Frontiers in Oncology (Feb 2022)

Response and Disease Dynamics in Untreated Metastatic Colorectal Cancer With Bevacizumab-Based Sequential vs. Combination Chemotherapy—Analysis of the Phase 3 XELAVIRI Trial

  • Annika Kurreck,
  • Volker Heinemann,
  • Volker Heinemann,
  • Ludwig Fischer von Weikersthal,
  • Thomas Decker,
  • Florian Kaiser,
  • Jens Uhlig,
  • Michael Schenk,
  • Jens Freiberg-Richter,
  • Bettina Peuser,
  • Claudio Denzlinger,
  • Ullrich Graeven,
  • Kathrin Heinrich,
  • Swantje Held,
  • Arndt Stahler,
  • Annabel Helga Sophie Alig,
  • Ivan Jelas,
  • Jobst C. von Einem,
  • Sebastian Stintzing,
  • Clemens Giessen-Jung,
  • Dominik P. Modest

DOI
https://doi.org/10.3389/fonc.2022.751453
Journal volume & issue
Vol. 12

Abstract

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IntroductionEarly tumor shrinkage (ETS), depth of response (DpR), and time to DpR represent exploratory endpoints that may serve as early efficacy parameters and predictors of long-term outcome in metastatic colorectal cancer (mCRC). We analyzed these endpoints in mCRC patients treated with first-line bevacizumab-based sequential (initial fluoropyrimidines) versus combination (initial fluoropyrimidines plus irinotecan) chemotherapy within the phase 3 XELAVIRI trial.MethodsDpR (change from baseline to smallest tumor diameter), ETS (≥20% reduction in tumor diameter at first reassessment), and time to DpR (study randomization to DpR image) were analyzed. We evaluated progression-free survival and overall survival with ETS as stratification parameter according to treatment arm, molecular subgroup, and sex.ResultsIn 370 patients analyzed, a higher rate of ETS (60.9% vs. 43.5%; p = 0.001) and significantly greater DpR (-40.0% vs. -24.7%; p < 0.001) were observed in the initial combination therapy arm. The improvement was pronounced in RAS/BRAF wild-type tumors. ETS correlated with improved survival irrespective of treatment arm (PFS: p < 0.001; OS: p = 0.012) and molecular subgroup (PFS: p < 0.001; OS: p < 0.001). Male patients in contrast to female patients with ETS had survival benefit (PFS: p < 0.001, HR 0.532; OS: p < 0.001, HR 0.574 vs. PFS: p = 0.107; OS: p = 0.965).ConclusionsInitial irinotecan-based combination therapy with bevacizumab improved ETS and DpR in mCRC patients with a particularly high irinotecan sensitivity of RAS/BRAF wild-type tumors. ETS seems to be a suitable prognostic marker for fluoropyrimidine- and bevacizumab-based combinations in mCRC. This finding was rather driven by male patients, potentially indicating that ETS might be less predictive of long-term outcome in an elderly, female population.

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