Long-term outcomes in patients with BRAF V600-mutant metastatic melanoma receiving dabrafenib monotherapy: Analysis from phase 2 and 3 clinical trials Journal Article


Authors: Hauschild, A.; Ascierto, P. A.; Schadendorf, D.; Grob, J. J.; Ribas, A.; Kiecker, F.; Dutriaux, C.; Demidov, L. V.; Lebbé, C.; Rutkowski, P.; Blank, C. U.; Gutzmer, R.; Millward, M.; Kefford, R.; Haas, T.; D'Amelio, A. Jr; Gasal, E.; Mookerjee, B.; Chapman, P. B.
Article Title: Long-term outcomes in patients with BRAF V600-mutant metastatic melanoma receiving dabrafenib monotherapy: Analysis from phase 2 and 3 clinical trials
Abstract: Background: Previous analyses of BREAK-2 and BREAK-3 showed that durable outcomes lasting ≥3 years are achievable with dabrafenib in some patients with BRAF V600-mutant metastatic melanoma (MM); however, additional follow-up is needed to fully characterise the long-term impact of dabrafenib in these patients. Methods: BREAK-2 was a single-arm phase 2 study evaluating dabrafenib in treatment-naive or previously treated BRAF V600E/K-mutant MM. BREAK-3, a randomised (3:1) phase 3 study, assessed dabrafenib versus dacarbazine in previously untreated unresectable or metastatic BRAF V600E-mutant melanoma. Five-year analyses were performed. Results: All BREAK-2 patients (N = 92 [V600E, n = 76; V600K, n = 16]) discontinued treatment by the data cutoff. Median follow-up was 13.0 months. In BRAF V600E patients, 5-year progression-free survival (PFS) and overall survival (OS) were 11% and 20%, respectively. Subsequent immunotherapy was received by 22% of patients. In BREAK-3, median follow-up was 17.0 and 12.0 months in the dabrafenib (n = 187) and dacarbazine (n = 63) arms, respectively. Thirty-seven patients (59%) receiving dacarbazine crossed over to dabrafenib following disease progression as per protocol. Five-year PFS was 12% in the dabrafenib arm; all dacarbazine-arm patients progressed or were censored by 5 years. Dabrafenib improved PFS versus dacarbazine, regardless of baseline lactate dehydrogenase levels. Five-year OS rates were 24% and 22% in the dabrafenib and dacarbazine arms, respectively. Subsequent therapy in each arm included anti–CTLA-4 (dabrafenib [24%] and dacarbazine [24%]) and/or anti–PD-1 (8% and 2%) treatment. No new safety signals were observed. Conclusions and Relevance: These data, representing extended follow-up for dabrafenib monotherapy, demonstrate that durable benefit lasting ≥5 years is achievable in a subset of patients. Trial registration: ClinicalTrials.gov (BREAK-2, NCT01153763; BREAK-3, NCT01227889). © 2019 Elsevier Ltd
Keywords: cancer chemotherapy; cancer survival; major clinical study; overall survival; cancer growth; drug efficacy; drug safety; drug withdrawal; monotherapy; treatment duration; unspecified side effect; outcome assessment; follow up; dacarbazine; interleukin 2; ipilimumab; cancer immunotherapy; melanoma; progression free survival; clinical assessment; clinical protocol; clinical evaluation; long term care; lactate dehydrogenase; cytotoxic t lymphocyte antigen 4; b raf kinase; disease exacerbation; treatment withdrawal; braf; metastatic; programmed death 1 ligand 1; metastatic melanoma; randomized controlled trial (topic); phase 2 clinical trial (topic); phase 3 clinical trial (topic); clinical outcome; long-term outcomes; vemurafenib; dabrafenib; human; priority journal; article; cobimetinib
Journal Title: European Journal of Cancer
Volume: 125
ISSN: 0959-8049
Publisher: Elsevier Inc.  
Date Published: 2020-01-01
Start Page: 114
End Page: 120
Language: English
DOI: 10.1016/j.ejca.2019.10.033
PROVIDER: scopus
PUBMED: 31864178
DOI/URL:
Notes: Source: Scopus
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  1. Paul Chapman
    279 Chapman