A Phase I trial showed that a combination of two oral targeted therapies – the oral MEK inhibitor GSK212 and the oral BRAF inhibitor GSK436 – was safe and had preliminary anti-tumour activity in patients with advanced melanoma.

The trial results are potentially important because they show promising synergistic anti-cancer activity for two oral targeted therapies for advanced melanoma, a difficult cancer to treat.

"With new therapies that target mutations in melanoma, we can now potentially select the right patients to receive them," said Jeffrey Infante, MD, director of drug development at the Sarah Cannon Research Institute in Nashville, Tennessee. "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."

The study is being conducted in three parts. In parts one and two of the Phase I portion of the study, 45 patients – including 43 with advanced melanoma – received one or more low doses of the drug combination. In part one, investigators found no significant drug-drug interactions in seven patients evaluated.

In part two, patients received slowly increasing amounts to measure tolerability and activity. Of 16 evaluable patients, 13 had partial responses, and three had stable disease, for an overall response rate of 81 percent. The authors found that the drugs combine safely and have fewer skin toxicities such as cutaneous squamous cell carcinoma and rashes than each drug alone.

In the study's third part – a 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 the BRAF inhibitor GSK436 at maximum dose plus the maximum dose of the MEK inhibitor GSK212. In the second arm, patients receive the highest possible dose of GSK436 and a slightly lower GSK212 dose, while in the third arm, patients receive GSK436 alone at the highest dose.

Both GSK436 and GSK212 have shown activity as single agents in patients with melanoma with BRAF V600 gene mutations, which are found in about half of all melanomas. In addition, the combination has shown effectiveness in laboratory models with BRAF-mutant cancer cells as compared to either drug alone. The combination has also suppressed resistance to GSK346 alone, and prevented proliferative skin lesions caused by BRAF inhibitor exposure in animal studies.



Source: ASCO

Reference: ASCO 2011 Abstract: CRA8503 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. R. Infante, G. S. Falchook, D. P. Lawrence, J. S. Weber, R. F. Kefford, J. C. Bendell, R. Kurzrock, G. Shapiro, R. R. Kudchadkar, G. V. Long, H. A. Burris III, K. B. Kim, A. Clements, S. Peng, B. Yi, A. J. Allred, D. Ouellet, K. Patel, P. F. Lebowitz, K. T. Flaherty.