An open-label, multicentre safety study of vemurafenib in patients with BRAFV600-mutant metastatic melanoma: final analysis and a validated prognostic scoring system

James Larkin, Michael P Brown, Ana M Arance, Axel Hauschild, Paola Queirolo, Michele Del Vecchio, Paolo A Ascierto, Ivana Krajsová, Jacob Schachter, Bart Neyns, Claus Garbe, Vanna Chiarion Sileni, Mario Mandalà, Helen Gogas, Enrique Espinosa, Geke Hospers, Paul Lorigan, Marta Nyakas, Alex Guminski, Gabriela Liszkay & 5 others Piotr Rutkowski, Wilson Miller, Margarita Donica, Martina Makrutzki, Christian Blank

Research output: Contribution to journalArticle

Abstract

BACKGROUND: The oncogenic BRAF inhibitor vemurafenib improves outcomes for patients with advanced BRAFV600 mutation-positive melanoma compared with cytotoxic chemotherapy. Vemurafenib is now approved for use in this patient population.

PATIENTS AND METHODS: In this open-label, multicentre study, patients with previously treated or untreated melanoma and the BRAFV600 mutation received vemurafenib 960 mg twice daily. The primary endpoint was safety. In a post hoc analysis, overall survival (OS) was analysed according to a prognostic scoring system developed using Eastern Cooperative Oncology Group performance status, existence of brain metastases and baseline serum lactate dehydrogenase level. The index was validated using data from patients treated with vemurafenib or dacarbazine in three clinical trials and data from patients treated with vemurafenib plus cobimetinib in two studies. The study is registered with ClinicalTrials.gov (NCT01307397).

RESULTS: Between March 2011 and January 2013, 3224 patients were enrolled, and 3219 patients received ≥1 dose of vemurafenib (safety population); median follow-up time was 33.4 months. Vemurafenib's long-term benefits were confirmed, and no new safety signals identified. The prognostic index showed between-group differences in OS, with tight, non-overlapping confidence intervals. Validation in a pooled group of 666 vemurafenib-treated clinical trial patients revealed a similar pattern; the pattern was similar in 280 patients treated with vemurafenib plus cobimetinib.

CONCLUSIONS: Final results from the vemurafenib safety study confirm vemurafenib's tolerability in BRAFV600 mutation-positive patients and resemble those seen in real-world clinical practice. This index may be useful in patients on combination therapy and as a basis for further work.

Original languageEnglish
Pages (from-to)175-185
Number of pages11
JournalEuropean Journal of Cancer
Volume107
Early online dateDec 20 2018
DOIs
Publication statusPublished - Jan 2019

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Multicenter Studies
Melanoma
Safety
Mutation
PLX4032
Clinical Trials
Dacarbazine
Survival Analysis
L-Lactate Dehydrogenase
Population
Confidence Intervals
Neoplasm Metastasis
Drug Therapy
Survival
Brain
Serum

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An open-label, multicentre safety study of vemurafenib in patients with BRAFV600-mutant metastatic melanoma : final analysis and a validated prognostic scoring system. / Larkin, James; Brown, Michael P; Arance, Ana M; Hauschild, Axel; Queirolo, Paola; Vecchio, Michele Del; Ascierto, Paolo A; Krajsová, Ivana; Schachter, Jacob; Neyns, Bart; Garbe, Claus; Sileni, Vanna Chiarion; Mandalà, Mario; Gogas, Helen; Espinosa, Enrique; Hospers, Geke; Lorigan, Paul; Nyakas, Marta; Guminski, Alex; Liszkay, Gabriela; Rutkowski, Piotr; Miller, Wilson; Donica, Margarita; Makrutzki, Martina; Blank, Christian.

In: European Journal of Cancer, Vol. 107, 01.2019, p. 175-185.

Research output: Contribution to journalArticle

Larkin, J, Brown, MP, Arance, AM, Hauschild, A, Queirolo, P, Vecchio, MD, Ascierto, PA, Krajsová, I, Schachter, J, Neyns, B, Garbe, C, Sileni, VC, Mandalà, M, Gogas, H, Espinosa, E, Hospers, G, Lorigan, P, Nyakas, M, Guminski, A, Liszkay, G, Rutkowski, P, Miller, W, Donica, M, Makrutzki, M & Blank, C 2019, 'An open-label, multicentre safety study of vemurafenib in patients with BRAFV600-mutant metastatic melanoma: final analysis and a validated prognostic scoring system' European Journal of Cancer, vol. 107, pp. 175-185. https://doi.org/10.1016/j.ejca.2018.11.018
Larkin, James ; Brown, Michael P ; Arance, Ana M ; Hauschild, Axel ; Queirolo, Paola ; Vecchio, Michele Del ; Ascierto, Paolo A ; Krajsová, Ivana ; Schachter, Jacob ; Neyns, Bart ; Garbe, Claus ; Sileni, Vanna Chiarion ; Mandalà, Mario ; Gogas, Helen ; Espinosa, Enrique ; Hospers, Geke ; Lorigan, Paul ; Nyakas, Marta ; Guminski, Alex ; Liszkay, Gabriela ; Rutkowski, Piotr ; Miller, Wilson ; Donica, Margarita ; Makrutzki, Martina ; Blank, Christian. / An open-label, multicentre safety study of vemurafenib in patients with BRAFV600-mutant metastatic melanoma : final analysis and a validated prognostic scoring system. In: European Journal of Cancer. 2019 ; Vol. 107. pp. 175-185.
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T1 - An open-label, multicentre safety study of vemurafenib in patients with BRAFV600-mutant metastatic melanoma

T2 - final analysis and a validated prognostic scoring system

AU - Larkin, James

AU - Brown, Michael P

AU - Arance, Ana M

AU - Hauschild, Axel

AU - Queirolo, Paola

AU - Vecchio, Michele Del

AU - Ascierto, Paolo A

AU - Krajsová, Ivana

AU - Schachter, Jacob

AU - Neyns, Bart

AU - Garbe, Claus

AU - Sileni, Vanna Chiarion

AU - Mandalà, Mario

AU - Gogas, Helen

AU - Espinosa, Enrique

AU - Hospers, Geke

AU - Lorigan, Paul

AU - Nyakas, Marta

AU - Guminski, Alex

AU - Liszkay, Gabriela

AU - Rutkowski, Piotr

AU - Miller, Wilson

AU - Donica, Margarita

AU - Makrutzki, Martina

AU - Blank, Christian

N1 - Copyright © 2018 Elsevier Ltd. All rights reserved.

PY - 2019/1

Y1 - 2019/1

N2 - BACKGROUND: The oncogenic BRAF inhibitor vemurafenib improves outcomes for patients with advanced BRAFV600 mutation-positive melanoma compared with cytotoxic chemotherapy. Vemurafenib is now approved for use in this patient population.PATIENTS AND METHODS: In this open-label, multicentre study, patients with previously treated or untreated melanoma and the BRAFV600 mutation received vemurafenib 960 mg twice daily. The primary endpoint was safety. In a post hoc analysis, overall survival (OS) was analysed according to a prognostic scoring system developed using Eastern Cooperative Oncology Group performance status, existence of brain metastases and baseline serum lactate dehydrogenase level. The index was validated using data from patients treated with vemurafenib or dacarbazine in three clinical trials and data from patients treated with vemurafenib plus cobimetinib in two studies. The study is registered with ClinicalTrials.gov (NCT01307397).RESULTS: Between March 2011 and January 2013, 3224 patients were enrolled, and 3219 patients received ≥1 dose of vemurafenib (safety population); median follow-up time was 33.4 months. Vemurafenib's long-term benefits were confirmed, and no new safety signals identified. The prognostic index showed between-group differences in OS, with tight, non-overlapping confidence intervals. Validation in a pooled group of 666 vemurafenib-treated clinical trial patients revealed a similar pattern; the pattern was similar in 280 patients treated with vemurafenib plus cobimetinib.CONCLUSIONS: Final results from the vemurafenib safety study confirm vemurafenib's tolerability in BRAFV600 mutation-positive patients and resemble those seen in real-world clinical practice. This index may be useful in patients on combination therapy and as a basis for further work.

AB - BACKGROUND: The oncogenic BRAF inhibitor vemurafenib improves outcomes for patients with advanced BRAFV600 mutation-positive melanoma compared with cytotoxic chemotherapy. Vemurafenib is now approved for use in this patient population.PATIENTS AND METHODS: In this open-label, multicentre study, patients with previously treated or untreated melanoma and the BRAFV600 mutation received vemurafenib 960 mg twice daily. The primary endpoint was safety. In a post hoc analysis, overall survival (OS) was analysed according to a prognostic scoring system developed using Eastern Cooperative Oncology Group performance status, existence of brain metastases and baseline serum lactate dehydrogenase level. The index was validated using data from patients treated with vemurafenib or dacarbazine in three clinical trials and data from patients treated with vemurafenib plus cobimetinib in two studies. The study is registered with ClinicalTrials.gov (NCT01307397).RESULTS: Between March 2011 and January 2013, 3224 patients were enrolled, and 3219 patients received ≥1 dose of vemurafenib (safety population); median follow-up time was 33.4 months. Vemurafenib's long-term benefits were confirmed, and no new safety signals identified. The prognostic index showed between-group differences in OS, with tight, non-overlapping confidence intervals. Validation in a pooled group of 666 vemurafenib-treated clinical trial patients revealed a similar pattern; the pattern was similar in 280 patients treated with vemurafenib plus cobimetinib.CONCLUSIONS: Final results from the vemurafenib safety study confirm vemurafenib's tolerability in BRAFV600 mutation-positive patients and resemble those seen in real-world clinical practice. This index may be useful in patients on combination therapy and as a basis for further work.

U2 - 10.1016/j.ejca.2018.11.018

DO - 10.1016/j.ejca.2018.11.018

M3 - Article

VL - 107

SP - 175

EP - 185

JO - European Journal of Cancer

JF - European Journal of Cancer

SN - 0959-8049

ER -