Gender-dependent survival benefit from first-line irinotecan in metastatic colorectal cancer. Subgroup analysis of a phase III trial (XELAVIRI-study, AIO-KRK-0110)

Abstract

Background: XELAVIRI compared sequential (Arm A) versus initial (Arm B) irinotecan in combination with fluoropyrimidine plus bevacizumab in patients with metastatic colorectal cancer, trial identification: NCT01249638. In the full analysis set of the study, non-inferiority of time to failure of strategy (TFS) was not shown. The present analysis was performed to evaluate the effect of gender on treatment outcome and tolerability.

Methods: The study end-points overall response rate (ORR), progression-free survival (PFS), TFS and overall survival (OS) were evaluated in female versus male patients and in molecular subgroups (i.e. RAS mutational status). Interaction of treatment and gender was tested by likelihood ratio tests.

Results: In total, 281 male and 140 female patients (n = 421) were evaluated. Among the male patients, the ORR was 33.6% without and 58.3% with initial irinotecan (P < 0.001). PFS (hazard ratio [HR] 0.54; 95% confidence interval [CI] 0.42-0.69; P < 0.001) and OS (HR 0.63; 95% CI 0.47-0.85; P = 0.002) were also significantly better with initial irinotecan. Among the female patients, the ORR was 42.7% in Arm A and 43.1% in Arm B, PFS was similar (HR 1.09; 95% CI 0.76-1.55; P = 0.649) without and with initial irinotecan. A strong trend for inferior outcome with regard to OS with initial irinotecan was observed (HR 1.46; 95% CI 0.95-2.24; P = 0.081) and the trend reached significance in the multivariate analysis (HR 1.78; 95% CI 1.08-2.95; P = 0.02). Formal interaction of treatment and gender was observed for ORR (P = 0.018), PFS (P = 0.002) and OS (P = 0.001). Treatment-related adverse events were not significantly different between male and female patients.

Conclusions: The present analysis suggests that gender interacts with efficacy of initial irinotecan when used in combination with fluoropyrimidines and bevacizumab. Although male patients derived a significant and clinically meaningful benefit from initial combination chemotherapy, this was not observed in female patients.

Keywords: Gender; Irinotecan; Metastatic colorectal cancer.

Conflict of interest statement

Conflict of interest statement The authors declare the following financial interests/personal relationships, which may be considered as potential competing interests: Kathrin Heinrich:Honoraria: Roche. Travel, Accommodations, Expenses: Lilly, AMGEN, Celgene. Dominik Paul Modest:Honoraria: Merck Serono, Amgen, Roche, Servier, Bristol-Myers Squibb, Pfizer, Sirtex Medical. Consulting or Advisory Role: Merck Serono, Amgen, Bayer. Research Funding: Merck Serono (Inst), Roche (Inst), Amgen (Inst). Travel, Accommodations, Expenses: Amgen, Merck Serono, Bayer, Servier, Bristol-Myers Squibb. Ingrid Ricard:Consulting or Advisory Role: Roche. Ludwig Fischer von Weikersthal:Honoraria: Novartis, Roche, Sanofi. Travel, Accommodations, Expenses: Amgen. Thomas Decker:Consulting or Advisory Role: Novartis. Ullrich Graeven:Honoraria: Servier, Boehringer Ingelheim, Sirtex Medical, Daiichi Sankyo. Consulting or Advisory Role: Novartis, Merck, Amgen, Hexal, Bristol-Myers Squibb. Travel, Accommodations, Expenses: Merck, Amgen. Claudio Denzlinger:Consulting or Advisory Role: Amgen, Roche, Janssen Pharmaceuticals. Travel, Accommodations, Expenses: Celgene, Janssen Pharmaceuticals, Novartis. Clemens Giessen-Jung:Travel, Accommodations, Expenses: Roche. Arndt Stahler:Honoraria: Roche. Travel, Accommodations, Expenses: AMGEN, Roche, MSD Sharp & Dohme. Marlies Michl:Honoraria: SIRTeX, Roche, MSD. Travel, Accommodations, Expenses: SIRTeX, Amgen, Merck. Andreas Jung:Consulting or Advisory Role: Boehringer Ingelheim, Roche, Biocartis, Bristol-Myers Squibb, Amgen, AstraZeneca, Thermo Fisher Scientific, Merck. Speakers' Bureau: AstraZeneca, Roche, Bristol-Myers Squibb, Amgen. Thomas Kirchner:Consulting/Advisory Role: Amgen, AstraZeneca, Merck KGaA, MSD, Novartis, Pfizer, Roche. Research Funding:Merck, Roche. Speaker's Bureau: Merck, Astra Zeneca. Sebastian Stintzing:Honoraria: Merck, Roche, Amgen, Bayer, Sanofi, Sirtex Medical, Eli Lilly. Consulting or Advisory Role: Merck, Roche, Sanofi, Bayer, Amgen, Boehringer Ingelheim, Eli Lilly, Takeda. Travel, Accommodations, Expenses: Merck, Roche, Sanofi, Bayer, Sirtex Medical, Amgen, Eli Lilly, Takeda. Volker Heinemann:Honoraria: Roche, Celgene, Amgen, Sanofi, Merck, Sirtex Medical, Baxalta, Eli Lilly, Boehringer Ingelheim, Taiho Pharmaceutical, Servier. Consulting or Advisory Role: Merck, Amgen, Roche, Sanofi, Boehringer Ingelheim, Celgene, Sirtex Medical, Baxalta, Servier, Halozyme, MSD, Bristol-Myers Squibb. Swantje Held, Jens Uhlig, Michael Schenk, Jens Freiberg-Richter, Bettina Peuser and Florian Kaiser: None declared.

Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.