Late breaking data from a Phase III study presented at the 48th Annual Meeting of the American Society of Clinical Oncology (ASCO) shows that the oral investigational drug trametinib (GlaxoSmithKline) delayed tumor growth and extended survival for patients with advanced melanoma who have BRAF mutations, compared with standard chemotherapy. This is the first Phase III trial evaluating a melanoma treatment that inhibits a protein known as MEK ? part of the MAP kinase signaling pathway, of which BRAF is also a component.

“This is the first in a new class of targeted drugs that could benefit patients with melanoma who have BRAF mutations. The findings show that targeting the MEK molecular pathway is a viable strategy for treating many people with the disease,” said Caroline Robert, MD, PhD, Head of Dermatology at the Institute Gustave Roussyin Paris, France. “Trametinib is likely to become another first-line treatment option for patients with advanced melanoma.”

Only one targeted therapy, vemurafenib (Zelboraf?, Genentech), is currently approved for advanced melanoma. Vemurafenib targets a protein produced by a mutation in the BRAF gene that fuels melanoma growth, and is present in roughly half of patients with melanoma. MEK lies downstream from BRAF in the same signaling pathway. Since most patients taking vemurafenib eventually develop resistance to the drug and many experience serious side effects, MEK inhibitors could help address a continuing need for new therapies in these patients.

Trial design
In this study, known as METRIC, patients with advanced BRAF-mutated melanoma who had received up to one prior chemotherapy regimen were randomly assigned to receive trametinib (214 patients) or standard chemotherapy (108 patients; either dacarbazine or paclitaxel). Overall, 22% of patients who received trametinib responded to treatment, compared with 8% of those who received chemotherapy.

Survival advantage
Median progression-free survival was significantly greater in the trametinib group (4.8 months) than the chemotherapy group (1.5 months) ? a 55% reduction in the risk of progression. Interim overall survival was also longer among the patients treated with trametinib, with a 46% reduced risk of death; 81% of patients in the trametinib group were alive after six months of follow-up, versus 67% in the chemotherapy group. Approximately half (47%) of patients whose disease progressed while on chemotherapy were permitted to take trametinib, so the overall survival advantage may ultimately prove to be greater if this “crossover effect” is taken into account, according to the researchers.

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Side effects of trametinib were generally manageable. Severe adverse events included skin rash (7% of patients), eye problems (less than 1%), high blood pressure (12%) and reduced heart function (7%).

?The results from this clinical study of trametinib represent important progress towards understanding how these investigational agents could benefit patients with advanced and metastatic melanoma. Importantly, trametinib is the first MEK inhibitor to demonstrate clinical benefit in a late phase melanoma trial.? said Rafael Amado, MD,Head of Oncology R&D for GlaxoSmithKline. ?We are planning regulatory submissions for dabrafenib and trametinib as single agent therapies and have recently started a Phase III programme to further investigate the effect of the combination in this disease.?

Cancer?s genetic weak spots
?This study demonstrate that we are solidly in the era of precision medicine, in which patients benefit from a growing understanding of cancer?s genetic weak spots,? said Sylvia Adams, MD, Assistant Professor in the Department of Medicine at New York University Langone Medical Center. ?This is one of the findings, presented at ASCO, that promises to expand the range of effective, targeted treatments for people with cancer. These findings also affirm that patients in all settings, from research hospitals to smaller community institutions, can expect to benefit in the years ahead.?

Presentation: Monday, June 4, 2012, 3:15 ? 3:30 PM CDT
Abstract: #LBA8509
Title: METRIC Phase 3 Study: Efficacy of Trametinib (T), a potent and selective MEK inhibitor (MEKi), in progression-free survival (PFS) and overall survival (OS), compared with chemotherapy (C) in patients (pts) with BRAFV600E/K mutant advanced or metastatic melanoma (MM)
Authors: Robert C, Flaherty, KT, Hersey P, Nathan PD, Garbe C, Milhem MM, et al.

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