477TiP A randomised phase II study of zimberelimab +/- domvanalimab immunotherapy in resectable mismatch repair deficient (dMMR) gastric and gastroesophageal junctional (G/GOJ) adenocarcinoma (ZODIAC)

Abstract

Background: Perioperative chemotherapy combined with surgery is a standard approach for operable gastric cancer; an intensive regimen which has limited benefit in some patients. Approximately 10% of resectable G/GOJ adenocarcinomas is dMMR, a subset where the efficacy of peri-operative chemotherapy is debated. dMMR is a well-established positive predictive biomarker for immune checkpoint inhibition (ICI), with small phase II studies showing encouraging responses to ICI alone in the resectable setting. However, not all dMMR patients respond, highlighting the need for novel combinations. TIGIT is an emerging immunotherapy target, with preclinical data suggesting that dual anti-PD1 and anti-TIGIT blockade may lead to enhanced T cell activation and increased antitumour activity. ZODIAC (NCT06250036) is an academic initiated and sponsored study to investigate the response of chemotherapy-sparing, perioperative ICI, in resectable dMMR G/GOJ cancer, and the possible contribution of component of novel anti-TIGIT therapy. Trial design: ZODIAC is a UK multicentre, prospective, randomised open label, phase II proof of concept study using a Simon two-stage, screen selected design. Patients are randomised 1:1 to: Arm A: zimberelimab (anti-PD1) Q3W (10 cycles: 4 neoadjuvant + 6 adjuvant) Arm B: zimberelimab + domvanalimab (anti-TIGIT) Q3W (10 cycles: 4 neoadjuvant + 6 adjuvant) The primary endpoint is pathological complete response (pCR) rate, with notable secondary endpoints including safety, surgical outcomes and quality of life. 25 patients per arm are required to test H0: pi = 40% pCR rate, with a one-sided alpha of 0.049 and 80.56% power. An interim futility analysis is planned after 7 evaluable patients per arm. Key eligibility criteria include: confirmed dMMR G/GOJ adenocarcinoma, resectable disease (stage II-IIIB) deemed suitable for surgery by MDT, and ECOG 0-2, with no upper age limit to ensure inclusivity given the higher prevalence of the dMMR biomarker in older patients. The study includes serial blood and tissue collection for planned translational analyses. ZODIAC is open to recruitment. Clinical trial identification: NCT06250036. Legal entity responsible for the study: The Royal Marsden. Funding(s): Gliead/Arcus. Disclosure: C. Fribbens: Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Other: Takaeda. M. Gerlinger: Financial Interests, Personal, Invited Speaker, Speaker fees for educational events: BMS, Merck KGA, Takeda, Servier; Financial Interests, Personal, Expert Testimony, Expert advisory role: MSD; Financial Interests, Personal, Other, Expert scientific advice: Roche; Financial Interests, Personal, Stocks/Shares: Vertex; Financial Interests, Institutional, Funding: Bristol Myers Squibb; Financial Interests, Institutional, Invited Speaker: Roche, Merck KG; Financial Interests, Institutional, Invited Speaker, CI role remuneration: AstraZeneca; Non-Financial Interests, Institutional, Other, Provision of research reagents: Roche. I. Chau: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, Eli-Lilly, MSD, Roche, Merck Serono, AstraZeneca, OncXerna, Astella, Incyte, GSK, Sotio, Daiichi Sankyo, Eisai, Taiho, Seagen, Turning Point Therapeutics, Novartis, Takeda, Elevation Oncology; Financial Interests, Personal, Invited Speaker: Eisai, Eli-Lilly, Servier, Roche; Financial Interests, Institutional, Invited Speaker: Cilag-Janssen, Eli-Lilly. D. Cunningham: Financial Interests, Institutional, Research Grant: MedImmune/AZ, Clovis, Eli Lilly, 4SC, Bayer, Celgene, Leap, Roche; Non-Financial Interests, Advisory Role: Ovibio. N. Starling: Financial Interests, Personal, Advisory Board: GSK, Novartis, MSD Oncology, Servier, AstraZeneca, Pfizer, Gilead Sciences, Seagen, Janssen, Takeda, Moderna, BMS; Financial Interests, Personal, Invited Speaker: Eli Lilly, Pierre Fabre, Amgen, Merck Serono, Novartis, MSD Oncology, GSK, Servier, Seagen, BMS, AstraZeneca, Astellas, Natera, Daiichi Sankyo; Financial Interests, Personal, Other, Travel and/or Accommodation Funded: MSD Oncology, Guardant, Servier, GSK, Takeda, BMS; Financial Interests, Institutional, Research Grant, Sept 2017 (24m) Paid to institution research: Merck; Financial Interests, Institutional, Research Grant, Nov 2017 (48m) -Paid to institution research fund: AstraZeneca; Financial Interests, Institutional, Research Grant, Jan 2018 - Paid to institution research fund: Pfizer; Financial Interests, Institutional, Research Grant, July 2018 (36m) Paid to institution research fund: BMS; Financial Interests, Institutional, Research Grant, June 2022 - ?Paid to institution research fund: Guardant; Financial Interests, Institutional, Research Grant, August 2023 - ?Paid to institution research fund: Gilead; Non-Financial Interests, Advisory Role, Ad Board uncompensated: Guardant. All other authors have declared no conflicts of interest.Copyright © 2025