Adverse events associated with encorafenib plus binimetinib in the COLUMBUS study: incidence, course and management

Helen J. Gogas, Keith T. Flaherty, Reinhard Dummer, Paolo A. Ascierto, Ana Arance, Mario Mandala, Gabriella Liszkay, Claus Garbe, Dirk Schadendorf, Ivana Krajsova, Ralf Gutzmer, Vanna Chiarion Sileni, Caroline Dutriaux, Jan Willem B. de Groot, Naoya Yamazaki, Carmen Loquai, Ashwin Gollerkeri, Michael D. Pickard, Caroline Robert

Research output: Contribution to journalArticle

Abstract

Background: Dual inhibition of the mitogen-activated protein kinase pathway with BRAF/MEK inhibitor (BRAFi/MEKi) therapy is a standard treatment for BRAFV600-mutant metastatic melanoma and has historically been associated with grade III pyrexia or photosensitivity depending on the combination used. The objective of this study was to fully describe adverse events from the COLUMBUS study evaluating the most recent BRAF/MEK inhibitor combination encorafenib+binimetinib. Patients and methods: Patients with locally advanced, unresectable or metastatic BRAFV600-mutant melanoma were randomised to receive encorafenib 450 mg once daily plus binimetinib 45 mg twice daily, encorafenib 300 mg once daily or vemurafenib 960 mg twice daily. Adverse events that represent known effects of available BRAFi and/or MEKi were evaluated. Results: The safety population included a total of 570 patients (encorafenib+binimetinib = 192; encorafenib = 192; vemurafenib = 186). Median duration of exposure was longer with encorafenib+binimetinib (51 weeks) than with encorafenib (31 weeks) or vemurafenib (27 weeks). Common BRAFi/MEKi toxicities with encorafenib+binimetinib were generally manageable, reversible and infrequently associated with discontinuation. Pyrexia was less frequent with encorafenib+binimetinib (18%) and encorafenib (16%) than with vemurafenib (30%) and occurred later in the course of therapy with encorafenib+binimetinib (median time to first onset: 85 days versus 2.5 days and 19 days, respectively). The incidence of photosensitivity was lower with encorafenib+binimetinib (5%) and encorafenib (4%) than with vemurafenib (30%). The incidence of serous retinopathy was higher with encorafenib+binimetinib (20%) than with encorafenib (2%) or vemurafenib (2%), but no patients discontinued encorafenib+binimetinib because of this event. Conclusion: Encorafenib+binimetinib is generally well tolerated and has a low discontinuation rate in patients with BRAFV600-mutant melanoma, with a distinct safety profile as compared with other anti-BRAF/MEK targeted therapies. Trial registration: ClinicalTrials.gov (Identifier: NCT01909453) and with EudraCT (number 2013-001176-38).

Original languageEnglish
Pages (from-to)97-106
Number of pages10
JournalEuropean Journal of Cancer
Volume119
DOIs
Publication statusPublished - Sep 1 2019

Fingerprint

Cohort Studies
Mitogen-Activated Protein Kinase Kinases
Melanoma
encorafenib
MEK162
Fever
Safety
Incidence
Therapeutics
Mitogen-Activated Protein Kinases
PLX4032

Keywords

  • Binimetinib
  • Encorafenib
  • Melanoma
  • Safety
  • Vemurafenib

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Adverse events associated with encorafenib plus binimetinib in the COLUMBUS study : incidence, course and management. / Gogas, Helen J.; Flaherty, Keith T.; Dummer, Reinhard; Ascierto, Paolo A.; Arance, Ana; Mandala, Mario; Liszkay, Gabriella; Garbe, Claus; Schadendorf, Dirk; Krajsova, Ivana; Gutzmer, Ralf; Sileni, Vanna Chiarion; Dutriaux, Caroline; de Groot, Jan Willem B.; Yamazaki, Naoya; Loquai, Carmen; Gollerkeri, Ashwin; Pickard, Michael D.; Robert, Caroline.

In: European Journal of Cancer, Vol. 119, 01.09.2019, p. 97-106.

Research output: Contribution to journalArticle

Gogas, HJ, Flaherty, KT, Dummer, R, Ascierto, PA, Arance, A, Mandala, M, Liszkay, G, Garbe, C, Schadendorf, D, Krajsova, I, Gutzmer, R, Sileni, VC, Dutriaux, C, de Groot, JWB, Yamazaki, N, Loquai, C, Gollerkeri, A, Pickard, MD & Robert, C 2019, 'Adverse events associated with encorafenib plus binimetinib in the COLUMBUS study: incidence, course and management', European Journal of Cancer, vol. 119, pp. 97-106. https://doi.org/10.1016/j.ejca.2019.07.016
Gogas, Helen J. ; Flaherty, Keith T. ; Dummer, Reinhard ; Ascierto, Paolo A. ; Arance, Ana ; Mandala, Mario ; Liszkay, Gabriella ; Garbe, Claus ; Schadendorf, Dirk ; Krajsova, Ivana ; Gutzmer, Ralf ; Sileni, Vanna Chiarion ; Dutriaux, Caroline ; de Groot, Jan Willem B. ; Yamazaki, Naoya ; Loquai, Carmen ; Gollerkeri, Ashwin ; Pickard, Michael D. ; Robert, Caroline. / Adverse events associated with encorafenib plus binimetinib in the COLUMBUS study : incidence, course and management. In: European Journal of Cancer. 2019 ; Vol. 119. pp. 97-106.
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abstract = "Background: Dual inhibition of the mitogen-activated protein kinase pathway with BRAF/MEK inhibitor (BRAFi/MEKi) therapy is a standard treatment for BRAFV600-mutant metastatic melanoma and has historically been associated with grade III pyrexia or photosensitivity depending on the combination used. The objective of this study was to fully describe adverse events from the COLUMBUS study evaluating the most recent BRAF/MEK inhibitor combination encorafenib+binimetinib. Patients and methods: Patients with locally advanced, unresectable or metastatic BRAFV600-mutant melanoma were randomised to receive encorafenib 450 mg once daily plus binimetinib 45 mg twice daily, encorafenib 300 mg once daily or vemurafenib 960 mg twice daily. Adverse events that represent known effects of available BRAFi and/or MEKi were evaluated. Results: The safety population included a total of 570 patients (encorafenib+binimetinib = 192; encorafenib = 192; vemurafenib = 186). Median duration of exposure was longer with encorafenib+binimetinib (51 weeks) than with encorafenib (31 weeks) or vemurafenib (27 weeks). Common BRAFi/MEKi toxicities with encorafenib+binimetinib were generally manageable, reversible and infrequently associated with discontinuation. Pyrexia was less frequent with encorafenib+binimetinib (18{\%}) and encorafenib (16{\%}) than with vemurafenib (30{\%}) and occurred later in the course of therapy with encorafenib+binimetinib (median time to first onset: 85 days versus 2.5 days and 19 days, respectively). The incidence of photosensitivity was lower with encorafenib+binimetinib (5{\%}) and encorafenib (4{\%}) than with vemurafenib (30{\%}). The incidence of serous retinopathy was higher with encorafenib+binimetinib (20{\%}) than with encorafenib (2{\%}) or vemurafenib (2{\%}), but no patients discontinued encorafenib+binimetinib because of this event. Conclusion: Encorafenib+binimetinib is generally well tolerated and has a low discontinuation rate in patients with BRAFV600-mutant melanoma, with a distinct safety profile as compared with other anti-BRAF/MEK targeted therapies. Trial registration: ClinicalTrials.gov (Identifier: NCT01909453) and with EudraCT (number 2013-001176-38).",
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T1 - Adverse events associated with encorafenib plus binimetinib in the COLUMBUS study

T2 - incidence, course and management

AU - Gogas, Helen J.

AU - Flaherty, Keith T.

AU - Dummer, Reinhard

AU - Ascierto, Paolo A.

AU - Arance, Ana

AU - Mandala, Mario

AU - Liszkay, Gabriella

AU - Garbe, Claus

AU - Schadendorf, Dirk

AU - Krajsova, Ivana

AU - Gutzmer, Ralf

AU - Sileni, Vanna Chiarion

AU - Dutriaux, Caroline

AU - de Groot, Jan Willem B.

AU - Yamazaki, Naoya

AU - Loquai, Carmen

AU - Gollerkeri, Ashwin

AU - Pickard, Michael D.

AU - Robert, Caroline

PY - 2019/9/1

Y1 - 2019/9/1

N2 - Background: Dual inhibition of the mitogen-activated protein kinase pathway with BRAF/MEK inhibitor (BRAFi/MEKi) therapy is a standard treatment for BRAFV600-mutant metastatic melanoma and has historically been associated with grade III pyrexia or photosensitivity depending on the combination used. The objective of this study was to fully describe adverse events from the COLUMBUS study evaluating the most recent BRAF/MEK inhibitor combination encorafenib+binimetinib. Patients and methods: Patients with locally advanced, unresectable or metastatic BRAFV600-mutant melanoma were randomised to receive encorafenib 450 mg once daily plus binimetinib 45 mg twice daily, encorafenib 300 mg once daily or vemurafenib 960 mg twice daily. Adverse events that represent known effects of available BRAFi and/or MEKi were evaluated. Results: The safety population included a total of 570 patients (encorafenib+binimetinib = 192; encorafenib = 192; vemurafenib = 186). Median duration of exposure was longer with encorafenib+binimetinib (51 weeks) than with encorafenib (31 weeks) or vemurafenib (27 weeks). Common BRAFi/MEKi toxicities with encorafenib+binimetinib were generally manageable, reversible and infrequently associated with discontinuation. Pyrexia was less frequent with encorafenib+binimetinib (18%) and encorafenib (16%) than with vemurafenib (30%) and occurred later in the course of therapy with encorafenib+binimetinib (median time to first onset: 85 days versus 2.5 days and 19 days, respectively). The incidence of photosensitivity was lower with encorafenib+binimetinib (5%) and encorafenib (4%) than with vemurafenib (30%). The incidence of serous retinopathy was higher with encorafenib+binimetinib (20%) than with encorafenib (2%) or vemurafenib (2%), but no patients discontinued encorafenib+binimetinib because of this event. Conclusion: Encorafenib+binimetinib is generally well tolerated and has a low discontinuation rate in patients with BRAFV600-mutant melanoma, with a distinct safety profile as compared with other anti-BRAF/MEK targeted therapies. Trial registration: ClinicalTrials.gov (Identifier: NCT01909453) and with EudraCT (number 2013-001176-38).

AB - Background: Dual inhibition of the mitogen-activated protein kinase pathway with BRAF/MEK inhibitor (BRAFi/MEKi) therapy is a standard treatment for BRAFV600-mutant metastatic melanoma and has historically been associated with grade III pyrexia or photosensitivity depending on the combination used. The objective of this study was to fully describe adverse events from the COLUMBUS study evaluating the most recent BRAF/MEK inhibitor combination encorafenib+binimetinib. Patients and methods: Patients with locally advanced, unresectable or metastatic BRAFV600-mutant melanoma were randomised to receive encorafenib 450 mg once daily plus binimetinib 45 mg twice daily, encorafenib 300 mg once daily or vemurafenib 960 mg twice daily. Adverse events that represent known effects of available BRAFi and/or MEKi were evaluated. Results: The safety population included a total of 570 patients (encorafenib+binimetinib = 192; encorafenib = 192; vemurafenib = 186). Median duration of exposure was longer with encorafenib+binimetinib (51 weeks) than with encorafenib (31 weeks) or vemurafenib (27 weeks). Common BRAFi/MEKi toxicities with encorafenib+binimetinib were generally manageable, reversible and infrequently associated with discontinuation. Pyrexia was less frequent with encorafenib+binimetinib (18%) and encorafenib (16%) than with vemurafenib (30%) and occurred later in the course of therapy with encorafenib+binimetinib (median time to first onset: 85 days versus 2.5 days and 19 days, respectively). The incidence of photosensitivity was lower with encorafenib+binimetinib (5%) and encorafenib (4%) than with vemurafenib (30%). The incidence of serous retinopathy was higher with encorafenib+binimetinib (20%) than with encorafenib (2%) or vemurafenib (2%), but no patients discontinued encorafenib+binimetinib because of this event. Conclusion: Encorafenib+binimetinib is generally well tolerated and has a low discontinuation rate in patients with BRAFV600-mutant melanoma, with a distinct safety profile as compared with other anti-BRAF/MEK targeted therapies. Trial registration: ClinicalTrials.gov (Identifier: NCT01909453) and with EudraCT (number 2013-001176-38).

KW - Binimetinib

KW - Encorafenib

KW - Melanoma

KW - Safety

KW - Vemurafenib

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