Phase III, randomized, open-label, multicenter trial (BREAK-3) comparing the BRAF kinase inhibitor dabrafenib (GSK2118436) with dacarbazine (DTIC) in patients with BRAFV600E-mutated melanoma.

Melanoma/Skin Cancers
Session Type and Session Title: 
Oral Abstract Session, Melanoma/Skin Cancers
Abstract Number: 


J Clin Oncol 30, 2012 (suppl; abstr LBA8500^)
Axel Hauschild, Jean Jacques Grob, Lev V. Demidov, Thomas Jouary, Ralf Gutzmer, Michael Millward, Piotr Rutkowski, Christian U. Blank, Beloo Mirakhur, Mary E. Guckert, R. Suzanne Swann, Patricia Haney, Anne-Marie Martin, Danielle Ouellet, Kelly Grotzinger, Vicki L. Goodman, Paul B. Chapman; Universitaetsklinikum Schleswig-Holstein, Kiel Schleswig-Holstein, Germany; Dermatology Department, University Hospital APHM, Marseille, France; N. N. Blokhin Cancer Research Center, Russian Academy of Medical Sciences, Moscow, Russia; Skin Cancer Unit, Dermatology Department, Hôpital Saint André, Bordeaux, France; Department of Dermatology and Allergy, Skin Cancer Center, Hannover Medical School, Hannover, Germany; Sir Charles Gairdner Hospital and University of Western Australia, Perth, Australia; Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland; Division of Medical Oncology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital (NKI-AVL), Amsterdam, Netherlands; GlaxoSmithKline, Collegeville, PA; Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY

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Abstract Disclosures


Background: Dabrafenib, a selective BRAF inhibitor, has shown activity with a manageable safety profile in phase I/II studies in patients (pts) with BRAFV600E-mutated metastatic melanoma (MM). This phase III trial (NCT01227889) compared progression-free survival (PFS) in pts with advanced MM treated either with dabrafenib or dacarbazine (DTIC). Methods: Pts with previously untreated, unresectable stage III or IV BRAFV600E-mutated melanoma were randomized (3:1) and stratified by stage to dabrafenib (150 mg po bid) or DTIC (1000 mg/m2, IV, q3w). Primary endpoint was investigator-assessed PFS. Primary analysis for PFS was planned after 102 events. Pts on the DTIC arm were allowed to cross over once progression was confirmed by independent review (IR). Secondary endpoints included PFS by IR, overall survival (OS), response rate (RR), duration of response, safety and pharmacokinetics. Results: 250 pts were enrolled at 93 centers globally from February to September 2011. 187 were randomized to dabrafenib and 63 to DTIC. 141pts were on study treatment at the data cut-off at December 19, 2011 (dabrafenib n = 127; DTIC n = 14), including 21/28 DTIC pts crossed over to dabrafenib. Median age was 52 years, 31% of pts were ECOG >1, 66% M1c, 33% LDH > ULN. Demographics were well balanced between the two arms. At the time of the primary analysis, there were 118 events (77 dabrafenib and 41 DTIC). The hazard ratio for PFS was 0.30 (95% CI: 0.18–0.53; p < 0.0001). Median PFS was 5.1 months for dabrafenib and 2.7 for DTIC. OS data were immature, with 30 deaths reported. Confirmed RR was 53% for dabrafenib and 19% for DTIC. Benefits in PFS and RR were observed in all subgroups evaluated. Common adverse events (AEs) on the dabrafenib arm were hyperkeratosis (37%), headache (32%), pyrexia (28%), arthralgia (27%), skin papillomas (24%). Serious AEs (> 1%) on the dabrafenib arm included pyrexia (4%), squamous cell carcinomas (6%), and new primary melanomas (2%). Conclusions: Dabrafenib demonstrated a significant improvement in PFS and ORR over DTIC with an acceptable safety profile.