Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2022 Feb 18:12:751453.
doi: 10.3389/fonc.2022.751453. eCollection 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  1 , Volker Heinemann  2   3 , Ludwig Fischer von Weikersthal  4 , Thomas Decker  5 , Florian Kaiser  6 , Jens Uhlig  7 , Michael Schenk  8 , Jens Freiberg-Richter  9 , Bettina Peuser  10 , Claudio Denzlinger  11 , Ullrich Graeven  12 , Kathrin Heinrich  2 , Swantje Held  13 , Arndt Stahler  14 , Annabel Helga Sophie Alig  14 , Ivan Jelas  1 , Jobst C von Einem  14 , Sebastian Stintzing  14 , Clemens Giessen-Jung  2 , Dominik P Modest  1
Affiliations

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 et al. Front Oncol. .

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).

PubMed Disclaimer

Conflict of interest statement

AK: Honoraria: Taiho Pharmaceutical, Servier; Travel, Accommodations, Expenses: Roche, Medac. VH: 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; Research Funding: Merck (Inst), Amgen (Inst), Roche (Inst), Celgene (Inst), Boehringer Ingelheim (Inst), Sirtex Medical (Inst), Shire (Inst); Travel, Accommodations, Expenses: Merck, Roche, Sirtex Medical, Amgen, Servier, Shire, MSD, Bristol-Myers Squibb. LF: Honoraria: Novartis, Roche, Sanofi; Travel, Accommodations, Expenses: Amgen. TD: Consulting or Advisory Role: Novartis. CD: Honoraria: Janssen, Novartis, Celgene, Incyte; Consulting or Advisory Role: Abbvie, Bayer; Travel, Accommodations, Expenses: Merck. UG: Honoraria: Servier, Boehringer Ingelheim, Sirtex Medical, Daiichi Sankyo; Consulting or Advisory Role: Novartis, Merck, Amgen, Hexal, Bristol-Myers Squibb;Travel, Accommodations, Expenses: Merck, Amgen. AS: Honoraria: Roche, Servier/Taiho; Travel, Accommodations, Expenses: Roche, Merck KGaA, MSD Sharp & Dohme, Pfizer, Amgen. KH: Honoraria: Roche; Travel, Accommodations, Expenses: AMGEN, Celgene, Lilly. SH: Employed: ClinAssess GmbH. AA: Consulting or Advisory Role: Roche; Travel, Accommodations, Expenses: Pfizer, Roche, Eli Lilly, Novartis, PharmaMar. JE: Honoraria: Merck, Roche, Amgen, Sanofi, Pierre-Fabre, Servier, Taiho, BMS, Eisai, Novartis; Consulting or Advisory Role: Amgen, Pierre-Fabre, BMS, Servier; Travel, Accommodations, Expenses: AstraZeneca, Apceth. SS: Honoraria: AMGEN, Bayer, BMS, ESAI, Lilly, Merck KGaA, MSD, Pierre-Fabre, Roche, Sanofi, Servier, Taiho, Takeda; Consulting or Advisory Role: AMGEN, Bayer, BMS, ESAI, Lilly, Merck KGaA, MSD, Pierre-Fabre, Roche, Sanofi, Servier, Taiho, Takeda; Travel, Accommodations, Expenses: Merck, Roche, Sanofi, Bayer, Sirtex Medical, Amgen, Eli Lilly, Takeda, Pierre Fabre. CG-J: Travel, Accommodations, Expenses: Roche. DPM: 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. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Best response in the trial. Blue images display response assessments of the sequential treatment arm (fluoropyrimidine plus bevacizumab), and red images show response assessments of the initial combination treatment arm (fluoropyrimidine, bevacizumab, and irinotecan) in (from top to bottom) groups: all patients, RAS/BRAF wild type, RAS mutant.
Figure 2
Figure 2
Kaplan–Meier estimates of time to DpR. (A) Time to DpR in study arms. (B) Time to DpR in molecular subgroups (both arms of study). (C) Time to DpR in male and female patients (both arms of study). Analyses are limited to patients with a DpR of at least 0% (no change) or reduction in tumor diameter.
Figure 3
Figure 3
Kaplan–Meier estimates for the association of ETS with PFS and OS. (A) Association of ETS with PFS in the study arms. (B) Association of ETS with OS in the study arms. (C) Association of ETS with PFS in molecular subgroups. (D) Association of ETS with OS in molecular subgroups. (E) Association of ETS with PFS according to sex. (F) Association of ETS with OS according to sex. Arm A: sequential treatment arm; Arm B: initial combination treatment arm; WT/WT: RAS/BRAF WT subgroup.
See this image and copyright information in PMC

References

    1. Arnold D, Lueza B, Douillard JY, Peeters M, Lenz HJ, Venook A, et al. . Prognostic and Predictive Value of Primary Tumour Side in Patients With RAS Wild-Type Metastatic Colorectal Cancer Treated With Chemotherapy and EGFR Directed Antibodies in Six Randomized Trials. Ann Oncol (2017) 28(8):1713–29. doi: 10.1093/annonc/mdx175 - DOI - PMC - PubMed
    1. Venook AP, Niedzwiecki D, Lenz HJ, Innocenti F, Fruth B, Meyerhardt JA, et al. . Effect of First-Line Chemotherapy Combined With Cetuximab or Bevacizumab on Overall Survival in Patients With KRAS Wild-Type Advanced or Metastatic Colorectal Cancer: A Randomized Clinical Trial. JAMA (2017) 317(23):2392–401. doi: 10.1001/jama.2017.7105 - DOI - PMC - PubMed
    1. Stintzing S, Modest DP, Rossius L, Lerch MM, von Weikersthal LF, Decker T, et al. . FOLFIRI Plus Cetuximab Versus FOLFIRI Plus Bevacizumab for Metastatic Colorectal Cancer (FIRE-3): A Post-Hoc Analysis of Tumour Dynamics in the Final RAS Wild-Type Subgroup of This Randomised Open-Label Phase 3 Trial. Lancet Oncol (2016) 17(10):1426–34. doi: 10.1016/S1470-2045(16)30269-8 - DOI - PubMed
    1. Holch JW, Ricard I, Stintzing S, Modest DP, Heinemann V. The Relevance of Primary Tumour Location in Patients With Metastatic Colorectal Cancer: A Meta-Analysis of First-Line Clinical Trials. Eur J Cancer (2017) 70:87–98. doi: 10.1016/j.ejca.2016.10.007 - DOI - PubMed
    1. Tejpar S, Stintzing S, Ciardiello F, Tabernero J, Van Cutsem E, Beier F, et al. . Prognostic and Predictive Relevance of Primary Tumor Location in Patients With RAS Wild-Type Metastatic Colorectal Cancer: Retrospective Analyses of the CRYSTAL and FIRE-3 Trials. JAMA Oncol (2016) 3(2):194–201. doi: 10.1001/jamaoncol.2016.3797 - DOI - PMC - PubMed

LinkOut - more resources