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

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.