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METRIC: Investigational inhibitor improves survival in advanced melanoma
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CHICAGO — Patients with advanced melanoma who have BRAF mutations experienced improved survival after treatment with the oral investigational drug trametinib compared with standard chemotherapy, according to results of the phase 3 METRIC trial.
Trametinib (GlaxoSmithKline), which had shown efficacy in phase 1 and phase 2 trials in patients with BRAF-mutant melanoma, is the first MEK inhibitor to show statistically significant PFS, OS and response rate benefits in patients with BRAF V600E-mutant metastatic melanoma when compared with chemotherapy, researcher Caroline Robert, MD, PhD, said during a press conference.
“This is the first in a new class of targeted drugs that could benefit patients with melanoma who have BRAF mutations,” said Robert, head of dermatology at the Institute Gustave Roussy in Paris. “Trametinib is likely to become another first-line treatment option for patients with advanced melanoma.”
Vemurafenib (Zelboraf, Genentech) is the only FDA-approved targeted therapy for advanced melanoma. Many patients treated with vemurafenib experience serious side effects, and most patients eventually develop resistance to the drug, so MEK inhibitors may help address the need for new therapies in these patients, the researchers said.
Robert and colleagues enrolled 322 patients with BRAF V600E-mutant metastatic melanoma who had received up to one prior chemotherapy regimen. The researchers randomized 214 patients to trametinib 2 mg daily and 108 patients to standard chemotherapy with either dacarbazine or paclitaxel.
Patients were stratified by baseline LDH level and prior chemotherapy. The primary endpoint was PFS. Secondary endpoints were OS, response rate and safety.
Twenty-two percent of patients assigned to trametinib responded to treatment, compared with 8% of patients assigned to chemotherapy (HR=0.44; 95% CI, 0.31-.0.64; P<.0001).
Patients in the trametinib group experienced significantly greater median PFS (4.8 months vs. 1.5 months).
An interim analysis also showed greater OS among patients in trametinib arm. Eighty-one percent of them were alive after 6 months of follow-up, compared with 67% of patients assigned to chemotherapy (HR=0.53; 95% CI, 0.30-0.94; P=.0181). The OS advantage with trametinib may prove to be even greater given that 47% percent of the chemotherapy-treated patients whose disease progressed were allowed to cross over to trametinib treatment, the researchers said.
The side effects associated with trametinib generally were manageable, the researchers said. The most common grade-3/grade-4 adverse events reported by trametinib-treated patients included hypertension (12%); skin rash (7%); and fatigue (4%). There were no reported cases of squamous cell carcinoma, Robert said.
“The findings show that targeting the MEK molecular pathway is a viable strategy for treating many people with the disease,” Robert said.
For more information:
Robert C. Abstract #LBA8509. Presented at: the 2012 American Society of Clinical Oncology Annual Meeting; June 1-5, 2012; Chicago.
Disclosure: The researchers report serving in consultant or advisory roles with, receiving honoraria and research funding from, and holding employment or leadership positions with Amgen, Bristol-Myers Squibb, GlaxoSmithKline, Novartis, Pfizer, Roche and several other pharmaceutical companies.
Perspective
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Kari L. Kendra, MD, PhD
Trametinib targets the same pathway as the BRAF inhibitors but blocks MEK downstream from the BRAF inhibitors. The data presented reaffirm the importance of this pathway in melanoma growth. As we look further into the molecular signatures of melanoma in different patients, many more mutations will be found. I look forward to the day when we can look at a patient’s mutational signature and provide the appropriate targeted therapy/combinations of targeted therapies for that individual. The responses seen with these agents is only the beginning of a changing paradigm in the systemic therapy for patients with cancer.
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