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

Axel Hauschild, Paolo A. Ascierto, Dirk Schadendorf, Jean Jacques Grob, Antoni Ribas, Felix Kiecker, Caroline Dutriaux, Lev V. Demidov, Céleste Lebbé, Piotr Rutkowski, Christian U. Blank, Ralf Gutzmer, Michael Millward, Richard Kefford, Tomas Haas, Anthony D'Amelio, Eduard Gasal, Bijoyesh Mookerjee, Paul B. Chapman

Research output: Contribution to journalArticle

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).

Original languageEnglish
Pages (from-to)114-120
Number of pages7
JournalEuropean Journal of Cancer
Volume125
DOIs
Publication statusPublished - Jan 2020

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Phase III Clinical Trials
Melanoma
Dacarbazine
Disease-Free Survival
dabrafenib
Therapeutics
L-Lactate Dehydrogenase
Immunotherapy
Disease Progression
Survival Rate

Cite this

Hauschild, Axel ; Ascierto, Paolo A. ; Schadendorf, Dirk ; Grob, Jean Jacques ; Ribas, Antoni ; Kiecker, Felix ; Dutriaux, Caroline ; Demidov, Lev V. ; Lebbé, Céleste ; Rutkowski, Piotr ; Blank, Christian U. ; Gutzmer, Ralf ; Millward, Michael ; Kefford, Richard ; Haas, Tomas ; D'Amelio, Anthony ; Gasal, Eduard ; Mookerjee, Bijoyesh ; Chapman, Paul B. / Long-term outcomes in patients with BRAF V600-mutant metastatic melanoma receiving dabrafenib monotherapy : Analysis from phase 2 and 3 clinical trials. In: European Journal of Cancer. 2020 ; Vol. 125. pp. 114-120.
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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).",
keywords = "BRAF, Dabrafenib, Long-term outcomes, Melanoma, Metastatic",
author = "Axel Hauschild and Ascierto, {Paolo A.} and Dirk Schadendorf and Grob, {Jean Jacques} and Antoni Ribas and Felix Kiecker and Caroline Dutriaux and Demidov, {Lev V.} and C{\'e}leste Lebb{\'e} and Piotr Rutkowski and Blank, {Christian U.} and Ralf Gutzmer and Michael Millward and Richard Kefford and Tomas Haas and Anthony D'Amelio and Eduard Gasal and Bijoyesh Mookerjee and Chapman, {Paul B.}",
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Hauschild, A, Ascierto, PA, Schadendorf, D, Grob, JJ, Ribas, A, Kiecker, F, Dutriaux, C, Demidov, LV, Lebbé, C, Rutkowski, P, Blank, CU, Gutzmer, R, Millward, M, Kefford, R, Haas, T, D'Amelio, A, Gasal, E, Mookerjee, B & Chapman, PB 2020, 'Long-term outcomes in patients with BRAF V600-mutant metastatic melanoma receiving dabrafenib monotherapy: Analysis from phase 2 and 3 clinical trials' European Journal of Cancer, vol. 125, pp. 114-120. https://doi.org/10.1016/j.ejca.2019.10.033

Long-term outcomes in patients with BRAF V600-mutant metastatic melanoma receiving dabrafenib monotherapy : Analysis from phase 2 and 3 clinical trials. / Hauschild, Axel; Ascierto, Paolo A.; Schadendorf, Dirk; Grob, Jean Jacques; Ribas, Antoni; Kiecker, Felix; Dutriaux, Caroline; Demidov, Lev V.; Lebbé, Céleste; Rutkowski, Piotr; Blank, Christian U.; Gutzmer, Ralf; Millward, Michael; Kefford, Richard; Haas, Tomas; D'Amelio, Anthony; Gasal, Eduard; Mookerjee, Bijoyesh; Chapman, Paul B.

In: European Journal of Cancer, Vol. 125, 01.2020, p. 114-120.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Long-term outcomes in patients with BRAF V600-mutant metastatic melanoma receiving dabrafenib monotherapy

T2 - Analysis from phase 2 and 3 clinical trials

AU - Hauschild, Axel

AU - Ascierto, Paolo A.

AU - Schadendorf, Dirk

AU - Grob, Jean Jacques

AU - Ribas, Antoni

AU - Kiecker, Felix

AU - Dutriaux, Caroline

AU - Demidov, Lev V.

AU - Lebbé, Céleste

AU - Rutkowski, Piotr

AU - Blank, Christian U.

AU - Gutzmer, Ralf

AU - Millward, Michael

AU - Kefford, Richard

AU - Haas, Tomas

AU - D'Amelio, Anthony

AU - Gasal, Eduard

AU - Mookerjee, Bijoyesh

AU - Chapman, Paul B.

PY - 2020/1

Y1 - 2020/1

N2 - 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).

AB - 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).

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KW - Dabrafenib

KW - Long-term outcomes

KW - Melanoma

KW - Metastatic

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U2 - 10.1016/j.ejca.2019.10.033

DO - 10.1016/j.ejca.2019.10.033

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EP - 120

JO - European Journal of Cancer

JF - European Journal of Cancer

SN - 0959-8049

ER -