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).

Keywords: BRAF; Dabrafenib; Long-term outcomes; Melanoma; Metastatic.

Conflict of interest statement

Conflict of interest statement

Dr Hauschild reported receiving clinical trial support (grant to institution) from Amgen, Bristol-Myers Squibb, Merck Serono, Merck Sharp & Dohme/Merck, Philogen, Pierre Fabre, Provectus, Regeneron, Roche, Sanofi-Genzyme, and Novartis Pharma; personal fees for speaker honoraria from Amgen, Bristol-Myers Squibb, Merck Sharp & Dohme/Merck, Pierre Fabre, Provectus, Regeneron, Roche, Sanofi-Genzyme, and Novartis Pharma; and personal fees for consultancy from Amgen, Bristol-Myers Squibb, Merck Serono, Merck Sharp & Dohme/Merck, Philogen, Pierre Fabre, Provectus, Regeneron, Roche, OncoSec, Sanofi Genzyme, Sun Pharma, and Novartis Pharma. Dr Ascierto reported receiving consulting fees from Bristol-Myers Squibb, Roche/Genentech, Merck Sharp & Dohme, Novartis, Array BioPharma, Merck Serono, Pierre Fabre, NewLink Genetics, Genmab, Incyte, MedImmune, AstraZeneca, Syndax, Sun Pharma, Sanofi, Idera, Ultimovacs, Sandoz, and Immunocore; travel, accommodations, and expenses from Merck Sharp & Dohme; and research funding from Bristol-Myers Squibb, Roche/Genentech, and Array BioPharma. Dr Schadendorf reported receiving consulting or advisory role fees from Roche/Genentech, Novartis, Bristol-Myers Squibb, Merck Sharp & Dohme, Merck Serono, Amgen, Immunocore, Incyte, 4SC, Pierre Fabre, Mologen, and Sanofi/Regeneron; honoraria from Roche/Genentech, Novartis, Bristol-Myers Squibb, Merck Sharp & Dohme, Merck Serono, Amgen, Immunocore, Incyte, 4SC, Pierre Fabre, Sysmex, Grünenthal Group, Agenus, Array BioPharma, AstraZeneca, LEO Pharma, Pfizer, Philogen, Regeneron, and Mologen; travel, accommodations, and expenses from Roche/Genentech, Novartis, Bristol-Myers Squibb, Merck Serono, Amgen, and Merck; speakers bureau fees from Novartis, Bristol-Myers Squibb, Merck Sharp & Dohme, Amgen, Incyte, Pierre Fabre, and Roche; and research funding from Novartis and Bristol-Myers Squibb. Dr Grob reported receiving honoraria from Roche, Bristol-Myers Squibb, Novartis, Merck Sharp & Dohme, Amgen, Pierre Fabre, Sanofi, Merck, and Pfizer; consulting or advisory role fees from Roche, Bristol-Myers Squibb, Novartis, Merck Sharp & Dohme, Amgen, Pierre Fabre, Sanofi, Merck, and Pfizer; travel, accommodations, and expenses from Bristol-Myers Squibb, Novartis, Merck Sharp & Dohme, and Pierre Fabre; and speakers bureau fees from Novartis. Dr Ribas reported receiving consulting or advisory role fees from Merck, Amgen, Novartis, Sanofi, and Chugai Pharma and stock or other ownership interests in Compugen, FLX Bio, CytomX Therapeutics, Five Prime Therapeutics, Advaxis, Arcus Biosciences, Tango Therapeutics, PACT Pharma, Merus, Rgenix, ImaginAb, and Lutris. Dr Kiecker reported receiving consulting fees and honoraria from Novartis. Dr Dutriaux reported receiving consulting or advisory role fees from Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, and Roche. Dr Lebbé reported receiving honoraria from Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Amgen, Roche, Pierre Fabre, Pfizer, and Incyte; consulting fees from Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Amgen, and Roche; speakers bureau fees from Bristol-Myers Squibb, Novartis, Amgen, and Roche; travel accommodations for meetings from Bristol-Myers Squibb and Merck Sharp & Dohme; advisory role fees from Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, and Roche; and advisory board honoraria from Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Amgen, Roche, and Avantis Medical Systems. Dr Rutkowski reported receiving honoraria for lectures from Novartis, Bristol-Myers Squibb, Roche, Merck Sharp & Dohme, GlaxoSmithKline, Amgen, Pfizer, and Pierre Fabre; and advisory board honoraria from Novartis, Bristol-Myers Squibb, Roche, Merck Sharp & Dohme, GlaxoSmithKline, Amgen, and Pierre Fabre. Dr Blank reported receiving research support from Bristol-Myers Squibb and Novartis and consulting fees from Bristol-Myers Squibb, Merck Sharp & Dohme, Roche, Novartis, Lilly, Pfizer, and GlaxoSmithKline. Dr Gutzmer reported receiving honoraria for lectures from Roche, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pfizer, Amgen, Merck Serono, Almirall Hermal, SUN Pharma, Sanofi, and Pierre Fabre; honoraria for advice from Bristol-Myers Squibb, Roche, Novartis, Almirall Hermal, Merck Sharp & Dohme, Amgen, Incyte, 4SC, SUN Pharma, Sanofi, Merck-Serono, and Pierre Fabre; research funding from Novartis, Pfizer, Johnson & Johnson, Amgen, and Merck Serono; and travel/meeting support from Roche, Bristol-Myers Squibb, Pierre Fabre, and Merck Serono. Dr Millward reported receiving advisory board honoraria from Bristol-Myers Squibb, AstraZeneca, Merck Sharp & Dohme, Provectus Biopharmaceuticals, Roche, Amgen, Pfizer, and Novartis; travel/conference support from Roche, Boehringer Ingelheim, AstraZeneca, Merck Sharp & Dohme, and Bristol-Myers Squibb; and honoraria from Bristol-Myers Squibb, AstraZeneca, Merck Sharp & Dohme, Roche, and Novartis. Dr Kefford reported receiving consulting or advisory role fees (to institution) from Amgen and Teva and travel, accommodations, and expenses from Bristol-Myers Squibb and Amgen. Dr Haas reported employment, travel, accommodations, expenses, and stock and other ownership interests from Novartis. Dr D’Amelio Jr reported employment and stock options from Novartis and stock options from GlaxoSmithKline. Dr Mookerjee reported employment and stock options from Novartis and stock options from GlaxoSmithKline and AstraZeneca. Dr Chapman reported receiving consulting, advisory, or speaking compensation from Immunocore, Merck, Cell Medica, Takeda Millennium, and AstraZeneca; research funding from Pfizer; and stocks from Rgenix. All authors received support for third-party medical writing and editorial assistance provided by ArticulateScience LLC, funded by Novartis Pharmaceuticals Corporation.

Copyright © 2019 Elsevier Ltd. All rights reserved.

Figures

Fig. 1.

PFS in intention-to-treat patients in BREAK-2 (A) and BREAK-3 (B) and in patients with normal (C) and elevated (D) baseline LDH levels in BREAK-3. CI, confidence interval; LDH, lactate dehydrogenase; PFS, progression-free survival.

Fig. 2.

OS in intention-to-treat patients in BREAK-2 (A) and BREAK-3 (B). CI, confidence interval; ITT, intention-to-treat; OS, overall survival. a Thirty-seven patients (59%) receiving dacarbazine crossed over to receive dabrafenib; these patients were analysed for OS in the dacarbazine arm following ITT principle.