Molecular hyperselection for optimal choice of first-line targeted therapy independent of primary tumor sidedness: An exploratory analysis of the randomized FIRE-3 study performed in RAS wild-type metastatic colorectal cancer
- PMID: 40222201
- DOI: 10.1016/j.ejca.2025.115399
Molecular hyperselection for optimal choice of first-line targeted therapy independent of primary tumor sidedness: An exploratory analysis of the randomized FIRE-3 study performed in RAS wild-type metastatic colorectal cancer
Abstract
Introduction: Molecular diagnostics play a pivotal role in guiding therapy for metastatic colorectal cancer (mCRC). Current guidelines recommend stratification based on biomarkers such as RAS, BRAF, and DNA mismatch-repair (MMR) status to select between anti-EGFR (epidermal growth factor receptor) and anti-VEGF (vascular endothelial growth factor) therapies.
Materials and methods: This retrospective analysis evaluated the randomized FIRE-3 study that compared first-line treatment with FOLFIRI plus cetuximab to FOLFIRI plus bevacizumab in RAS wild-type patients. The present analysis included 199 patients with RAS/BRAF wild-type MMR proficient tumors. Next-generation sequencing (NGS) was successfully performed in all patients and allowed stratification into hyperselected (no predefined genetic alterations) or gene altered subgroups using the previously published approach of the PRESSING-studies.
Results: Hyperselection according to PRESSING-3 was associated with a survival benefit from anti-EGFR-based therapy compared to bevacizumab (38.5 months vs. 27.5 months; HR 0.68; 95 % CI, 0.44-1.05; P = 0.08). This benefit was observed in both, right- and left-sided tumors, (HR 0.58 and HR 0.70). Patients with gene alterations showed inferior survival compared to hyperselected patients across all subgroups. In this unfavorable subgroup, application of cetuximab and bevacizumab were associated with comparable OS (total cohort: HR 1.04; 95 % CI, 0.61-1.79). Again, this finding was independent of primary tumor sidedness (left-sided tumors: HR 1.10; 95 % CI, 0.59-2.07; right-sided tumors: HR 1.05; 95 % CI, 0.31-3.55).
Conclusion: Molecular hyperselection facilitated by next generation sequencing could replace primary tumor sidedness as a tool of decision making for optimal choice of targeted therapy in first-line treatment of RAS wild-type mCRC.
Keywords: Hyperselection; Metastatic colorectal cancer; Next generation sequencing; Precision medicine; Targeted therapy.
Copyright © 2025 The Authors. Published by Elsevier Ltd.. All rights reserved.
Conflict of interest statement
Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Lena Weiss: Honoraria: Roche, Servier; Travel Expenses: Merck KGaA, Amgen; Advisory Role: Roche. Sebastian Stintzing: Consulting or Advisory Role: Merck KGaA, Roche, Amgen, Pierre Fabre, MSD, AstraZeneca, Servier, GalaxoSmithKline, Termuo, Nordic Bioscience, Seagen, Daiichi Sankyo Europe gmbH, CV6 Therapeutics, Isofol Medical; Travel Expenses: Merck KGaA, Roche, Sanofi, Bayer, Sirtex Medical, Amgen, Lilly, Takeda, Pierre Fabre, AstraZeneca Honoraria: Merck KGaA, Roche, Amgen, ervier, MSD, Pfizer, Pierre Fabre, BMS, Nordic Bioscience, AstraZeneca, Daiichi Sankyo Europe GmbH. Arndt Stahler: Honoraria: Takeda; Merck KGaA, Amgen, Daiichi Sankyo Europe GmbH, MSD; Travel expenses: Amgen, Roche, Lilly, Pfizer, Merck KGaA; Consulting or Advisory Role: Takeda. C. Benedikt Westphalen: has received honoraria from Amgen, Bayer, BMS, Chugai, Celgene, Falk, GSK, Janssen, Ipsen, MSD, Merck, Roche, Servier, SIRTeX, Taiho. Served on advisory boards for Bayer, BMS, Celgene, Incyte, Janssen, Lily, MSD, Servier, Shire/Baxalta, Rafael Pharmaceuticals, RedHill, Roche. Has received travel support by Bayer, Celgene, Janssen, MSD, RedHill, Roche, Servier, Taiho and research grants (institutional) by Roche and Deutsche Krebshilfe (institutional). Serves as faculty for European Society of Medical Oncology (ESMO), Deutsche Krebshilfe (DKH) and Arbeitsgemeinschaft internistische Onkologie (AIO). Is a member of the EU Commission expert group: Mission Board for cancer. Is a member of the BMBF expert group: Forum Zukunftsstrategie. Is a member of the BMBF steering committee: Strategiekreis Dekade gegen Krebs Thomas Decker: reports advisory role for Novartis, Lilly, Astra Zeneca. Kathrin Heinrich: Consulting or Advisory Role: Amgen, Servier, MSD (Institutional), Merck, Janssen; Travel Expenses: Amgen, Servier, Merck KGaA; Honoraria: Amgen, BMS, Merck, MSD, Roche, Taiho, Servier, streamedup! Julian Holch: served on advisory board for Merck, Roche and Servier, has received travel support from Novartis, Merck and Servier. Annabel Alig: Honoraria: MSD, Servier, Merck KgaA, MSD, Pfizer, Pierre-Fabre, Roche, AMGEN, BMS; Travel Expenses: Nordic, Servier, Merck KgaA, MSD, Pfizer, Pierre-Fabre, Roche, AMGEN, Daiichi Sankyo; Advisory Role: Beigene. Dominik Paul Modest: Consulting or Advisor Role: Merck, Amgen, Servier, Pierre Fabre, Lilly, Cor2Ed, Onkowissen, Regeneron, GalaxoSmithKline, Takeda, Incyte; Travel Expenses: Amgen, Merck, Servier; Honoraria: Merck, Amgen, Servier, BMS, Taiho, Onkowissen, Pierre Fabre, AstraZeneca, Lilly, Takeda, GalaxoSmithKline, Seagen, Cor2Ed, Boehringer Ingelheim, Regeneron, Bicara Therapeutics, Rottapharm Biotech, IKF Klinische Krebsforschung, 21up Volker Heinemann: reports receiving fees for talks and advisory board roles from Merck, Amgen, Roche, Sanofi, Servier, Pfizer, Pierre-Fabre, AstraZeneca, BMS, MSD, Novartis, Terumo, Oncosil, NORDIC, Seagen, GSK and for receiving research funding from Merck, Amgen, Roche, Sanofi, Boehringer-Ingelheim, SIRTEX, Servier. All remaining authors declare no conflict of interest.
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