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06-06-2011 | Genetics | Article

Vemurafenib effective against melanoma with BRAF V600E mutation

Abstract

Free abstract

MedWire News: Results from a phase III trial show that vemurafenib is significantly more effective than dacarbazine for improving survival and reducing progression of metastatic melanoma with the BRAF V600E mutation.

Around half of all cutaneous melanomas carry mutations in the BRAF gene and the majority (90%) of these result from a glutamic acid to valine substitution at codon 600 (V600E) of BRAF.

The BRAF kinase inhibitor vemurafenib is a strong inhibitor of BRAF with the V600E mutation, and has been shown to have strong antitumor effects against this strain of melanoma in phase I and II trials.

In this study, Paul Chapman (Memorial Sloan-Kettering Cancer Center, New York, USA) and colleagues compared treatment with oral vemurafenib (n=337; 960 mg, twice daily) to treatment with intravenous dacarbazine (n=338; 1000 mg/m2 body surface area every 3 weeks) in patients with previously untreated BRAF V600E metastatic melanoma.

The 675 patients were randomly assigned to receive one of the two treatments and were followed-up for overall and progression-free survival (primary endpoints), as well as response rate and duration and tolerability (secondary endpoints).

Writing in the NEJM, the team reports that overall survival at 6 months was significantly higher in the vemurafenib compared with the dacarbazine group, at 84% versus 64%.

The researchers calculated that patients given vemurafenib had a significant 63% relative reduction in the risk for death and a significant 74% reduction in the relative risk for death or disease progression compared with those treated with dacarbazine.

The percentage of patients who had some improvement (response) with vemurafenib was also significantly higher than with dacarbazine, at 48% and 5%, respectively.

The most common adverse events seen in patients treated with vemurafenib were cutaneous events, arthralgia, and fatigue, and the most common with dacarbazine were fatigue, nausea, vomiting, and neutropenia.

Adverse events that required dose modification or interruption were seen in 38% of the vemurafenib group versus 16% of the dacarbazine group.

Dacarbazine is currently the only drug approved in the USA for treatment of metastatic melanoma, but generally has a low patient response rate (7-12%). It is also associated with an overall survival rate of less than 1 year after initiating treatment.

Although vemuramab cannot be given to all metastatic melanoma patients, in the subset with the BRAF V600E strain it has the potential to be significantly more effective than dacarbazine.

Editorialist Marc Ernstoff, from Dartmouth Medical School in Lebanon, New Hampshire, USA, commented: "The new understanding of molecular pathways changes the way we classify melanomas and influences therapy. The development of vemurafenib is an example of the translation of these concepts into clinical practice."

He explained: "For patients with metastatic melanoma with the BRAF V600E mutation, the availability of vemurafenib is a major defining moment that will have an important effect on survival and quality of life.

"Vemurafenib will be part of our therapeutic armamentarium for patients with melanoma and potentially for those with other cancers harboring BRAF V600E mutations, as well as a valuable tool for exploring new approaches to melanoma treatment."

MedWire (www.medwire-news.md) is an independent clinical news service provided by Springer Healthcare Limited. © Springer Healthcare Ltd; 2011

By Helen Albert

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