PMID- 34547581 OWN - NLM STAT- MEDLINE DCOM- 20211029 LR - 20211029 IS - 2059-7029 (Electronic) IS - 2059-7029 (Linking) VI - 6 IP - 5 DP - 2021 Oct TI - Trifluridine/tipiracil in combination with oxaliplatin and either bevacizumab or nivolumab in metastatic colorectal cancer: a dose-expansion, phase I study. PG - 100270 LID - S2059-7029(21)00232-5 [pii] LID - 10.1016/j.esmoop.2021.100270 [doi] LID - 100270 AB - BACKGROUND: In preclinical studies trifluridine/tipiracil (FTD/TPI) plus oxaliplatin (Industriestrasse, Holzkirchen, Germany) sensitised microsatellite stable (MSS) metastatic colorectal cancer (mCRC) to anti-programmed cell death protein-1; the addition of oxaliplatin or bevacizumab (F Hoffmann- la ROCHE AG, Kaiseraugst, Switzerland) enhanced the antitumour effects of FTD/TPI. This study aimed to investigate the safety and efficacy of FTD/TPI plus oxaliplatin and either bevacizumab or nivolumab (Uxbridge business Park, Uxbridge, United Kingdom) in patients with mCRC who had progressed after at least one prior line of treatment. PATIENTS AND METHODS: In 14-day cycles, patients received FTD/TPI 35 mg/m(2) (twice daily, days 1-5) plus oxaliplatin 85 mg/m(2) (day 1), and, on day 1, either bevacizumab 5 mg/kg (cohort A) or nivolumab 3 mg/kg (cohort B). Patients in Cohort B had confirmed MSS status. RESULTS: In total, 54 patients were enrolled: 37 in cohort A and 17 in cohort B. Recruitment in cohort B was stopped early due to the low response rate (RR) observed at interim analyses of efficacy. The most common adverse events (AEs) in cohort A were neutropenia/decreased neutrophils (75.7%), nausea (59.5%), vomiting (40.5%), diarrhoea (37.8%), peripheral sensory neuropathy (37.8%), fatigue (35.1%) and decreased appetite (35.1%). In cohort B, the most common AEs were neutropenia/decreased neutrophils (70.6%), diarrhoea (58.8%), nausea (47.1%), vomiting (47.1%), fatigue (47.1%), asthenia (41.2%), paraesthesia (41.2%), thrombocytopenia/decreased platelets (35.3%) and decreased appetite (35.3%). Confirmed objective RR was 17.1% in cohort A and 7.1% in cohort B; the corresponding values for median progression-free survival in the two cohorts were 6.3 and 6.0 months. CONCLUSION: FTD/TPI plus oxaliplatin and bevacizumab or nivolumab had an acceptable safety profile and demonstrated antitumour activity in previously treated patients with mCRC. CI - Copyright (c) 2021 The Authors. Published by Elsevier Ltd.. All rights reserved. FAU - Bordonaro, R AU - Bordonaro R AD - Azienda Ospedaliera ARNAS Garibaldi, Catania, Italy. Electronic address: rbordonaro63@gmail.com. FAU - Calvo, A AU - Calvo A AD - Gregorio Maranon University General Hospital, Madrid, Spain. FAU - Auriemma, A AU - Auriemma A AD - Azienda Ospedaliera Universitaria Integrat, University of Verona, Verona, Italy. FAU - Hollebecque, A AU - Hollebecque A AD - Drug Development Department, Gustave Roussy Cancer Campus, Villejuif, France. FAU - Rubovszky, G AU - Rubovszky G AD - Department of Medical Oncology and Clinical Pharmacology, National Institute of Oncology Hungary, Budapest, Hungary. FAU - Saunders, M P AU - Saunders MP AD - Christie NHS Foundation Trust, Manchester, UK. FAU - Papai, Z AU - Papai Z AD - Department of Medical Oncology, Duna Medical Centre, Budapest, Hungary. FAU - Prager, G AU - Prager G AD - Comprehensive Cancer Centre Vienna, Medical University Vienna, Austria. FAU - Stein, A AU - Stein A AD - UKE Universitatsklinikum Hamburg-Eppendorf KMTZ, Hamburg, Germany. FAU - Andre, T AU - Andre T AD - Sorbonne Universite et Hopital Saint-Antoine, Service d'Oncologie Medicale, Paris, France. FAU - Argiles, G AU - Argiles G AD - Vall d'Hebron University Hospital and Institute of Oncology (VHIO), Barcelona, Spain. FAU - Cubillo, A AU - Cubillo A AD - Medical Oncology, Hospital Universitario Madrid Sanchinarro Centro Integral Oncologico Clara Campal, Madrid, Spain. FAU - Dahan, L AU - Dahan L AD - Aix Marseille University; Assistance Publique Hopitaux de Marseille, Centre d'Essais Precoces en Cancerologie de Marseille CLIP, Marseille, France. FAU - Edeline, J AU - Edeline J AD - Department of Medical Oncology, Centre Eugene Marquis, ARPEGO network, Rennes, France. FAU - Leger, C AU - Leger C AD - Institut de Recherches Internationales Servier, Suresnes, France. FAU - Cattan, V AU - Cattan V AD - Institut de Recherches Internationales Servier, Suresnes, France. FAU - Fougeray, R AU - Fougeray R AD - Institut de Recherches Internationales Servier, Suresnes, France. FAU - Amellal, N AU - Amellal N AD - Institut de Recherches Internationales Servier, Suresnes, France. FAU - Tabernero, J AU - Tabernero J AD - Vall d'Hebron University Hospital and Institute of Oncology (VHIO), Barcelona, Spain; UVic-UCC, IOB-Quiron, Barcelona, Spain. LA - eng PT - Clinical Trial, Phase I PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20210920 PL - England TA - ESMO Open JT - ESMO open JID - 101690685 RN - 0 (Pyrrolidines) RN - 04ZR38536J (Oxaliplatin) RN - 2S9ZZM9Q9V (Bevacizumab) RN - 31YO63LBSN (Nivolumab) RN - NGO10K751P (tipiracil) RN - QR26YLT7LT (Thymine) RN - RMW9V5RW38 (Trifluridine) SB - IM MH - Antineoplastic Combined Chemotherapy Protocols/adverse effects MH - Bevacizumab/therapeutic use MH - *Colorectal Neoplasms/drug therapy MH - Humans MH - Nivolumab/therapeutic use MH - Oxaliplatin/therapeutic use MH - Pyrrolidines MH - Thymine MH - *Trifluridine/therapeutic use PMC - PMC8453191 OTO - NOTNLM OT - fluoropyrimidines OT - metastatic colorectal cancer OT - oxaliplatin OT - trifluridine/tipiracil COIS- Disclosure RB has received honoraria from Bayer, AstraZeneca, Sanofi, Novartis, Amgen, Hoffmann La Roche, Pfizer, Janssen-Cilag, Bristol Myers Squibb and Merck. AC has received consulting/advisory honoraria from Lilly, Amgen, Servier, BMS and Sanofi, and travel accommodation from Amgen, Servier and Merck. AH reports personal fees and nonfinancial support from Servier, during the conduct of the study; grants from Incyte; personal fees from Amgen, Lilly, Debiopharm, Incyte, Bayer, EISAI; grants and nonfinancial support from AstraZeneca; grants from Boehringer Ingelheim, Janssen-Cilag, Merck, Novartis, Pfizer, BMS and Sanofi. GR received honoraria from Novartis, Pfizer, Lilly, Amgen, Roche, SWIXX and Merck. MPS reports personal fees from Servier, Amgen and Merck. GP reports advisory role and speakers honorarium from Servier. AS reports grants and/or personal fees or consulting or advisory role, speakers bureau, research funding, travel/accommodations/expenses from Merck KGaA, Bristol-Myers Squibb, Amgen, Roche, MSD, Servier, Sanofi, AstraZeneca, Bayer, Lilly and Celgene. TA has served in a consulting/advisory role and/or received honoraria for Amgen, Bristol-Myers Squibb, Chugai, Clovis, Grindstone, GSK, HalioDx, MSD Oncology, Pierre Fabre, Roche/Ventana, Sanofi, Servier and Tesaro, and has received travel, accommodation and other expenses from Roche/Genentech/Ventana, MSD Oncology and Bristol-Myers Squibb. GA received honoraria for consulting/advisory roles from Amgen, Bristol-Myers Squibb, Merck Serono, Roche, Bayer, Servier and Sanofi; travel and accommodation expenses from Amgen, Roche, Servier, Bayer and Sanofi and has had an advisory role without compensation for Treos Bio Limited. JE has received honoraria from Servier, Eisai, MSD, BTG, BMS, Ipsen, Bayer and Roche. JT reports personal financial interest in the form of a scientific consultancy role for Array Biopharma, AstraZeneca, Bayer, BeiGene, Biocartis, Boehringer Ingelheim, Chugai, F. Hoffmann-La Roche Ltd., Foundation Medicine, Genentech Inc., Genmab A/S, HalioDx SAS, Halozyme, Imugene Ltd., Inflection Biosciences Ltd., Ipsen, Kura Oncology, Lilly, MSD, Menarini, Merck Serono, Merrimack, Merus, Molecular Partners, Novartis, Peptomyc, Pfizer, Pharmacyclics, ProteoDesign SL, Rafael Pharmaceuticals, Roche Diagnostics, Sanofi, Seagen, Seattle Genetics, Servier, Symphogen, Taiho and VCN Biosciences. CL, NA, VC and RF are employees of Servier. All other authors have declared no conflicts of interest. EDAT- 2021/09/22 06:00 MHDA- 2021/10/30 06:00 PMCR- 2021/09/20 CRDT- 2021/09/21 20:20 PHST- 2021/05/11 00:00 [received] PHST- 2021/08/13 00:00 [revised] PHST- 2021/08/20 00:00 [accepted] PHST- 2021/09/22 06:00 [pubmed] PHST- 2021/10/30 06:00 [medline] PHST- 2021/09/21 20:20 [entrez] PHST- 2021/09/20 00:00 [pmc-release] AID - S2059-7029(21)00232-5 [pii] AID - 100270 [pii] AID - 10.1016/j.esmoop.2021.100270 [doi] PST - ppublish SO - ESMO Open. 2021 Oct;6(5):100270. doi: 10.1016/j.esmoop.2021.100270. Epub 2021 Sep 20.