Phase II Trial (BREAK-2) of the BRAF Inhibitor Dabrafenib (GSK2118436) in Patients With Metastatic Melanoma

Author:

Ascierto Paolo A.1,Minor David1,Ribas Antoni1,Lebbe Celeste1,O'Hagan Anne1,Arya Niki1,Guckert Mary1,Schadendorf Dirk1,Kefford Richard F.1,Grob Jean-Jacques1,Hamid Omid1,Amaravadi Ravi1,Simeone Ester1,Wilhelm Tabea1,Kim Kevin B.1,Long Georgina V.1,Martin Anne-Marie1,Mazumdar Jolly1,Goodman Vicki L.1,Trefzer Uwe1

Affiliation:

1. 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...

Abstract

Purpose 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 BRAFV600E/K mutation–positive metastatic melanoma (mut+ MM). Patients and Methods Histologically confirmed patients with stage IV BRAFV600E/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 BRAFV600E 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. Results Seventy-six patients with BRAFV600E and 16 patients with BRAFV600K mut+ MM were enrolled onto the study. In the BRAFV600E 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 BRAFV600K mut+ MM had a confirmed partial response (95% CI, 0 to 28.7). In the BRAFV600E and BRAFV600K 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 BRAFV600E mut+ MM patients. Conclusion Dabrafenib was well tolerated and clinically active in patients with BRAFV600E/K mut+ MM. cfDNA may be a useful prognostic and response marker in future studies.

Publisher

American Society of Clinical Oncology (ASCO)

Subject

Cancer Research,Oncology

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