116TiP - Randomized, open-label, phase II study of botensilimab (BOT) alone and in combination with balstilimab (BAL) versus standard-of-care in patients with refractory metastatic colorectal cancer

Background

Over 95% of patients with metastatic colorectal cancer (mCRC) are ineligible for immune checkpoint inhibitors as standard of care due to a lack of observed response in microsatellite stable/mismatch repair proficient (MSS/pMMR) tumors. Current standard of care includes chemotherapy and targeted therapy regimens. Botensilimab (BOT) – a multifunctional Fc-enhanced anti-CTLA-4 antibody designed to enhance T cell priming, activation, and memory formation; deplete intratumoral T_reg cells; and minimize complement fixation – has demonstrated preclinical and promising early phase clinical data. In an ongoing Phase 1 study (NCT03860272), BOT ± balstilimab (BAL; anti-PD-1) has shown responses across a wide variety of cold/I-O refractory solid tumors, particularly in CRC patients without active liver metastases, with a managable safety profile. The aim of this randomized Phase 2 study is to evaluate the clinical efficacy and safety of BOT alone and in combination with BAL in patients with refractory non-microsatellite instability-high (non-MSI-H)/non-deficient MMR mCRC.

Trial Design

This study (NCT05608044) includes adults ≥18 years old with confirmed non-MSI-H/non-deficient MMR mCRC who have received ≥1 prior chemotherapy regimen for metastatic disease with fluoropyrimidine, oxaliplatin, and irinotecan plus a monoclonal antibody as appropriate. Patients are excluded if they have active liver metastases or have previously received an immune checkpoint inhibitor, regorafenib, or trifluridine/tipiracil. Patients are randomized 1:1:1:1:1 to the following treatments: Arm A: BOT dose 1 every 6 weeks (Q6W) and BAL dose Q2W; Arm B: BOT dose 2 Q6W and BAL dose Q2W; Arm C: BOT dose 1 Q6W; Arm D: BOT dose 2 Q6W; Arm E: Investigator choice of regorafenib or trifluridine/tipiracil until disease progression/unacceptable toxicity. The primary endpoint is objective response rate (ORR) by RECISTv1.1. Secondary endpoints include duration of response, progression-free survival, overall survival, and safety. Global enrollment is ongoing with 111 patients currently enrolled across 8 countries.

Clinical trial identification

NCT05608044.

Editorial acknowledgement

Editorial assistance was provided by Dan Rigotti and Frankie Sorrell, Excel Medical Affairs, Glasgow, UK.

Legal entity responsible for the study

Agenus Inc.

Funding

Agenus Inc.

Disclosure

E. Van Cutsem: Financial Interests, Personal, Advisory Board: AbbVie, ALX, Amgen, Array, Astellas, AstraZeneca, Bayer, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi, GSK, Incyte, Ipsen, Lilly, Merck Sharp & Dohme, Merck KGaA, Mirati, Novartis, Nordic, Pierre Fabre, Pfizer, Roche, Seattle Genetics, Servier, Takeda, Terumo, Taiho, Zymeworks; Financial Interests, Institutional, Research Grant: Amgen, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Ipsen, Lilly, Merck Sharp & Dohme, Merck KGaA, Novartis, Roche, Servier. M. Fakih: Financial Interests, Personal, Advisory Board, Consultant: AstraZeneca, Bayer Corporation, Bristol Myers Squibb; Financial Interests, Personal, Advisory Board, One meeting: Eisai Oncology; Financial Interests, Personal, Advisory Board, One meeting: Entos, Merck, Seattle Genetics, Xenthera; Financial Interests, Personal, Advisory Board, Also Editorial Boards & Consulting: Mirati Therapeutics; Financial Interests, Personal, Advisory Board: Nouscom, Roche/Genentech; Financial Interests, Personal, Advisory Board, Consulting: Pfizer, Taiho Oncology; Financial Interests, Institutional, Research Grant: AgenusBio, Genentech / imCORE, Verastem. N.H. Segal: Financial Interests, Personal, Advisory Role: Agenus, Puretech, Novartis, Numab, AstraZeneca, GSK, ABL Bio, Revitope, Roche/Genentech, Boehringer Ingelheim; Financial Interests, Personal, Funding: AstraZeneca, Regeneron; Financial Interests, Institutional, Funding: Roche/Genentech, Pfizer, Merck, BMS, AstraZeneca, Puretech, Immunocore, Regeneron, Agenus. B. Johnson: Financial Interests, Personal, Research Grant: Gateway for Cancer Research, Syntrix , BMS; Financial Interests, Personal, Speaker, Consultant, Advisor: Incyte, Taiho Oncology, Insmed Oncology, Iota, Gritstone Bio. A. Kardosh: Financial Interests, Personal, Funding: Nastera Inc.; Financial Interests, Personal, Speaker, Consultant, Advisor: Seagen, AstraZeneca, Genentech, Exelixis, Seagen. J. Dekervel: Financial Interests, Personal, Invited Speaker: Amgen, Bayer, Eisai, Ipsen, Lilly, Merck, MSD, Roche; Financial Interests, Personal, Advisory Board: BMS, Eisai, Novartis, Roche; Financial Interests, Institutional, Research Grant: Bayer. B.L. Schlechter: Financial Interests, Personal, Advisory Board: Janssen Pharmaceuticals, Quercegen Pharmaceuticals. J. Grossman: Financial Interests, Personal, Full or part-time Employment: Agenus; Financial Interests, Personal, Other, Patent: Agenus; Financial Interests, Personal, Stocks/Shares: Agenus. M.E. Elez Fernandez: Financial Interests, Personal, Advisory Board: Hoffman-La Roche, Servier, Amgen, Merck Serono, Sanofi, Bayer, Pierre Fabre, MSD, Takeda; Financial Interests, Personal, Invited Speaker: Organon, Novartis, Pfizer; Financial Interests, Personal, Other, Educational training: Seagen International GmbH; Financial Interests, Institutional, Funding: Hoffmann-La Roche Ltd, Sanofi Aventis Recherche & Développement, Amgen Inc., Boehringer Ingelheim, Novartis Farmacéutica SA, Bristol Myers Squibb International Corporation, BeiGene, HalioDX SAS, Janssen-Cilag SA, Merck Health KGAA, Merck Sharp & Dohme de España SA, PharmaMar SA, Servier, Taiho Pharma USA Inc, Hutchison MediPharma International, Menarini, Merus NV, Pfizer, Mirati, Array Biopharma Inc, AstraZeneca Pharmaceuticals LP, Celgene International SARL, Debiopharm International SA, Genentech Inc, MedImmune; Non-Financial Interests, Personal, Other, Coordinator of the SEOM +MIR Section of Residents and Young Assistants: Sociedad Española de Oncología Médica (SEOM); Non-Financial Interests, Personal, Other, Speaker of the ESMO Academy: European Society for Medical Oncology (ESMO); Non-Financial Interests, Personal, Other, Volunteer member of the ASCO Annual Meeting Scientific Program Committee: Developmental Therapeutics – Immunotherapy: American Society of Clinical Oncology (ASCO); Other, Personal, Other, Travel, accommodations, expenses: Roche, Merck Serono, Sanofi, Amgen, Array BioPharma, Servier, Bristol Myers Squibb. C. Eng: Financial Interests, Personal, Advisory Board: AbbVie, Amgen, California Institute of Regenerative Medicine, Hoopika, Janssen, Merck, Taiho, Takeda, Seagen; Financial Interests, Institutional, Local PI: Janssen, Gritstone, Pfizer, Merck, Sumitomo, Agenus; Financial Interests, Institutional, Research Grant: Haystack, Natera; Financial Interests, Institutional, Coordinating PI: Hutchinson. M.P. Ducreux: Financial Interests, Personal, Invited Speaker: Roche, Amgen, Pierre Fabre, Merck Kga, Pfizer, Bayer, Lilly, Servier, MSD; Financial Interests, Personal, Advisory Board: Roche, Basilea, Sotio, Pierre Fabre, Boehringer, Rafael, Servier, Zymeworks, Ipsen, Bayer, HalioDX, Lilly, GSK, Daiichi Sankyo, MSD, Servier; Financial Interests, Institutional, Advisory Board: AstraZeneca; Financial Interests, Institutional, Funding, Partial funding of a trial evaluating the role of bevacizumab in NET: Roche; Financial Interests, Institutional, Funding, Partial funding of a trial evaluating the role of steptozotocin in NET: Keocyt; Financial Interests, Institutional, Local PI: Rafael, Amgen; Financial Interests, Institutional, Funding: Bayer; Other, Personal, Other, My wife is head of the oncology business unit in the French Affiliate of Sandoz France. T. André: Financial Interests, Personal, Advisory Board, Advosiry Board on February 12, 2021: Astellas pharma; Financial Interests, Personal, Advisory Board, Advisory Board on February 2021: Kaleido Biosciences; Financial Interests, Personal, Invited Speaker, and advisory board 2021: Amgen; Financial Interests, Personal, Invited Speaker, Invited speaker in a symposuim december 2020: AstraZeneca; Financial Interests, Personal, Advisory Board, and consultant fees and consultant contract 2021 and 2022: Bristol Myers Squibb; Financial Interests, Personal, Advisory Board, Advisory board in Janaury 2020: Clovis; Financial Interests, Personal, Advisory Board, Advisory board in January 2020: Gritstone Oncology; Financial Interests, Personal, Advisory Board, Advisory board 2020: Haliodx; Financial Interests, Personal, Advisory Board, and consultant fees/consultant contract and invited speaker: MSD Oncology; Financial Interests, Personal, Invited Speaker, and other: Pierre Fabre; Financial Interests, Personal, Invited Speaker, in an symposuim in 2020: Roche; Financial Interests, Personal, Invited Speaker, in a meeting in 2019: Ventana; Financial Interests, Personal, Invited Speaker in a educational meeting in 2019: Sanofi; Financial Interests, Personal, Advisory Board, in a symposuim in 2020: Servier; Financial Interests, Personal, Advisory Board, Consultant with personal fees and invited speaker: Servier; Financial Interests, Personal, Advisory Board, in 2019: GSK; Financial Interests, Personal, Invited Speaker, in 2020 and 2021: GSK; Financial Interests, Personal, Invited Speaker, Virtual symposium Lecture: 1 MSI-H CRC: Implementation of Immunotherapy in clinical practice (30 minutes) – (this will be pre-recorded)Q&A – Live Q&A – (10 minutes) (on July 2, 2021): MSD Oncology; Financial Interests, Personal, Invited Speaker, June 2022: Sanofi; Financial Interests, Personal, Advisory Board, Contract 2021, 2022, 2023: Merck & Co., Inc; Financial Interests, Personal, Advisory Board, Contrat 2019, 2020, 2021, 2022: BMS; Financial Interests, Personal, Advisory Board, Contract 2021: Gritstone Oncologie; Financial Interests, Personal, Invited Speaker, June 2022 and June 2023 during ESMO GI meeting: Seagen; Financial Interests, Personal, Writing Engagement, Contract of consulting 2021 and 2022 and 2023: MSD Oncology; Financial Interests, Personal, Advisory Board, September 2022: GSK, Seagen; Financial Interests, Personal, Writing Engagement, Contract of consulting 2022 and 2023: GSK; Financial Interests, Personal, Writing Engagement, Contract of consulting 2022: Nordic Pharma; Financial Interests, Personal, Invited Speaker, October 2022: Merk Serono; Financial Interests, Personal, Other, Educationnal in 2022: Roche; Financial Interests, Personal, Other, Contract of consulting 2020, 2021, 2022,2023: Servier; Financial Interests, Personal, Advisory Board, Gilead Sciences Global GI Advisory Board on January 18, 2023: Aptitude Health, Glilead; Financial Interests, Personal, Other, Consultant like member of the SGNTUC-029 Steering Committee (the “Steering Committee”) Services related to the Company’s Study titled “An Open-label Randomized Phase 3 Study of Tucatinib in Combination with Trastuzumab and mFOLFOX6 versus mFOLFOX6 given with or without either Cetuximab or Bevacizumab as First-line Treatment for Subjects with HER2+ Metastatic Colorectal Cancer” (collectively, the “Services”).Including teleconferences and board preparation before the board (6h)Participation of the Board on September 2022 in Paris, September 10, 2022 MOUNTAINEER-03 Steering Committee Meeting during ESMO: Seagen; Financial Interests, Personal, Other, Consultant like member of the to be a member of the Colorectal Program Scientific Advisory Committee (SAC). In charges for reviewing V940 Pembro on Engagezone (as per your contract in ref).and also an interview about Pembrolizumab for MSI/dMMR Metastaic colo-rectal 2023: MSD Oncology; Financial Interests, Personal, Advisory Board, but also formation for the Takeda team, and consultant for Takeda Contract beetween 1 sept 2023 and 15 october 2024: Takeda; Financial Interests, Personal, Advisory Board, Board Meeting (October 19, 2023): AbbVie; Financial Interests, Institutional, Coordinating PI, PI Garnet study: GSK; Financial Interests, Institutional, Coordinating PI, Keynote 164 and 171 and 811 and C08: MSD; Financial Interests, Institutional, Coordinating PI, BMS CA209-8HW, BMS CA209-142, BMS CA209-577: BMS; Financial Interests, Institutional, Coordinating PI, SPOTLIGHT study: Astellas; Financial Interests, Personal, Steering Committee Member, and international PI (trial chair Solstice study): Servier; Financial Interests, Personal, Steering Committee Member, MOUNTAINEER and MOUNTAINEER-03 study (PI for France) 2022, 2023: Seagen; Financial Interests, Institutional, Local PI, A randomized, open-label, phase 2 study of botensilimab (agen1181) as monotherapy and in combination with balstilimab (agen2034) or Investigator’s choice standard of care (regorafenib or trifluridine and tipiracil) for the treatment of refractory metastatic colorectal cancer: Agenus; Non-Financial Interests, Personal, Member of Board of Directors, Investigator: Gercor group; Non-Financial Interests, Personal, Member of Board of Directors, President since October 2022: ARCAD Foundation. J. Tabernero: Financial Interests, Personal, Advisory Board, scientific consultancy role: Orion Biotechnology, Array Biopharma, AstraZeneca, Bayer, Boehringer Ingelheim, Chugai, Daiichi Sankyo, F. Hoffmann-La Roche Ltd, Genentech Inc., HalioDX SAS, Ikena Oncology, IQVIA, Lilly, Menarini, Merck Serono, Merus, MSD, Mirati, Neophore, Novartis, Peptomyc, Pfizer, Pierre Fabre, Samsung Bioepis, Sanofi, Seattle Genetics, Servier, Taiho, Tessa Therapeutics, TheraMyc, Hutchinson MediPharma International, Scandion Oncology, Ona Therapeutics, Sotio Biotech, Inspirna Inc, Scorpion Therapeutics, Tolremo Therapeutics; Financial Interests, Personal, Invited Speaker, educational collaboration: Medscape Education, Physicians Education Resource (PER), PeerView Institute for Medical Education, Imedex / HMP; Financial Interests, Personal, Invited Speaker, educacional collaboration: MJH Life Sciences; Financial Interests, Personal, Advisory Board: Cardiff Oncology; Financial Interests, Personal, Stocks/Shares: Oniria Therapeuics; Financial Interests, Institutional, Research Grant, ACRCelerate: Colorectal Cancer Stratified: Fundación Científica de la Asociación Española Contra el Cáncer; Financial Interests, Institutional, Research Grant, OPTIMISTICC: Opportunity to Investigate the Microbiome’s Impact on Science and Treatment In Colorectal Cancer: Cancer Research UK; Financial Interests, Institutional, Funding, Clinical Trials & Research: Amgen Inc, Array Biopharma Inc, Debiopharm International SA, AstraZeneca Pharmaceuticals LP, Bristol Myers Squibb International Corporation, Celgene International SARL, F. Hoffmann-La Roche Ltd, Merck, Sharp & Dohme de España, SA, Genentech Inc, Janssen-Cilag International NV, Merck Health KGAA, Novartis Farmacéutica SA, PharmaMar SA, Sanofi-Aventis Recherche & Développement, Servier, Taiho Pharma USA, Inc, BeiGene, Boehringer Ingelheim, HalioDX SAS, Hutchinson Medipharma, MedImmune, Menarini, Merus N V, Pfizer, Mirati; Non-Financial Interests, Personal, Leadership Role, External Scientific Committee: IdiSNA –Universidad de Navarra, Institute for Health Research INCLIVA – Clinical Hospital of Valencia; Non-Financial Interests, Personal, Member of Board of Directors, Board of Directors: Cancer Core Europe, Spanish Association Against Cancer -AECC; Non-Financial Interests, Personal, Member of Board of Directors, General Assembly: Horizon Europe Cancer Mission; Non-Financial Interests, Personal, Leadership Role, Scientific Advisory Board: Spanish National Cancer Research Centre (CNIO); Non-Financial Interests, Personal, Advisory Role, International Scientific Evaluation Committee: Bosch Health Campus (BHC); Non-Financial Interests, Personal, Advisory Role, Review Board: National Decade Against Cancer (NCT) - German Consortium for Translational Cancer Research (DKTK); Non-Financial Interests, Personal, Advisory Role, Scientific Advisory Board: Karolinska Comprehensive Cancer Centre; Non-Financial Interests, Personal, Advisory Role, International Review Committee (IRC): Oncode Institute; Non-Financial Interests, Personal, Advisory Role, Scientific Advisory Board (SAB): Oslo University Hospital Comprehensive Cancer Centre (OUH CCC); Non-Financial Interests, Personal, Leadership Role, Governance Advisory Committee: European Organization for Research and Treatment of Cancer -EORTC; Non-Financial Interests, Personal, Leadership Role, Vice Chairman: World Innovative Networking (WIN) Consortium in Personalized Cancer Medicine; Non-Financial Interests, Personal, Other, Coordinating PI & Steering Committee Member. Clinical Trials & Research: AstraZeneca Pharmaceutical LP, Array Biopharma Inc., Boehringer Ingelheim, MedImmune, Menarini, Merck Healthcare KGAA, Merck, Sharp & Dohme de España SA, Pfizer, Servier; Non-Financial Interests, Personal, Principal Investigator, Clinical Trials & Research: Array Biopharma Inc., AstraZeneca Pharmaceutics LP, BeiGene, Boehringer Ingelheim, F. Hoffmann-La Roche Ltd, Debiopharm International SA, Bristol Myers Squibb International Corporation, Celgene International SARL, Genentech Inc., HalioDX SAS, Hutchinson Medipharma, Menarini, Janssen-Cilag International NV, MedImmune, Merck Healthcare KGAA, Merck, Sharp & Dohme de España SA, Mirati, Merus NV, Novartis Farmacéutica SA, Pfizer, Sanofi-Aventis Recherche & Développement, Servier, Taiho Pharma USA Inc; Non-Financial Interests, Personal, Other, Steering Committee Member. Clinical Trials & Research: Debiopharm International SA, F. Hoffmann-La Roche Ltd, Genentech Inc., HalioDX SAS, Hutchinson Medipharma, Janssen-Cilag International NV, Merus NV, Taiho Pharma USA Inc; Non-Financial Interests, Personal, Other, Coordinating PI. Clinical Trials & Research: Mirati; Non-Financial Interests, Personal, Member: AACR, ASCO, EACR, EORTC, SEOM; Other, Personal, Other, Advisory Committee: Advisory Committee on Pharmaceutical Provision Financing under the Spanish National Health System; Other, Personal, Other, President: Oncology Master Plan – Catalonia Department of Health. H.J. Lenz: Financial Interests, Personal, Advisory Board, Advisory Role and Lectures: Bayer; Financial Interests, Personal, Advisory Board, Advisory ROle and Lectures: Merck; Financial Interests, Personal, Advisory Board, Advisory Role and lecture: ROche; Financial Interests, Personal, Advisory Board: Jazz Pharmaceuticals, oncocyte, Orion, Astellas, BMS; Financial Interests, Personal, Advisory Board, Scientific Advisory Board: 3T Biosscience; Financial Interests, Personal, Advisory Board, Advisory Board: Fulgent, G1 Therapeutics, BioNtech; Financial Interests, Personal, Advisory Board, advisory board: Cardiff; Financial Interests, Personal, Stocks/Shares, Advisory Board: Fulgent. M. Hidalgo: Financial Interests, Personal, Research Grant: PanCan, Rank Therapeutics; Financial Interests, Personal, Licencing Fees or royalty for IP: Miriad, Khar; Financial Interests, Personal, Speaker, Consultant, Advisor: MinKi, Oncomatrix, Inxmed, Peaches, Khar; Financial Interests, Personal, Funding: Agenus; Financial Interests, Personal, Other, Board of Directors: BMS; Financial Interests, Personal, Stocks/Shares: Champions Oncology, Nelum, Inxmed. All other authors have declared no conflicts of interest.