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Ref Type Journal Article
PMID (22735384)
Authors Hauschild A, Grob JJ, Demidov LV, Jouary T, Gutzmer R, Millward M, Rutkowski P, Blank CU, Miller WH, Kaempgen E, Martín-Algarra S, Karaszewska B, Mauch C, Chiarion-Sileni V, Martin AM, Swann S, Haney P, Mirakhur B, Guckert ME, Goodman V, Chapman PB
Title Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial.
Journal Lancet (London, England)
Vol 380
Issue 9839
Date 2012 Jul 28
URL
Abstract Text Dabrafenib, an inhibitor of mutated BRAF, has clinical activity with a manageable safety profile in studies of phase 1 and 2 in patients with BRAF(V600)-mutated metastatic melanoma. We studied the efficacy of dabrafenib in patients with BRAF(V600E)-mutated metastatic melanoma.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 BRAF(V600E) mutation-positive melanoma were randomly assigned (3:1) to receive dabrafenib (150 mg twice daily, orally) or dacarbazine (1000 mg/m(2) 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.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.Dabrafenib significantly improved progression-free survival compared with dacarbazine.GlaxoSmithKline.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Dabrafenib Dabrafenib 56 14
Drug Name Trade Name Synonyms Drug Classes Drug Description
Dabrafenib Tafinlar GSK2118436 BRAF Inhibitor 20 Tafinlar (dabrafenib) inhibits the activity of BRAF, including V600E, which results in inhibition of tumor cell proliferation (PMID: 22735384). Tafinlar (dabrafenib) is FDA approved for BRAF V600E positive unresectable or metastatic melanoma, and in combination with Mekinist (trametinib) for BRAF V600E/K-mutant melanoma, BRAF V600E-mutant non-small cell lung cancer, and BRAF V600E-mutant anaplastic thyroid cancer (FDA.gov).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
BRAF V600E melanoma sensitive Dabrafenib FDA approved - On Companion Diagnostic Actionable In a Phase III clinical trial (BREAK-3) that supported FDA approval, Tafinlar (dabrafenib) improved median progression-free survival compared to Deticene (dacarbazine) (5.1 vs 2.7 months, HR=0.3, p<0.0001) in patients with BRAF V600E positive melanoma (PMID: 22735384; NCT01227889). detail... detail... 22735384