A phase 2 trial of trifluridine/tipiracil plus nivolumab in patients with heavily pretreated microsatellite-stable metastatic colorectal cancer

Abstract

Background: Microsatellite-stable (MSS) colorectal cancer (CRC) tends to be poorly immunogenic, with limited treatment options. In MSS CRC xenograft models, trifluridine/tipiracil (FTD/TPI) plus programed death 1 inhibitors resulted in synergistic antitumor activity and increased tumor immunogenicity. This phase 2 study evaluated FTD/TPI plus nivolumab in patients with MSS metastatic CRC.

Methods: This single-arm, safety lead-in study used a Simon's two-stage design (enrolling 6 patients in the safety lead-in, proceeding to stage 2 if ≥2 of the first 15 patients achieved a partial or complete response per immune-related response criteria [irRC] within 6 months). Patients with histologically proven MSS mCRC, and disease progression after ≥2 prior chemotherapy regimens received FTD/TPI (35 mg/m2 twice daily; days 1-5 and 8-12 every 28 days) plus nivolumab (3 mg/kg every 2 weeks).

Results: Between August 2016 and January 2017, 18 patients (50% men; median age 56.5 years) were enrolled; 72% had colon cancer and 56% had KRAS mutations. All patients received treatment (median, 2.5 cycles [range, 1-8]). No dose-limiting toxicities were observed in the study. The most frequent adverse events (AEs) of any cause and grade were nausea (67%), diarrhea (61%), and neutropenia (50%); 13 patients (72%) experienced grade ≥3 AEs. No patients discontinued treatment because of AEs. No patient achieved a tumor response (either per Response Evaluation Criteria in Solid Tumors [RECIST] or irRC), and the study did not progress to the second stage. Stable disease was achieved in 8 patients per irRC and in 10 patients per RECIST. Median progression-free survival was 2.2 months (95% CI, 1.8-6.0 months) per irRC and 2.8 months (95% CI, 1.8-5.1 months) per RECIST.

Conclusion: Patients with refractory MSS metastatic CRC failed to experience clinical benefit with FTD/TPI plus nivolumab, although safety data in this population indicated tolerability and feasibility of this combination.

Trial registration number: NCT02860546.

Keywords: chemotherapy; clinical trials; colorectal cancer; immunotherapy.

Conflict of interest statement

MRP reports speakers bureau honoraria from Taiho Oncology and reports institutional funding from Acerta Pharma, ADC Therapeutics, Agenus, Aileron Therapeutics, AstraZeneca, Bicycle Therapeutics, BioNTech, Boehringer Ingelheim, Calithera, Celgene, Checkpoint Therapeutics, Ciclomed, Clovis, Curis, Cyteir Therapeutics, Daiichi Sankyo, Effector Therapeutics, Eli Lilly, EMD Serono, Evelo Biosciences, Forma Therapeutics, Genentech/Roche, Gilead, GlaxoSmithKline, H3 Biomedicine, Hengrui, Hutchinson MediPharma, Ignyta, Incyte, Jacobio, Janssen, Jounce Therapeutics, Klus Pharma, Kymab, Loxo Oncology, LSK Biopartners, Lycera, Macrogenics, Merck, Millennium Pharmaceuticals, Mirati Therapeutics, ModernaTX, Pfizer, Phoenix Molecular Designs, Placon Therapeutics, Portola Pharmaceuticals, Prelude Therapeutics, Qilu Puget Sound Biotherapeutics, Revolution Medicines, Ribon Therapeutics, Seven and Eight Biopharmaceuticals, Syndax, Synthorx, Stemline Therapeutics, Taiho, Takeda, Tesaro, TopAlliance, Vedanta, Verastem, Vigeo, and Xencor. GF reports institutional research funding from 3‐V Biosciences, Abbisko, AbbVie, ADC Therapeutics, Aileron, American Society of Clinical Oncology, Amgen, ARMO, AstraZeneca, BeiGene, Bioatla, Biothera, Celldex, Celgene, Ciclomed, Curegenix, Curis, Cyteir, Daiichi, DelMar, eFFECTOR, Eli Lilly, EMD Serono, Epizyme, Exelixis, Fujifilm, Genmab, GlaxoSmithKline, Hutchison MediPharma, Ignyta, Incyte, Jacobio, Jounce, Kolltan, Loxo, MedImmune, Millennium, Merck, miRNA Therapeutics, National Institutes of Health, Novartis, OncoMed, Oncorus, Oncothyreon, Poseida, Precision Oncology, Prelude, Regeneron, Rgenix, Ribon, Strategia, Syndax, Taiho, Takeda, Tarveda, Tesaro, Tocagen, Turning Point Therapeutics, U.T. MD Anderson Cancer Center, Vegenics,and Xencor; speakers bureau honoraria from Total Health Conferencing and Rocky Mountain Oncology Society; travel fees from Bristol‐Myers Squibb (2015), EMD Serono (2011, 2012, 2013), Fujifilm (2018), Millennium (2013), Sarah Cannon Research Institute; advisory role at EMD Serono, and royalties from Wolters Kluwer. KH is a salaried employee at Taiho Oncology and reports personal fees from Taiho Oncology during the study and outside the submitted work. LH is a paid consultant to and reports personal fees from Taiho Oncology during the study and outside the submitted work. JCB reports institutional research funding from Gilead, Genentech/Roche, Bristol‐Myers Squibb, Five Prime, Lilly, Merck, MedImmune, Celgene, EMD Serono, Taiho, Macrogenics, GlaxoSmithKline, Novartis, Oncomed, LEAP, TG Therapeutics, AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, Bayer, Incyte, Apexigen, Koltan, SynDevRex, Forty Seven, AbbVie, Array, Onyx, Sanofi, Takeda, Eisai, Celldex, Agios, Cytomx, Nektar, ARMO, Boston Biomedical, Ipsen, Merrimack, Tarveda, Tyrogenex, Oncogenex, Marshall Edwards, Pieris, Mersana, Calithera, Blueprint, Evelo, FORMA, Merus, Jacobio, Effector, Novocare, Arrys, Tracon, Sierra, Innate, Arch Oncology, Prelude Therapeutics, Unum Therapeutics, Vyriad, Harpoon, ADC, Amgen, Pfizer, Millennium, Imclome, Acerta Pharma, Rgenix, Bellicum, Gossamer Bio, Arcus Bio, Seattle Genetics, Tempest Tx, Shattuck Labs, Synthorx, Revolution Medicines, Bicycle Therapeutics, Zymeworks, Relay Therapeutics; institutional payment for consulting services from Gilead, Genentech/Roche, Bristol‐Myers Squibb, Five Prime, Lilly, Merck, MedImmune, Celgene, Taiho, Macrogenics, GlaxoSmithKline, Novartis, OncoMed, LEAP, TG Therapeutics, AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, Bayer, Incyte, Apexigen, Array, Sanofi, Agios, ARMO, Ipsen, Merrimack, Oncogenex, Evelo, FORMA, Innate, Arch Oncology, Prelude Therapeutics, Amgen, Seattle Genetics, Bicycle Therapeutics, Relay Therapeutics, Phoenix Bio, Cyteir, Molecular Partners, Torque, Tizona, Janssen, Tolero, TD2 (Transitional Drug Development), Moderna Therapeutics, Tanabe Research Laboratories, Beigene, and Continuum Clinical.

© 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Figures

FIGURE 1

Radiologic PFS with FTD/TPI plus nivolumab. PFS was defined as the time from the first dose of study drug to disease progression as assessed per (A) irRC criteria or (B) RECIST v1.1. irRC, immune‐related response criteria; PFS, progression‐free survival; RECIST v1.1, Response Evaluation Criteria in Solid Tumors version 1.1.