Hitting 2 targets may be better than 1 in advanced melanoma, suggests a preliminary trial of combination therapy with the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib. Combined targeting with these 2 agents achieved tumor regression with a lower incidence of skin side effects compared with published data on standard single-agent BRAF inhibitor therapy with vemurafenib (Zelboraf).
These results are from an expanded phase 1 trial that included 125 patients with advanced melanoma harboring a BRAF mutation; 77 did not have previous BRAFtargeted therapy, and this subset is the population of focus, explained lead author Jeffrey Weber, MD, PhD, senior member at H. Lee Moffitt Cancer Center and director of the Donald A. Adam Comprehensive Melanoma Research Center, Tampa, Florida. Weber reported the results at a pre-ASCO press telecast and also at ASCO 2012 (Abstract 8510).
About half of all melanomas have a V600E mutation in the BRAF gene, and in these patients, the MEK pathway is also activated. Most patients with a BRAF mutation will respond to treatment with vemurafenib, which is now FDA-approved for advanced melanoma, but will eventually become resistant to the drug.
The subgroup of 77 patients who never received BRAF-targeted therapy received 4 different dose levels of the 2 drugs; the dose chosen to go forward with in future studies is dabrafenib 150 mg and trametinib 2 mg.
With the 150-mg/2-mg dose, median progression-free survival (PFS) was 10.8 months, which is “extremely encouraging,” Weber said. Single-agent studies of vemurafenib showed median PFS of 7.4 months, he added.
Looking at a waterfall plot that shows tumor shrinkage, overall about 95% of patients had their disease controlled on the 2 agents, as reflected by stable disease (38%), partial response (PR, 49%), or complete response (CR, 8%). Looking at the group treated with the 150-mg/2-mg dose, CR was 8%, PR was 54%, and stable disease was 38%.
“This waterfall plot shows the best responses I’ve seen in advanced melanoma,” Weber said during the press telecast.
The rates of skin toxicities on combination therapy were much lower than what has been reported with other BRAF inhibitors as single-agent therapy, Weber continued. The rate of squamous cell cancer was 3% compared with 15% to 25% seen with other BRAF-inhibiting agents; the rates of actinic keratosis (5%) and papilloma (2%) were also much lower than with BRAF inhibition alone.
Grade 3 or higher toxicities on the combination therapy were as follows: pyrexia, 52% (23% required dose reductions); chills, 38% (10% required dose reductions); fatigue, 37%; and nausea, 34%.
A phase 3 trial of the combination therapy is now under way. “Look for the results,” Weber told the audience.
Incoming ASCO President Sandra Swain, MD, commented that the hope with dual targeted therapy is that more patients with advanced melanoma will be cured. “This combination reduced skin side effects [compared with vemurafenib],” she noted. Swain is the medical director of the Washington Cancer Institute of the Washington Hospital Center and professor of medicine at Georgetown University in Washington, DC.
“Cancers are smart and can get around 1 pathway that is inhibited. Targeting 2 pathways is a smart approach and a creative strategy for treating cancers,” she stated.