ArticlesDabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial
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,
References (15)
- et al.
New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1)
Eur J Cancer
(2009) - et al.
Dabrafenib in patients with melanoma, untreated brain metastases, and other solid tumors: a phase 1 dose-escalation trial
Lancet
(2012) - et al.
Cancer statistics, 2012
CA Cancer J Clin
(2012) - et al.
GLOBOCAN 2008 v1.2, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 10
(2010) - et al.
Mutations of the BRAF gene in human cancer
Nature
(2002) - et al.
Distinct sets of genetic alterations in melanoma
N Engl J Med
(2005) - et al.
NRAS mutation status is an independent prognostic factor in metastatic melanoma
Cancer
(2011)
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