Axel Hauschild1, Paolo A Ascierto2, Dirk Schadendorf3, Jean Jacques Grob4, Antoni Ribas5, Felix Kiecker6, Caroline Dutriaux7, Lev V Demidov8, Céleste Lebbé9, Piotr Rutkowski10, Christian U Blank11, Ralf Gutzmer12, Michael Millward13, Richard Kefford14, Tomas Haas15, Anthony D'Amelio16, Eduard Gasal16, Bijoyesh Mookerjee16, Paul B Chapman17. 1. University Hospital Schleswig-Holstein, Kiel, Germany. Electronic address: ahauschild@dermatology.uni-kiel.de. 2. Istituto Nazionale Tumori IRCCS Fondazione "G. Pascale," Naples, Italy. 3. University Hospital of Essen, Essen, Germany; German Cancer Consortium, Heidelberg, Germany. 4. Aix-Marseille University, Marseille, France. 5. UCLA Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA. 6. Charité-Universitätsmedizin Berlin, Berlin, Germany. 7. Hôpital Saint-André, Bordeaux, France. 8. N.N. Blokhin Russian Cancer Research Center, Moscow, Russia. 9. APHP Dermatology and CIC Department, Hôpital Saint-Louis, INSERM U976, University Paris Diderot, Paris, France. 10. Maria Sklodowska-Curie Institute - Oncology Center, Warsaw, Poland. 11. The Netherlands Cancer Institute, Amsterdam, the Netherlands. 12. Hannover Medical School, Hannover, Germany. 13. University of Western Australia, Sir Charles Gairdner Hospital, Perth, WA, Australia. 14. Westmead Hospital and Macquarie University, Sydney, NSW, Australia. 15. Novartis Pharma AG, Basel, Switzerland. 16. Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA. 17. Memorial Sloan Kettering Cancer Center, New York, NY, USA.
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).
RCT Entities:
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 BRAFV600E/K-mutant MM. BREAK-3, a randomised (3:1) phase 3 study, assessed dabrafenib versus dacarbazine in previously untreated unresectable or metastatic BRAFV600E-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 BRAFV600Epatients, 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).
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