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MEK and BRAF Therapy Combo Promising for Advanced Melanoma

Jonathan S. Batchelor
Published: Sunday, Jun 05, 2011

Jeffrey Infante, MD
Jeffrey Infante, MD
The combination of a duo of oral therapies, the MEK inhibitor GSK212 and the oral BRAF inhibitor GSK436, safely resulted in antitumor activity in patients with advanced melanoma, according to data presented Saturday, June 4th at the American Society of Clinical Oncology conference.

“This is a notoriously difficult disease to treat for those of us who care for patients with metastatic melanoma,” commented Sonali Smith, MD, an associate professor of medicine at the Center for Advanced Medicine at the University of Chicago Medical Center, who moderated the press conference at which the study was presented. “It is radioresistant, it is chemoresistant and, in general, this is a disease that does not fare very well.”

The study, conducted by Jeffrey Infante, MD, director of drug development at the Sarah Cannon Research Institute in Nashville, Tennessee, and colleagues, is being conducted in three parts among 109 patients with BRAF V600 mutation-positive melanoma. Part one consisted of a pharmacokinetic drug–drug interaction study. Part two was a dose-escalation study and part three is a randomized phase II trial of patients with untreated stage IV melanoma.

“The first goal of combination is to get synergy,” noted Infante. “There's also preclinical data that it can prevent or overcome potential monotherapy resistance. The third thing, preclinically, is that it can potentially decrease the incidence of BRAF-induced hyper-proliferative skin lesions.”

Patients were treated with both the BRAF inhibitor GSK436 and the MEK inhibitor GSK212 at escalating doses in part two of the study. 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 in a 4-step process.

He reported that the researchers found that the drugs combine safely and have fewer skin toxicities, such as cutaneous squamous cell carcinoma and rashes, than each drug alone. “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,” commented Infante.

In the randomized Phase II trial approximately 50 patients, each with stage IV metastatic melanoma who had no previous chemotherapy, are currently being assigned to one of three treatment arms. In one arm, patients receive GSK436 at 150 mg twice daily as well as 2 mg per day of  GSK212. In the second arm, they receive 150 mg twice daily of GSK436 and a slightly lower GSK212 dose, while in the third arm, patients receive 150 mg twice daily of GSK436.

“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,” noted Smith. “I think 10 years ago a lot of the phase I 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 I-to-II setting.”


Infante JR, Falchook GS, Lawrence DP, et. al. Phase I/II study to assess safety, pharmacokinetics, and efficacy of the oral MEK 1/2 inhibitor GSK1120212 (GSK212) dosed in combination with the oral BRAF inhibitor GSK2118436 (GSK436). J Clin Oncol 29: 2011 (suppl; abstr CRA8503).



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