Active Cancer NIHR-supported project Digestion, Kidneys & Other Organs

A phase II study of Zimberelimab anti PD1 immunOtherapy +/- Domvanalimab anti-TIGIT therapy in resectable mismatch repair deficient gastric/gastro-oesophageal junctional AdenoCarinoma (ZODIAC)

Funder NIHR (part of DHSC)
Recipient organisation NIHR Barts Biomedical Research Centre
NIHR support Recorded as supported by this research centre
Period Mar 2025 — Apr 2031

In plain English

AI plain-English summary

Surgeons and oncologists are testing whether adding a second immunotherapy drug—one that blocks a protein called TIGIT—can improve outcomes for patients with a specific type of stomach cancer before and after surgery. Around one in ten operable stomach or gastro-oesophageal junction cancers have a genetic signature called mismatch repair deficiency (MMRd). These tumours do not respond well to standard chemotherapy, and patients often relapse. However, MMRd tumours are highly sensitive to immune checkpoint inhibitors—drugs that help the immune system recognise and attack cancer cells. Early studies have shown that combining two such inhibitors can produce strong responses, with many patients remaining relapse-free after a year. This trial compares a single PD-1 inhibitor (zimberelimab) against the same drug combined with an anti-TIGIT antibody (domvanalimab) in patients who will receive treatment both before and after surgery. If the combination proves more effective, it could change the standard of care for this subset of gastric cancer patients, sparing them ineffective chemotherapy and reducing the risk of relapse. The work is a proof-of-concept study, meaning it will determine whether a larger, definitive trial is warranted.

View original technical description
A proof of concept phase II study of peri-operative anti-PD1 (Zimberelimab) +/- anti-TIGIT (Domvanalimab) in resectable mismatch repair deficient (MMRd)/ high micro-satellite instability (MSI-H) gastric/gastro-oesophageal junctional (GOJ) adenocarcinoma (AC). Gastric cancer is the 5th most commonly diagnosed cancer each year and the third most common cause of cancer death worldwide. The current standard of care for patients diagnosed with operable gastric/GOJ AC is surgery combined with perioperative chemotherapy, and even following this toxic regimen, about half go on to relapse and die from their cancer. On average 10% of resectable gastro-oesophageal cancer is MMRd. Peri-operative chemotherapy remains debatable for this subset of patients and the MAGIC trial actually suggests that patients with MMRd tumours have a worse overall survival when treated with peri-operative chemotherapy. MMRd is a positive predictive biomarker for immune checkpoint inhibition. Immune checkpoint inhibition has been shown to be effective in the advanced setting, and more recently in the peri-operative curative setting, with unprecedented high pathological response rates demonstrated in the NEONPIGA study (pCR rate 58.6%), and 93.7% patients alive without relapse at 12 months. And confirmed in the INFITNITY trial, reviewing dual ICI in resectable gastric/GOJ AC, with a 60% pCR rate. With regards to the combination of anti-TIGIT and PD-L1 therapy, this has been shown to be effective an well tolerated in the LBA-5 study. Therefore peri-operative dual immune checkpoint inhibition seems to be an excellent choice for these patients to improve outcomes. A UK multicentre, prospective, randomised open label phase II proof of concept study with screen selection design. There will be two cohorts with a 1:1 randomisation: Arm A: Single agent zimberelimab (PD-1 inhibitor) Arm B: Combination zimberelimab + domvanalimab (anti-TIGIT). Each cohort will complete 12 weeks (4 cycles) of pre-operative treatment and 18 weeks (6 cycles) of post operative treatment.

Researchers

Marco Gerlinger (Principal Investigator)

Related Research

Grants with similar aims, by meaning.

A Randomized, Open-Label, Multicenter Phase 3 Trial of Domvanalimab, Zimberelimab, and Chemotherapy Versus Nivolumab and Chemotherapy in Participants with Previously Untreated Locally Advanced Unresectable or Metastatic Gastric, Gastroesophageal Junction, and Esophageal Adenocarcinoma
A Randomized, Open-Label, Multicenter Phase 3 Trial of Domvanalimab, Zimberelimab, and Chemotherapy Versus Nivolumab and Chemotherapy in Participants with Previously-Untreated Locally Advanced Unresectable or Metastatic Gastric, Gastroesophageal Junction, and Esophageal Adenocarcinoma.
ZODIAC: A randomised phase II study of Zimberelimab anti-PD1 immunOtherapy +/- Domvanalimab anti-TIGIT immunotherapy in resectable mismatch repair deficient gastric and gastro-oesophageal junctional AdenoCarcinoma
Peri-operative Immuno-Chemotherapy in Operable oesophageal aNd gastrIc Cancer (ICONIC Trial)
A Randomized, Open-Label, Phase 3 Study to Evaluate Zimberelimab and Domvanalimab in Combination with Chemotherapy Versus Pembrolizumab with Chemotherapy for the First-Line Treatment of Patients With Metastatic Non–Small Cell Lung Cancer With No Epidermal Growth Factor Receptor or Anaplastic Lymphoma Kinase Genomic Tumor Aberrations

Original classification

Precision Cancer Care

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