Elsevier

The Lancet

Volume 380, Issue 9839, 28 July–3 August 2012, Pages 358-365
The Lancet

Articles
Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial

https://doi.org/10.1016/S0140-6736(12)60868-XGet rights and content

Summary

Background

Dabrafenib, an inhibitor of mutated BRAF, has clinical activity with a manageable safety profile in studies of phase 1 and 2 in patients with BRAFV600-mutated metastatic melanoma. We studied the efficacy of dabrafenib in patients with BRAFV600E-mutated metastatic melanoma.

Methods

We enrolled patients in this open-label phase 3 trial between Dec 23, 2010, and Sept 1, 2011. This report is based on a data cutoff date of Dec 19, 2011. Patients aged 18 years or older with previously untreated, stage IV or unresectable stage III BRAFV600E mutation-positive melanoma were randomly assigned (3:1) to receive dabrafenib (150 mg twice daily, orally) or dacarbazine (1000 mg/m2 intravenously every 3 weeks). Patients were stratified according to American Joint Committee on Cancer stage (unresectable III+IVM1a+IVM1b vs IVM1c). The primary endpoint was investigator-assessed progression-free survival and was analysed by intention to treat; safety was assessed per protocol. This study is registered with ClinicalTrials.gov, number NCT01227889.

Findings

Of the 733 patients screened, 250 were randomly assigned to receive either dabrafenib (187 patients) or dacarbazine (63 patients). Median progression-free survival was 5·1 months for dabrafenib and 2·7 months for dacarbazine, with a hazard ratio (HR) of 0·30 (95% CI 0·18–0·51; p<0·0001). At data cutoff, 107 (57%) patients in the dabrafenib group and 14 (22%) in the dacarbazine group remained on randomised treatment. Treatment-related adverse events (grade 2 or higher) occurred in 100 (53%) of the 187 patients who received dabrafenib and in 26 (44%) of the 59 patients who received dacarbazine. The most common adverse events with dabrafenib were skin-related toxic effects, fever, fatigue, arthralgia, and headache. The most common adverse events with dacarbazine were nausea, vomiting, neutropenia, fatigue, and asthenia. Grade 3–4 adverse events were uncommon in both groups.

Interpretation

Dabrafenib significantly improved progression-free survival compared with dacarbazine.

Funding

GlaxoSmithKline.

Introduction

In 2008, about 46 000 people died from melanoma in the world.1, 2 When we initiated this clinical trial, standard therapy for metastatic melanoma was either chemotherapy (ie, dacarbazine) or high-dose interleukin 2 (in USA). About 50% of melanomas have an activating mutation in the BRAF gene.3, 4, 5 80–90% of BRAF-mutated melanomas have a V600E mutation and 10–20% have a V600K mutation. Other V600 mutations are rare.5 Melanomas with BRAF mutations seem to be dependent on mutated BRAF, which is constitutively active and drives cell proliferation in many cases of melanoma. In vitro and preclinical data show that inhibitors of mutated BRAF induce clear antiproliferative effects in BRAFV600E-mutated melanomas, but not in melanomas with wild-type BRAF. Substantial clinical effects were noted in patients with BRAF-mutated melanoma treated with vemurafenib, the first BRAF inhibitor brought to the clinic. Vemurafenib induced objective responses in 48% of patients and was associated with improvement in overall survival and progression-free survival.6 Since completion of accrual to the trial we report here, vemurafenib was approved by the US Food and Drug Administration and the European Medicines Agency.

Dabrafenib is a reversible, ATP-competitive inhibitor that selectively inhibits BRAFV600E kinase with a concentration required for 50% inhibition of the kinase activity (IC50) five times lower than the IC50 for wild-type BRAF or CRAF.7 Preclinical data show that dabrafenib inhibits the MAPK pathway in BRAFV600E-mutated melanoma cells leading to decreased proliferation and regression in xenograft mouse models. In a phase 2 trial,8 dabrafenib showed a confirmed response rate (complete response+partial respone) of 59%. To assess whether dabrafenib was better than standard dacarbazine chemotherapy, we did a phase 3, multicentre, randomised trial in previously untreated melanoma patients whose tumours harboured a BRAFV600E mutation.

Section snippets

Study design and patients

We enrolled patients from 70 sites (hospitals, outpatient clinics, academic institutions) in 12 countries. Patients with histologically confirmed, measurable metastatic melanoma (stage IV or unresectable stage III) shown to have a BRAFV600E mutation by central testing using an investigational-use-only assay, were eligible for the study.

No previous antitumour therapy for unresectable or metastatic melanoma was allowed other than interleukin 2. Other eligibility criteria included age of 18 years

Results

Between Dec 23, 2010, and Sept 1, 2011, patients were screened at 70 institutions. The most common reason for screening failure was absence of BRAFV600E mutation or failure to meet other eligibility requirements (figure 1). Of the 733 patients screened, 250 patients were randomly assigned to receive dabrafenib (187 patients) or dacarbazine (63 patients; figure 1, table 1). Treatment groups were well balanced for age, sex, race and disease status (table 1). As of Dec 19, 2011, the date of the

Discussion

These results show that most patients have a substantial response to dabrafenib and an improvement in progression-free survival compared with dacarbazine. Overall, 733 patients were screened to determine BRAF mutation status. Of those, 362 patients were found to have a BRAFV600E mutation; 112 of these patients did not meet other entry criteria. The reasons why these patients did not meet eligibility criteria were failing to meet the biochemical criteria, presence of baseline brain metastases,

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