Consensus molecular subtypes in metastatic colorectal cancer treated with sequential versus combined fluoropyrimidine, bevacizumab and irinotecan (XELAVIRI trial).
Adult
Aged
Aged, 80 and over
Antineoplastic Combined Chemotherapy Protocols
/ therapeutic use
Bevacizumab
/ administration & dosage
Colorectal Neoplasms
/ drug therapy
Female
Fluorouracil
/ administration & dosage
Genes, ras
Humans
Irinotecan
/ administration & dosage
Male
Middle Aged
Neoplasm Metastasis
Proto-Oncogene Proteins B-raf
/ genetics
Bevacizumab
Consensus molecular subtypes
Metastatic colorectal cancer
RAS
Sequential
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:
11 2021
11 2021
Historique:
received:
05
07
2021
revised:
09
08
2021
accepted:
11
08
2021
pubmed:
11
9
2021
medline:
1
12
2021
entrez:
10
9
2021
Statut:
ppublish
Résumé
The XELAVIRI trial compared sequential (fluoropyrimidine and bevacizumab; irinotecan (Iri) at progression) versus initial combination therapy (fluoropyrimidine, bevacizumab, Iri) of treatment-naïve metastatic colorectal cancer (mCRC). In the confirmatory analysis, the primary end-point (non-inferiority of sequential therapy regarding time to failure of strategy, TFS) was not met. Nevertheless, significant differences regarding treatment efficacy were observed according to RAS status. Here, we evaluate the consensus molecular subtypes (CMS) as additional biomarkers for sequential versus combination therapy. Gene expression was measured using NanoString after mRNA extraction from formalin-fixed paraffin-embedded tumour specimens. CMS were predicted using multinomial regression and correlated with updated data for TFS, overall (OS) and progression-free survival. CMS were predicted in 337 of 421 (80.0%) patients (CMS1: 18.4%; CMS2: 51.6%; CMS3: 2.7%; CMS4: 27.3%). CMS2 together with RAS/BRAF wild-type status was identified as potential predictive marker of benefit from initial combination therapy for OS (HR 0.56, 95% CI 0.33-0.96, p = 0.036) and progression-free survival (HR 0.28, 95% CI 0.29-0.79, p = 0.004) and also trending in TFS (HR 0.63, 90% CI 0.41-0.95, p = 0.066). In patients with RAS-mutated mCRC, CMS1 was associated with longer OS after initial combination therapy (HR 0.43, 95% CI 0.20-0.95, p = 0.038). Interaction testing (two-sided) of CMS and RAS/BRAF status in favour of the combination treatment strategy was significant for OS (p = 0.012) CONCLUSIONS: In patients with RAS/BRAF wild-type mCRC, CMS2 may serve as an additional biomarker of benefit from the initial combination therapy, including Iri. Trial registration ID (clinicaltrials.gov) NCT01249638.
Sections du résumé
BACKGROUND
The XELAVIRI trial compared sequential (fluoropyrimidine and bevacizumab; irinotecan (Iri) at progression) versus initial combination therapy (fluoropyrimidine, bevacizumab, Iri) of treatment-naïve metastatic colorectal cancer (mCRC). In the confirmatory analysis, the primary end-point (non-inferiority of sequential therapy regarding time to failure of strategy, TFS) was not met. Nevertheless, significant differences regarding treatment efficacy were observed according to RAS status. Here, we evaluate the consensus molecular subtypes (CMS) as additional biomarkers for sequential versus combination therapy.
MATERIAL AND METHODS
Gene expression was measured using NanoString after mRNA extraction from formalin-fixed paraffin-embedded tumour specimens. CMS were predicted using multinomial regression and correlated with updated data for TFS, overall (OS) and progression-free survival.
RESULTS
CMS were predicted in 337 of 421 (80.0%) patients (CMS1: 18.4%; CMS2: 51.6%; CMS3: 2.7%; CMS4: 27.3%). CMS2 together with RAS/BRAF wild-type status was identified as potential predictive marker of benefit from initial combination therapy for OS (HR 0.56, 95% CI 0.33-0.96, p = 0.036) and progression-free survival (HR 0.28, 95% CI 0.29-0.79, p = 0.004) and also trending in TFS (HR 0.63, 90% CI 0.41-0.95, p = 0.066). In patients with RAS-mutated mCRC, CMS1 was associated with longer OS after initial combination therapy (HR 0.43, 95% CI 0.20-0.95, p = 0.038). Interaction testing (two-sided) of CMS and RAS/BRAF status in favour of the combination treatment strategy was significant for OS (p = 0.012) CONCLUSIONS: In patients with RAS/BRAF wild-type mCRC, CMS2 may serve as an additional biomarker of benefit from the initial combination therapy, including Iri.
TRIAL REGISTRATION
Trial registration ID (clinicaltrials.gov) NCT01249638.
Identifiants
pubmed: 34507244
pii: S0959-8049(21)00535-9
doi: 10.1016/j.ejca.2021.08.017
pii:
doi:
Substances chimiques
Bevacizumab
2S9ZZM9Q9V
Irinotecan
7673326042
BRAF protein, human
EC 2.7.11.1
Proto-Oncogene Proteins B-raf
EC 2.7.11.1
Fluorouracil
U3P01618RT
Banques de données
ClinicalTrials.gov
['NCT01249638']
Types de publication
Clinical Trial, Phase III
Comparative Study
Journal Article
Randomized Controlled Trial
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
71-80Informations de copyright
Copyright © 2021 Elsevier Ltd. All rights reserved.