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; 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:10.3389/fonc.2022.751453

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

Front Oncol. 2022 Feb 18:12:751453. doi: 10.3389/fonc.2022.751453. eCollection 2022.

Authors

Annika Kurreck¹, Volker Heinemann^{2

3}, Ludwig Fischer von Weikersthal⁴, Thomas Decker⁵, Florian Kaiser⁶, Jens Uhlig⁷, Michael Schenk⁸, Jens Freiberg-Richter⁹, Bettina Peuser¹⁰, Claudio Denzlinger¹¹, Ullrich Graeven¹², Kathrin Heinrich², Swantje Held¹³, Arndt Stahler¹⁴, Annabel Helga Sophie Alig¹⁴, Ivan Jelas¹, Jobst C von Einem¹⁴, Sebastian Stintzing¹⁴, Clemens Giessen-Jung², Dominik P Modest¹

Affiliations

¹ Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Hematology, Oncology, and Tumor Immunology Charité Virchow Klinikum (CVK), Berlin, Germany.
² 2 Department of Medicine III, University Hospital, Ludwig-Maximilians-Universität (LMU) Munich, München, Germany.
³ German Cancer Consortium (DKTK), Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany.
⁴ Gesundheitszentrum St. Marien, Amberg, Germany.
⁵ Oncological Practice, Ravensburg, Germany.
⁶ Oncological Practice, Landshut, Germany.
⁷ Oncological Practice, Naunhof, Germany.
⁸ Department of Hematology and Oncology, Clinic "Barmherzige Brüder Regensburg", Regensburg, Germany.
⁹ Oncological Practice, Dresden, Germany.
¹⁰ Oncological Practice am Diakonissenhaus, Leipzig, Germany.
¹¹ Department of Internal Medicine III (Oncology, Hematology, Palliative Care) Marienhospital, Stuttgart, Germany.
¹² Department of Hematology, Oncology, and Gastroenterology, Kliniken Maria Hilf GmbH, Mönchengladbach, Germany.
¹³ ClinAssess GmbH, Leverkusen, Germany.
¹⁴ Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Hematology, Oncology, and Tumor Immunology Campus Charité Mitte (CCM), Berlin, Germany.

Abstract

Introduction: Early 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.

Methods: DpR (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.

Results: In 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).

Conclusions: Initial 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.

Keywords: combination chemotherapy; depth of response; disease dynamics; early tumor shrinkage; metastatic colorectal cancer (CRC).

Copyright © 2022 Kurreck, Heinemann, Fischer von Weikersthal, Decker, Kaiser, Uhlig, Schenk, Freiberg-Richter, Peuser, Denzlinger, Graeven, Heinrich, Held, Stahler, Alig, Jelas, von Einem, Stintzing, Giessen-Jung and Modest.