Consensus molecular subtypes in metastatic colorectal cancer treated with sequential versus combined fluoropyrimidine, bevacizumab and irinotecan (XELAVIRI trial).
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.
['Stahler|Arndt|A|', 'Heinemann|Volker|V|', 'Schuster|Veronika|V|', 'Heinrich|Kathrin|K|', 'Kurreck|Annika|A|', 'Gießen-Jung|Clemens|C|', 'Fischer von Weikersthal|Ludwig|L|', 'Kaiser|Florian|F|', 'Decker|Thomas|T|', 'Held|Swantje|S|', 'Graeven|Ullrich|U|', 'Schwaner|Ingo|I|', 'Denzlinger|Claudio|C|', 'Schenk|Michael|M|', 'Neumann|Jens|J|', 'Kirchner|Thomas|T|', 'Jung|Andreas|A|', 'Kumbrink|Jörg|J|', 'Stintzing|Sebastian|S|', 'Modest|Dominik P|DP|']
D000328:Adult D000368:Aged D000369:Aged, 80 and over D000971:Antineoplastic Combined Chemotherapy Protocols D000068258:Bevacizumab D015179:Colorectal Neoplasms D005260:Female D005472:Fluorouracil D011905:Genes, ras D006801:Humans D000077146:Irinotecan D008297:Male D008875:Middle Aged D009362:Neoplasm Metastasis D048493:Proto-Oncogene Proteins B-raf
Consensus molecular subtypes Metastatic colorectal cancer Sequential Bevacizumab RAS