ASCO 2012 Report – Combination targeted therapy shows efficacy and fewer toxicities in advanced melanoma treatment

by Bruce Sylvester – Results from an expanded Phase IB trial presented at ASCO suggest that combination therapy with two investigational and targeted drugs, BRAF inhibitor dabrafenib and MEK inhibitor trametinib, impedes cancer progression  and does so with fewer skin-related side effects than the current standard single-agent BRAF-targeted therapy, vemurafenib (Zelboraf).

The investigators enrolled subjects with advanced melanoma, a V600 BRAF mutation and no prior BRAF-targeted treatment.

As background, the investigators noted that about half of all melanomas harbor a V600E mutation in the BRAF gene, and in those patients, the nearby MEK pathway is also highly active. And even though the approval of vemurafenib in 2011 was a major advance major clinical advance, most patients eventually develop resistance to the drug.

“It’s fascinating to find such promising effects with this combination regimen. Not only are the two drugs causing shrinkage of the cancer, but we’re seeing that a second anti-cancer therapy may actually suppress the side effects of the first,” said Jeffrey Weber, MD, PhD, a senior member at H. Lee Moffitt Cancer Center and director of the Donald A. Adam Comprehensive Melanoma Research Center, Tampa, Florida, USA.

The overall trial included 125 subjects who were treated with various doses of dabrafenib and trametinib. The current analysis focused on a sub-group of 77 patients who received no prior BRAF-targeted therapy (other prior therapies, such as chemotherapy, were permitted), and thus had no prior resistance to BRAF-targeted therapy.

For the 77 patients, median progression-free survival was 7.4 months, a period like that observed in past single-agent vemurafenib studies. Survival data will be forthcoming later this year.

Skin lesions happen in up to one-quarter of vemurafenib-treated patients. The investigators reported that these toxicities were much less common in this trial, with only 2 percent of the 125 patients in the overall trial developing squamous cell carcinomas and another 2 percent developing actinic keratoses.

Other side effects of the dual therapy included fever, fatigue and dehydration. All were manageable.

The investigators concluded, “The combination of dabrafenib/trametinib has an acceptable safety profile, with a lower incidence of MEKi-related rash and BRAFi-induced hyperproliferative skin lesions compared with the single agents. The clinical activity of dabrafenib/trametinib observed in pts with V600 BRAF mutant metastatic melanoma is encouraging and will be investigated further in a phase III trial.”

 

The study was funded by GlaxoSmithKline.