Paolo A Ascierto1, David Minor, Antoni Ribas, Celeste Lebbe, Anne O'Hagan, Niki Arya, Mary Guckert, Dirk Schadendorf, Richard F Kefford, Jean-Jacques Grob, Omid Hamid, Ravi Amaravadi, Ester Simeone, Tabea Wilhelm, Kevin B Kim, Georgina V Long, Anne-Marie Martin, Jolly Mazumdar, Vicki L Goodman, Uwe Trefzer. 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 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.
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 BRAF(V600E/K) mutation-positive metastatic melanoma (mut(+) MM). PATIENTS AND METHODS: 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. RESULTS: 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. CONCLUSION: 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.
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 BRAF(V600E/K) mutation-positive metastatic melanoma (mut(+) MM). PATIENTS AND METHODS: 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(+) MMpatients. 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 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(+) MMpatients. CONCLUSION: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.
Authors: Eva Muñoz-Couselo; Jesús Soberino García; José Manuel Pérez-García; Vanesa Ortega Cebrián; Javier Cortés Castán Journal: Ann Transl Med Date: 2015-09