the BRAF inhibitor GSK436 and the MEK inhibitor GSK212 at escalating doses. Patients received GSK436 at 75 mg twice daily through 150 mg twice daily, and GSK212 at 1 mg per day through 2 mg per day. According to the researchers, there was no clinically significant drug-drug interaction, and patients were able to receive the recommended monotherapy dose of each drug safely. In addition, administering both drugs at their monotherapy dose in combination resulted in fewer toxicities, according to Infante.

“The take-home message is we’re able to give both drugs together at full doses and then, as compared with monotherapy, the combination improved some of the troublesome toxicities. [There was a] lower incidence of skin rash and one event of squamous cell carcinoma,” Infante said during a press conference here today.

Seventy-one patients reached the re-staging scan period, according to Infante, and there have been five complete responses thus far.

“The clinical activity of the BRAF in melanoma is compelling and these are early data. Over 80% of the patients who are still on the study are at different dose levels, and we are still anxiously awaiting the long-term data.”

For more information:

Infante JR. #CRA 8503. Presented at: 2011 ASCO Annual Meeting; Chicago; June 3-7, 2011.

Disclosure: Dr. Infante reported no relevant financial disclosures.

Having rationally designed drugs based on the pathways that are important in different diseases I think this is a very nice example of how two very novel agents could be combined in a rational way and hopefully lead to some better results for patients. I think 10 years ago a lof of the phase 1 trials were just random drugs that had activity and were not rationally designed, so it’s nice to see how double inhibition of a pathway can actually be done in a phase 1-to-2 setting.

- Sonali Smith, MD
Associate Professor of Medicine at the Center for Advanced Medicine,
University of Chicago Medical Center

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