Study protocol of the FIRE-8 (AIO-KRK/YMO-0519) trial: a prospective, randomized, open-label, multicenter phase II trial investigating the efficacy of trifluridine/tipiracil plus panitumumab versus trifluridine/tipiracil plus bevacizumab as first-line treatment in patients with metastatic colorectal cancer

G Sommerhäuser, A Kurreck, S Stintzing, V Heinemann, L Fischer von Weikersthal, T Dechow, F Kaiser, M Karthaus, I Schwaner, M Fuchs, A König, C Roderburg, I Hoyer, M Quante, A Kiani, S Fruehauf, L Müller, A Reinacher-Schick, T J Ettrich, A Stahler, D P Modest, G Sommerhäuser, A Kurreck, S Stintzing, V Heinemann, L Fischer von Weikersthal, T Dechow, F Kaiser, M Karthaus, I Schwaner, M Fuchs, A König, C Roderburg, I Hoyer, M Quante, A Kiani, S Fruehauf, L Müller, A Reinacher-Schick, T J Ettrich, A Stahler, D P Modest

Abstract

Background: Initial systemic therapy for patients with metastatic colorectal cancer (mCRC) is usually based on two- or three-drug chemotherapy regimens with fluoropyrimidine (5-fluorouracil (5-FU) or capecitabine), oxaliplatin and/or irinotecan, combined with either anti-VEGF (bevacizumab) or, for RAS wild-type (WT) tumors, anti-EGFR antibodies (panitumumab or cetuximab). Recommendations for patients who are not eligible for intensive combination therapies are limited and include fluoropyrimidine plus bevacizumab or single agent anti-EGFR antibody treatment. The use of a monochemotherapy concept of trifluridine/ tipiracil in combination with monoclonal antibodies is not approved for first-line therapy, yet. Results from the phase II TASCO trial evaluating trifluridine/ tipiracil plus bevacicumab in first-line treatment of mCRC patients and from the phase I/II APOLLON trial investigating trifluridine/ tipiracil plus panitumumab in pre-treated mCRC patients suggest favourable activity and tolerability of these new therapeutic approaches.

Methods: FIRE-8 ( NCT05007132 ) is a prospective, randomized, open-label, multicenter phase II study which aims to evaluate the efficacy of first-line treatment with trifluridine/tipiracil (35 mg/m2 body surface area (BSA), orally twice daily on days 1-5 and 8-12, q28 days) plus either the anti-EGFR antibody panitumumab (6 mg/kg body weight, intravenously on day 1 and 15, q28 days) [arm A] or (as control arm) the anti-VEGF antibody bevacizumab (5 mg/kg body weight, intravenously on day 1 and 15, q28 days) [arm B] in RAS WT mCRC patients. The primary objective is to demonstrate an improved objective response rate (ORR) according to RECIST 1.1 from 30% (control arm) to 55% with panitumumab. With a power of 80% and a two-sided significance level of 0.05, 138 evaluable patients are needed. Given an estimated drop-out rate of 10%, 153 patients will be enrolled.

Discussion: To the best of our knowledge, this is the first phase II trial to evaluate the efficacy of trifluridine/tipiracil plus panitumumab in first-line treatment of RAS WT mCRC patients. The administration of anti-EGFR antibodies rather than anti-VEGF antibodies in combination with trifluridine/tipiracil may result in an increased initial efficacy.

Trial registration: EU Clinical Trials Register (EudraCT) 2019-004223-20 . Registered October 22, 2019, ClinicalTrials.gov NCT05007132 . Registered on August 12, 2021.

Keywords: Bevacizumab; First-line treatment; Metastatic Colorectal Cancer; Panitumumab; Trifluridine/tipiracil.

Conflict of interest statement

Greta Sommerhäuser: none.

Annika Kurreck: expenses for travel and accomodations: Amgen.

Sebastian Stintzing: honoraria for talks and CME activities: Amgen, Astra-Zeneca, Bayer, BMS, ESAI, LEO Pharma, Lilly, Merck KGaA, MSD, Pierre-Fabre, Roche, Sanofi, Servier, Taiho, Takeda; research funding: Merck KGaA, Pierre-Fabre, Servier, Roche.

Volker Heinemann: honoraria for talks and advisory board role: Merck, Amgen, Roche, Sanofi, SIRTEX, Servier, Pfizer, Pierre-Fabre, Astra-Zeneca, BMS; MSD, Novartis, Boehringer Ingelheim, Pierre-Fabre, Celgene, SIRTEX, Terumo, Oncosil, Seagen; research funding: Merck, Amgen, Roche, Sanofi, Boehringer-Ingelheim, SIRTEX, Servier.

Ludwig Fischer von Weikersthal: honoraria for talks: Lilly, Novartis, Pierre-Fabre.

Tobias Dechow: none.

Florian Kaiser: honoraria: Astellas, GSK, MSD, Novartis und Elsevier.

Meinolf Karthaus: none.

Ingo Schwaner: honoraria from AbbVie, Amgen, AstraZeneca, Beigene, BMS, Celgene, Incyte, Janssen, Lilly, Novartis, Roche, Servier.

Martin Fuchs: honoraria for talks: BMS, MSD, Pierre-Fabre, Roche, Sanofi, Servier.

Alexander König: none.

Christoph Roderburg: research funding: Servier.

Inna Hoyer: none.

Michael Quante: honoraria from MSD, Celgene, Lilly, Servier, Merk.

Alexander Kiani: honoria and travel: Amgen, Roche.

Stefan Fruehauf: none.

Lothar Müller: none.

Anke Reinacher-Schick: honoraria for talks: Amgen, Roche, Merck Serono, Bristol-Myers Squibb, MSD, MCI Group, AstraZeneca; advisory board member: Amgen, Roche, Merck Serono, Bristol-Myers Squibb, MSD, AstraZeneca, Pierre Fabre; travel support: Roche; Studies (trial support institution/study grant institution): Roche, Ipsen; funding of scientific investigations (studies and research): Roche, Celgene, Ipsen, Amgen, Alexion Pharmaceuticals, Astra Zeneca, Lilly, Servier, AIO Studien gGmbH, Rafael Pharmaceutics, Erytech Pharma, BioNTech; consulting or advisory role: BMS, Lilly, Sanofi, Incyte, Ipsen, Bayer, Bristol-Myers Squibb, Pierre Fabre, Eisai, MSD, Roche, SERVIER, AstraZeneca, Merck Serono; research funding: Servier; travel, accommodations: Ipsen, Pierre Fabre.

Thomas Ettrich: consulting or advisory role: BMS, Lilly, Sanofi, Incyte, Ipsen, Bayer, Bristol-Myers Squibb, Pierre Fabre, Eisai, MSD, Roche, Servier, AstraZeneca, Merck Serono; research funding: Servier; travel, accommodations: Ipsen, Pierre Fabre.

Arndt Stahler: honoria: Roche, Taiho Pharmaceutical, Servier; expenses for travel and accomodations: Roche, Merck KGaA, Amgen, Pfizer, Lilly Oncology.

Dominik Modest: honoraria: Amgen, Merck, Servier, Pierrefabre, BMS, MSD, Incyte, Lilly, Sanofi, G1, Transgene, Seagen, Onkowissen; research funding (inst): Servier, Amgen.

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
FIRE-8 Study Design. Legend: mCRC, metastatic colorectal cancer; R, randomization; BSA, body surface area; BID, twice daily; BW, body weight. Microsoft PowerPoint version 16.62 was used to generate this figure
Fig. 2
Fig. 2
FIRE-8 translational research. Microsoft PowerPoint version 16.62 was used to generate this figure

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