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J Clin Oncol. 2013 Sep 10;31(26):3205-11. doi: 10.1200/JCO.2013.49.8691. Epub 2013 Aug 5.

Phase II trial (BREAK-2) of the BRAF inhibitor dabrafenib (GSK2118436) in patients with metastatic melanoma.

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Paolo A. Ascierto, Ester Simeone, Instituto Nazionale Tumori Fondazione "G. Pascale," Napoli, Italy; David Minor, California Pacific Center for Melanoma Research and Treatment, San Francisco; Antoni Ribas, Jonsson Comprehensive Cancer Center, University of California, Los Angeles; Omid Hamid, Experimental Therapeutics/Immunotherapy, The Angeles Clinic and Research Institute, Los Angeles, CA; Anne O'Hagan, Niki Arya, Mary Guckert, Anne-Marie Martin, Jolly Mazumdar, Vicki L. Goodman, GlaxoSmithKline Oncology, Collegeville; Ravi Amaravadi, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA; Kevin B. Kim, The University of Texas MD Anderson Cancer Center, Houston, TX; Celeste Lebbe, Assistance Publique-Hôpitaux de Paris, Hôpital Saint Louis, Paris, Université Paris Diderot, Paris; Jean-Jacques Grob, Aix-Marseille University, Assistance Publique-Hôpitaux de Marseille, Hôpital Timone, Marseille, France; Dirk Schadendorf, University Hospital Essen, Essen; Tabea Wilhelm, Uwe Trefzer, Charité-Universitätsmedizin, Berlin, Germany; Richard F. Kefford, Georgina V. Long, Westmead Hospital and Melanoma Institute Australia, University of Sydney, Sydney, Australia.



Dabrafenib (GSK2118436) is a potent inhibitor of mutated BRAF kinase. Our multicenter, single-arm, phase II study assessed the safety and clinical activity of dabrafenib in BRAF(V600E/K) mutation-positive metastatic melanoma (mut(+) MM).


Histologically confirmed patients with stage IV BRAF(V600E/K) mut(+) MM received oral dabrafenib 150 mg twice daily until disease progression, death, or unacceptable adverse events (AEs). The primary end point was investigator-assessed overall response rate in BRAF(V600E) mut(+) MM patients. Secondary end points included progression-free survival (PFS) and overall survival (OS). Exploratory objectives included the comparison of BRAF mutation status between tumor-specific circulating cell-free DNA (cfDNA) and tumor tissue, and the evaluation of cfDNA as a predictor of clinical outcome.


Seventy-six patients with BRAF(V600E) and 16 patients with BRAF(V600K) mut(+) MM were enrolled onto the study. In the BRAF(V600E) group, 45 patients (59%) had a confirmed response (95% CI, 48.2 to 70.3), including five patients (7%) with complete responses. Two patients (13%) with BRAF(V600K) mut(+) MM had a confirmed partial response (95% CI, 0 to 28.7). In the BRAF(V600E) and BRAF(V600K) groups, median PFS was 6.3 months and 4.5 months, and median OS was 13.1 months and 12.9 months, respectively. The most common AEs were arthralgia (33%), hyperkeratosis (27%), and pyrexia (24%). Overall, 25 patients (27%) experienced a serious AE and nine patients (10%) had squamous cell carcinoma. Baseline cfDNA levels predicted response rate and PFS in BRAF(V600E) mut(+) MM patients.


Dabrafenib was well tolerated and clinically active in patients with BRAF(V600E/K) mut(+) MM. cfDNA may be a useful prognostic and response marker in future studies.

[Indexed for MEDLINE]

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