Safety and efficacy of vemurafenib in BRAFV600E and BRAFV600K mutation-positive melanoma (BRIM-3): Extended follow-up of a phase 3, randomised, open-label study

Grant A. McArthur; Paul B. Chapman; Caroline Robert; James Larkin; John B. Haanen; Reinhard Dummer; Antoni Ribas; David Hogg; Omid Hamid; Paolo A. Ascierto; Claus Garbe; Alessandro Testori; Michele Maio; Paul Lorigan; Celeste Lebbé; Thomas Jouary; Dirk Schadendorf; Stephen J. O'Day; John M. Kirkwood; Alexander M. Eggermont; Brigitte Dréno; Jeffrey A. Sosman; Keith T. Flaherty; Ming Yin; Ivor Caro; Suzanne Cheng; Kerstin Trunzer; Axel Hauschild

doi:10.1016/S1470-2045(14)70012-9

Safety and efficacy of vemurafenib in BRAFV600E and BRAFV600K mutation-positive melanoma (BRIM-3): Extended follow-up of a phase 3, randomised, open-label study

Grant A. McArthur, Paul B. Chapman, Caroline Robert, James Larkin, John B. Haanen, Reinhard Dummer, Antoni Ribas, David Hogg, Omid Hamid, Paolo A. Ascierto, Claus Garbe, Alessandro Testori, Michele Maio, Paul Lorigan, Celeste Lebbé, Thomas Jouary, Dirk Schadendorf, Stephen J. O'Day, John M. Kirkwood, Alexander M. EggermontBrigitte Dréno, Jeffrey A. Sosman, Keith T. Flaherty, Ming Yin, Ivor Caro, Suzanne Cheng, Kerstin Trunzer, Axel Hauschild

Research output: Contribution to journal › Article › peer-review

Abstract

Background: In the BRIM-3 trial, vemurafenib was associated with risk reduction versus dacarbazine of both death and progression in patients with advanced BRAFV600 mutation-positive melanoma. We present an extended follow-up analysis of the total population and in the BRAFV600E and BRAFV600K mutation subgroups. Methods: Patients older than 18 years, with treatment-naive metastatic melanoma and whose tumour tissue was positive for BRAFV600 mutations were eligible. Patients also had to have a life expectancy of at least 3 months, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and adequate haematological, hepatic, and renal function. Patients were randomly assigned by interactive voice recognition system to receive either vemurafenib (960 mg orally twice daily) or dacarbazine (1000 mg/m2 of body surface area intravenously every 3 weeks). Coprimary endpoints were overall survival and progression-free survival, analysed in the intention-to-treat population (n=675), with data censored at crossover. A sensitivity analysis was done. This trial is registered with ClinicalTrials.gov, NCT01006980. Findings: 675 eligible patients were enrolled from 104 centres in 12 countries between Jan 4, 2010, and Dec 16, 2010. 337 patients were randomly assigned to receive vemurafenib and 338 to receive dacarbazine. Median follow-up was 12·5 months (IQR 7·7-16·0) on vemurafenib and 9·5 months (3·1-14·7) on dacarbazine. 83 (25%) of the 338 patients initially randomly assigned to dacarbazine crossed over from dacarbazine to vemurafenib. Median overall survival was significantly longer in the vemurafenib group than in the dacarbazine group (13·6 months [95% CI 12·0-15·2] vs 9·7 months [7·9-12·8]; hazard ratio [HR] 0·70 [95% CI 0·57-0·87]; p=0·0008), as was median progression-free survival (6·9 months [95% CI 6·1-7·0] vs 1·6 months [1·6-2·1]; HR 0·38 [95% CI 0·32-0·46]; p

Original language	English
Pages (from-to)	323-332
Number of pages	9
Journal	Lancet Oncology
Volume	15
Issue number	3
DOIs	https://doi.org/10.1016/S1470-2045(14)70012-9
Publication status	Published - Mar 2014

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10.1016/S1470-2045(14)70012-9

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McArthur, G. A., Chapman, P. B., Robert, C., Larkin, J., Haanen, J. B., Dummer, R., Ribas, A., Hogg, D., Hamid, O., Ascierto, P. A., Garbe, C., Testori, A., Maio, M., Lorigan, P., Lebbé, C., Jouary, T., Schadendorf, D., O'Day, S. J., Kirkwood, J. M., ... Hauschild, A. (2014). Safety and efficacy of vemurafenib in BRAFV600E and BRAFV600K mutation-positive melanoma (BRIM-3): Extended follow-up of a phase 3, randomised, open-label study. Lancet Oncology, 15(3), 323-332. https://doi.org/10.1016/S1470-2045(14)70012-9

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title = "Safety and efficacy of vemurafenib in BRAFV600E and BRAFV600K mutation-positive melanoma (BRIM-3): Extended follow-up of a phase 3, randomised, open-label study",

abstract = "Background: In the BRIM-3 trial, vemurafenib was associated with risk reduction versus dacarbazine of both death and progression in patients with advanced BRAFV600 mutation-positive melanoma. We present an extended follow-up analysis of the total population and in the BRAFV600E and BRAFV600K mutation subgroups. Methods: Patients older than 18 years, with treatment-naive metastatic melanoma and whose tumour tissue was positive for BRAFV600 mutations were eligible. Patients also had to have a life expectancy of at least 3 months, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and adequate haematological, hepatic, and renal function. Patients were randomly assigned by interactive voice recognition system to receive either vemurafenib (960 mg orally twice daily) or dacarbazine (1000 mg/m2 of body surface area intravenously every 3 weeks). Coprimary endpoints were overall survival and progression-free survival, analysed in the intention-to-treat population (n=675), with data censored at crossover. A sensitivity analysis was done. This trial is registered with ClinicalTrials.gov, NCT01006980. Findings: 675 eligible patients were enrolled from 104 centres in 12 countries between Jan 4, 2010, and Dec 16, 2010. 337 patients were randomly assigned to receive vemurafenib and 338 to receive dacarbazine. Median follow-up was 12·5 months (IQR 7·7-16·0) on vemurafenib and 9·5 months (3·1-14·7) on dacarbazine. 83 (25%) of the 338 patients initially randomly assigned to dacarbazine crossed over from dacarbazine to vemurafenib. Median overall survival was significantly longer in the vemurafenib group than in the dacarbazine group (13·6 months [95% CI 12·0-15·2] vs 9·7 months [7·9-12·8]; hazard ratio [HR] 0·70 [95% CI 0·57-0·87]; p=0·0008), as was median progression-free survival (6·9 months [95% CI 6·1-7·0] vs 1·6 months [1·6-2·1]; HR 0·38 [95% CI 0·32-0·46]; p",

author = "McArthur, {Grant A.} and Chapman, {Paul B.} and Caroline Robert and James Larkin and Haanen, {John B.} and Reinhard Dummer and Antoni Ribas and David Hogg and Omid Hamid and Ascierto, {Paolo A.} and Claus Garbe and Alessandro Testori and Michele Maio and Paul Lorigan and Celeste Lebb{\'e} and Thomas Jouary and Dirk Schadendorf and O'Day, {Stephen J.} and Kirkwood, {John M.} and Eggermont, {Alexander M.} and Brigitte Dr{\'e}no and Sosman, {Jeffrey A.} and Flaherty, {Keith T.} and Ming Yin and Ivor Caro and Suzanne Cheng and Kerstin Trunzer and Axel Hauschild",

year = "2014",

month = mar,

doi = "10.1016/S1470-2045(14)70012-9",

language = "English",

volume = "15",

pages = "323--332",

journal = "Lancet Oncology",

issn = "1470-2045",

publisher = "Elsevier BV",

number = "3",

}

McArthur, GA, Chapman, PB, Robert, C, Larkin, J, Haanen, JB, Dummer, R, Ribas, A, Hogg, D, Hamid, O, Ascierto, PA, Garbe, C, Testori, A, Maio, M, Lorigan, P, Lebbé, C, Jouary, T, Schadendorf, D, O'Day, SJ, Kirkwood, JM, Eggermont, AM, Dréno, B, Sosman, JA, Flaherty, KT, Yin, M, Caro, I, Cheng, S, Trunzer, K & Hauschild, A 2014, 'Safety and efficacy of vemurafenib in BRAFV600E and BRAFV600K mutation-positive melanoma (BRIM-3): Extended follow-up of a phase 3, randomised, open-label study', Lancet Oncology, vol. 15, no. 3, pp. 323-332. https://doi.org/10.1016/S1470-2045(14)70012-9

TY - JOUR

T1 - Safety and efficacy of vemurafenib in BRAFV600E and BRAFV600K mutation-positive melanoma (BRIM-3): Extended follow-up of a phase 3, randomised, open-label study

AU - McArthur, Grant A.

AU - Chapman, Paul B.

AU - Robert, Caroline

AU - Larkin, James

AU - Haanen, John B.

AU - Dummer, Reinhard

AU - Ribas, Antoni

AU - Hogg, David

AU - Hamid, Omid

AU - Ascierto, Paolo A.

AU - Garbe, Claus

AU - Testori, Alessandro

AU - Maio, Michele

AU - Lorigan, Paul

AU - Lebbé, Celeste

AU - Jouary, Thomas

AU - Schadendorf, Dirk

AU - O'Day, Stephen J.

AU - Kirkwood, John M.

AU - Eggermont, Alexander M.

AU - Dréno, Brigitte

AU - Sosman, Jeffrey A.

AU - Flaherty, Keith T.

AU - Yin, Ming

AU - Caro, Ivor

AU - Cheng, Suzanne

AU - Trunzer, Kerstin

AU - Hauschild, Axel

PY - 2014/3

Y1 - 2014/3

N2 - Background: In the BRIM-3 trial, vemurafenib was associated with risk reduction versus dacarbazine of both death and progression in patients with advanced BRAFV600 mutation-positive melanoma. We present an extended follow-up analysis of the total population and in the BRAFV600E and BRAFV600K mutation subgroups. Methods: Patients older than 18 years, with treatment-naive metastatic melanoma and whose tumour tissue was positive for BRAFV600 mutations were eligible. Patients also had to have a life expectancy of at least 3 months, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and adequate haematological, hepatic, and renal function. Patients were randomly assigned by interactive voice recognition system to receive either vemurafenib (960 mg orally twice daily) or dacarbazine (1000 mg/m2 of body surface area intravenously every 3 weeks). Coprimary endpoints were overall survival and progression-free survival, analysed in the intention-to-treat population (n=675), with data censored at crossover. A sensitivity analysis was done. This trial is registered with ClinicalTrials.gov, NCT01006980. Findings: 675 eligible patients were enrolled from 104 centres in 12 countries between Jan 4, 2010, and Dec 16, 2010. 337 patients were randomly assigned to receive vemurafenib and 338 to receive dacarbazine. Median follow-up was 12·5 months (IQR 7·7-16·0) on vemurafenib and 9·5 months (3·1-14·7) on dacarbazine. 83 (25%) of the 338 patients initially randomly assigned to dacarbazine crossed over from dacarbazine to vemurafenib. Median overall survival was significantly longer in the vemurafenib group than in the dacarbazine group (13·6 months [95% CI 12·0-15·2] vs 9·7 months [7·9-12·8]; hazard ratio [HR] 0·70 [95% CI 0·57-0·87]; p=0·0008), as was median progression-free survival (6·9 months [95% CI 6·1-7·0] vs 1·6 months [1·6-2·1]; HR 0·38 [95% CI 0·32-0·46]; p

AB - Background: In the BRIM-3 trial, vemurafenib was associated with risk reduction versus dacarbazine of both death and progression in patients with advanced BRAFV600 mutation-positive melanoma. We present an extended follow-up analysis of the total population and in the BRAFV600E and BRAFV600K mutation subgroups. Methods: Patients older than 18 years, with treatment-naive metastatic melanoma and whose tumour tissue was positive for BRAFV600 mutations were eligible. Patients also had to have a life expectancy of at least 3 months, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and adequate haematological, hepatic, and renal function. Patients were randomly assigned by interactive voice recognition system to receive either vemurafenib (960 mg orally twice daily) or dacarbazine (1000 mg/m2 of body surface area intravenously every 3 weeks). Coprimary endpoints were overall survival and progression-free survival, analysed in the intention-to-treat population (n=675), with data censored at crossover. A sensitivity analysis was done. This trial is registered with ClinicalTrials.gov, NCT01006980. Findings: 675 eligible patients were enrolled from 104 centres in 12 countries between Jan 4, 2010, and Dec 16, 2010. 337 patients were randomly assigned to receive vemurafenib and 338 to receive dacarbazine. Median follow-up was 12·5 months (IQR 7·7-16·0) on vemurafenib and 9·5 months (3·1-14·7) on dacarbazine. 83 (25%) of the 338 patients initially randomly assigned to dacarbazine crossed over from dacarbazine to vemurafenib. Median overall survival was significantly longer in the vemurafenib group than in the dacarbazine group (13·6 months [95% CI 12·0-15·2] vs 9·7 months [7·9-12·8]; hazard ratio [HR] 0·70 [95% CI 0·57-0·87]; p=0·0008), as was median progression-free survival (6·9 months [95% CI 6·1-7·0] vs 1·6 months [1·6-2·1]; HR 0·38 [95% CI 0·32-0·46]; p

U2 - 10.1016/S1470-2045(14)70012-9

DO - 10.1016/S1470-2045(14)70012-9

M3 - Article

SN - 1470-2045

VL - 15

SP - 323

EP - 332

JO - Lancet Oncology

JF - Lancet Oncology

IS - 3

ER -

Safety and efficacy of vemurafenib in BRAFV600E and BRAFV600K mutation-positive melanoma (BRIM-3): Extended follow-up of a phase 3, randomised, open-label study

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