Adverse events associated with encorafenib plus binimetinib in the COLUMBUS study: incidence, course and management.
Antineoplastic Combined Chemotherapy Protocols
/ administration & dosage
Benzimidazoles
/ administration & dosage
Carbamates
/ administration & dosage
Fatigue
/ chemically induced
Female
Humans
Incidence
Male
Melanoma
/ drug therapy
Middle Aged
Mitogen-Activated Protein Kinases
/ antagonists & inhibitors
Mutation
Nausea
/ chemically induced
Protein Kinase Inhibitors
/ administration & dosage
Proto-Oncogene Proteins B-raf
/ antagonists & inhibitors
Skin Neoplasms
/ drug therapy
Sulfonamides
/ administration & dosage
Vemurafenib
/ administration & dosage
Vomiting
/ chemically induced
Binimetinib
Encorafenib
Melanoma
Safety
Vemurafenib
Journal
European journal of cancer (Oxford, England : 1990)
ISSN: 1879-0852
Titre abrégé: Eur J Cancer
Pays: England
ID NLM: 9005373
Informations de publication
Date de publication:
09 2019
09 2019
Historique:
received:
28
05
2019
revised:
17
07
2019
accepted:
19
07
2019
pubmed:
23
8
2019
medline:
9
6
2020
entrez:
23
8
2019
Statut:
ppublish
Résumé
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 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. 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. 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. ClinicalTrials.gov (Identifier: NCT01909453) and with EudraCT (number 2013-001176-38).
Sections du résumé
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).
Identifiants
pubmed: 31437754
pii: S0959-8049(19)30424-1
doi: 10.1016/j.ejca.2019.07.016
pii:
doi:
Substances chimiques
Benzimidazoles
0
Carbamates
0
Protein Kinase Inhibitors
0
Sulfonamides
0
binimetinib
181R97MR71
Vemurafenib
207SMY3FQT
encorafenib
8L7891MRB6
Proto-Oncogene Proteins B-raf
EC 2.7.11.1
Mitogen-Activated Protein Kinases
EC 2.7.11.24
Banques de données
ClinicalTrials.gov
['NCT01909453']
Types de publication
Clinical Trial, Phase III
Journal Article
Multicenter Study
Randomized Controlled Trial
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
97-106Informations de copyright
Copyright © 2019 The Author(s). Published by Elsevier Ltd.. All rights reserved.