Targeted therapies and personalized medicine were a focus of the 2012 ASCO Annual Meeting
Trametinib and dabrafenib, two drugs designed specifically to inhibit pathways associated with BRAF
-mutated melanoma, delayed disease progression and showed a trend toward improved survival in patients with advanced melanoma.
The results of two separate studies regarding these targeted therapies were presented on Monday at the American Society of Clinical Oncology (ASCO) annual meeting in Chicago.
The mitogen-activated protein kinase (MAPK) pathway is associated with cellular growth and survival of tumors. Within the MAPK pathway are two genes, BRAF
, that have been associated with disease progression in patients with melanoma. A specific mutation within the BRAF
gene, V600E, is found in nearly 50% of melanoma patients. BRAF
inhibitors represent a promising new class of drugs for melanoma patients, especially after one such drug, vemurafenib (Zelboraf, Genentech/Daiichi-Sankyo), was the first new major treatment option approved by the FDA in several years for advanced melanoma patients, receiving approval in August 2011.
However, patients who have received vemurafenib have been found to have an increased risk of developing a secondary malignancy— squamous cell carcinoma (SCC)—as a result of the treatment. Hence, researchers have been looking toward inhibiting the MEK
gene as a means of preventing such malignancies from developing.
Two studies focused on how drugs designed to target each of these genes have shown improved outcomes in patients with advanced melanoma.
A study presented on Monday showed some of the results from the phase III METRIC trial, which tested the efficacy of trametinib, a MEK
inhibitor, to determine if it was capable of improving progression-free survival (PFS) in advanced or metastatic melanoma patients with the BRAFV600E/K
Caroline Robert, MD, PhD
"Trametinib is a very potent and selective inhibitor of this protein and has already shown efficacy in phase I and phase II trials," said Caroline Robert, MD, PhD, head of dermatology at the Institute Gustave Roussy in Paris, France, and lead author of the study. "Because MEK
is downstream from BRAF
in the MAPK pathway, you have less risk to have another activated event further downstream."
The study enrolled 322 patients with advanced BRAF
-mutated melanoma who had received up to one prior chemotherapy regimen. Those patients were randomized in a 2:1 ratio to receive either trametinib (214 patients) or a standard chemotherapy regimen of dacarbazine or paclitaxel (108 patients).
According to the results presented on Monday, patients in the trametinib group experienced a PFS period of 4.8 months compared with 1.5 months in the chemotherapy group, a 55% reduction in the risk of progression of the disease (hazard ratio[HR] = 0.44; 95% CI, 0.31-0.64, P
< .0001). An interim analysis showed that there was also improvement in overall survival with a 46% reduced risk of death (HR = 0.53; 95% CI, 0.30-0.94; P
= .0181). The overall response rate to trametinib was 22% compared with 8% in the chemotherapy group.
Robert noted that the overall survival data could be affected by the fact that approximately 47% of patients in the chemotherapy group crossed over into the trametinib arm. Normally, crossover would show that the overall survival rates in both arms would be similar, but Robert said that despite this, there is still a difference observed, suggesting that the drug is effective early on in treatment.