Background Doublet cytotoxic treatment demonstrates survival benefit over single drug therapies in patients with advanced esophagogastric cancer (EGC). Previous clinical data suggests an improved survival outcome in patients with microsatellite instability (MSI) treated with PD-1 inhibitor monotherapy or in combination with chemotherapy in first line palliative treatment. The positive effect of immunotherapy was only seen after a couple of months of treatment. This suggests that the patient might benefit from a short course of chemotherapy at the start of treatment. However, reports on the effects of cytotoxic treatment in MSI-high tumors range from beneficial to detrimental. Thus, the value of cytotoxic treatment, as well as the effect on the tumor immune microenvironment (TME) in MSI-high tumors is unclear. Therefore, in AuspiCious-dMMR we will study the effect of sequential treatment in patients with mismatch repair deficient (dMMR) EGC on the tumor immune microenvironment and, more specifically, the impact on the infiltration of cytotoxic T cells, before and after a short course of chemotherapy, and during treatment with PD-1 inhibition.

Materials and Methods AuspiCiOus is a multi-center, open-label, single arm (phase 2) study in patients with dMMR irresectable or metastatic EGC adenocarcinoma (NCT05177133). Patients are treated with Capecitabine and Oxaliplatin for two 3-weekly cycles, after which treatment is continued with retifanlimab (PD-1 inhibitor) for 4-weekly cycles up to progression or unacceptable toxicity, with a maximum of two years. Before treatment, after chemotherapy and after two cycles of immunotherapy fresh tumor biopsies are collected to study the primary outcome (T cell infiltration and the interferon-γ signature) as well as for translational research purposes (flow cytometry, nanostring profiling, (multicolor) immunohistochemistry and organoid culturing). Blood is collected at the same time points and on day 3 after the first course of immunotherapy for isolation of peripheral blood mononuclear cell, and determination of cytokine/chemokine profile, circulating stromal markers, and circulating tumor DNA. Also, fecal samples are collected to determine changes in the intestinal microbiome and patient reported outcome measures are used to determine quality of life. (s)AEs are assessed according to CTCAE v5 and tumor response is determined according to (i)RECIST 1.1. Key eligibility criteria are 1) histological confirmed diagnosis of untreated metastatic or irresectable HER2- adenocarcinoma of stomach or junction and 2) dMMR determination by IHC. Study is open for inclusion and 19 of planned 25 patients have been enrolled.

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J. Bos: None. N. Haj Mohammad: B. Research Grant (principal investigator, collaborator or consultant and pending grants as well as grants already received); Significant; Servier. F. Consultant/Advisory Board; Modest; BMS, Astra Zeneca, Servier, Merck. S. Derks: B. Research Grant (principal investigator, collaborator or consultant and pending grants as well as grants already received); Significant; Incyte. D. Speakers Bureau/Honoraria (speakers bureau, symposia, and expert witness); Modest; Servier, BMS, Benecke. F. Consultant/Advisory Board; Modest; BMS. H.W.M. van Laarhoven: B. Research Grant (principal investigator, collaborator or consultant and pending grants as well as grants already received); Significant; Incyte, Servier, Auristone, ORCA, Merck. D. Speakers Bureau/Honoraria (speakers bureau, symposia, and expert witness); Modest; Astellas, Novartis, Benecke, Daiichy-Sankyo, JAAP, Medtalks, Travel Congress Management BV. F. Consultant/Advisory Board; Modest; BMS, Dragonfly, Eli Lilly, MSD, Nordic Pharma, Servier, Amphera, Astra Zeneca, Beigene, Daiichy-Sankyo.