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

• Published in: Journal of clinical oncology Vol. 31; no. 26; pp. 3205 - 3211
• Main Authors: ASCIERTO, Paolo A, MINOR, David, HAMID, Omid, AMARAVADI, Ravi, SIMEONE, Ester, WILHELM, Tabea, KIM, Kevin B, LONG, Georgina V, MARTIN, Anne-Marie, MAZUMDAR, Jolly, GOODMAN, Vicki L, TREFZER, Uwe, RIBAS, Antoni, LEBBE, Celeste, O'HAGAN, Anne, ARYA, Niki, GUCKERT, Mary, SCHADENDORF, Dirk, KEFFORD, Richard F, GROB, Jean-Jacques
• Format: Journal Article Conference Proceeding
• Language: English
• Published: Alexandria, VA American Society of Clinical Oncology 10.09.2013
• Subjects: Adult; Aged; Aged, 80 and over; Biological and medical sciences; Brain Neoplasms - drug therapy; Brain Neoplasms - mortality; Brain Neoplasms - secondary; Dermatology; Female; Follow-Up Studies; Humans; Imidazoles - therapeutic use; International Agencies; Male; Medical sciences; Melanoma - drug therapy; Melanoma - mortality; Melanoma - pathology; Middle Aged; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Mutation - genetics; Oximes - therapeutic use; Prognosis; Proto-Oncogene Proteins B-raf - antagonists & inhibitors; Proto-Oncogene Proteins B-raf - genetics; Survival Rate; Tumors; Tumors of the skin and soft tissue. Premalignant lesions; Young Adult; Human; Break; Dabrafenib; Malignant tumor; Metastasis; BRAF Gene; Cancerology; C-Onc gene; Phase II trial; Malignant melanoma; Advanced stage; Inhibitor; Protooncogene; Cancer
• ISSN: 0732-183X; 1527-7755
• DOI: 10.1200/JCO.2013.49.8691

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.