Anti-PD-1 and CapOx for the First-line Treatment of dMMR Esophagogastric Cancer (AuspiCiOus)

Inclusion Criteria:

• Patients must provide written informed consent according to ICH/GCP, andnational/local regulations prior to any screening procedures.

• Male or female adult patients (≥ 18 years).

• Patients with histologically confirmed diagnosis of metastatic or irresectable HER2negative adenocarcinoma of the stomach or gastroesophageal junction (Siewert II andIII); patients with HER2 positive disease are eligible when treatment withtrastuzumab is contraindicated. If histology cannot be obtained, cytology isacceptable to prove metastatic disease.

• Patients with metastatic or irresectable adenocarcinoma of the stomach or oesophagusnot pre-treated with chemotherapy or radiotherapy for irresectable or metastaticdisease. Palliative radiotherapy on the primary tumor or a metastatic lesion isallowed if other untreated lesions eligible for evaluation are present.

• Measurable disease as assessed by RECIST 1.1

• dMMR identified by IHC of mismatch repair proteins MLH1, PMS2, MSH2 en MSH6

• Primary tumor or metastasis accessible for repeat fresh histological biopsies

• ECOG (WHO) performance status 0-2

• Patient has adequate bone marrow and organ function as defined by the followinglaboratory values:

• Absolute Neutrophil Count (ANC) > 1.5 x 109 /L

• Hemoglobin (Hgb) > 5.6 mmol/L

• Platelets > 100 x 109 /L

• Serum total bilirubin within ≤ 1.5 x ULN (upper limit of normal); or total bilirubin < 3.0 x ULN with direct bilirubin within normal range in patients with welldocumented Gilbert's syndrome; biliary drainage is allowed for biliary obstruction

• Serum creatinine < 1.5 x ULN or creatinine clearance >30 mL/min/1.73 m2

• Alanine aminotransferase (AST) and aspartate aminotransferase (ALT) < 2.5x ULNwithin normal range or < 5.0 x ULN if liver metastases are present

• If a female patient is of child-bearing potential, as evidenced by regular menstrualperiods, she must have a negative pregnancy test (urine or serum; beta-humanchorionic gonadotropin (β-hCG)) documented prior to the first administration ofstudy drug. If sexually active, the patient must agree to use contraceptionconsidered adequate and appropriate by the Investigator during the period ofadministration of study drug and after the end of treatment as recommended.

• Absence of any psychological, familial, sociological or geographical conditionpotentially hampering compliance with the study protocol and follow-up schedule;those conditions should be discussed with the patient before registration in thetrial.

Exclusion Criteria:

• Severe renal impairment (CLcr ≤ 30 ml/min)

• Any clinically significant disorder impacting the risk-benefit balance negativelyper physician's judgment.

• Any prior anti-cancer chemotherapy, biologic or investigational therapy formetastatic or irresectable stomach or oesophageal cancer

• Disease progression within six months after completion of (neo)adjuvant chemotherapycontaining a fluoropyrimidine and/or platinum compound. (Disease progression within 6 months after completion of neoadjuvant chemoradiation carboplatin AUC 2 andpaclitaxel 50 mg/m2 is allowed.)

• All target lesions in a radiation field without documented disease progression.

• Patient has known brain metastases, unless previously treated and well-controlledfor at least 3 months (defined as clinically stable, no edema, no steroids andstable in 2 scans at least 4 weeks apart).

• Past or current malignancy other than entry diagnosis interfering with prognosis ofmetastatic gastroesophageal cancer.

• Known uncontrollable hypersensitivity or contraindications to any of the componentsof retifanlimab, fluoropyrimidines, leucovorin, oxaliplatin. Patients with previousdose reductions or delays are eligible.

• Complete dihydropyrimidine dehydrogenase deficiency.

• Patient has active, uncontrolled bacterial, viral or fungal infection(s) requiringsystemic therapy.

• Patient has known past or active infection with human immunodeficiency virus (HIV),hepatitis B or hepatitis C.

• Signs of interstitial lung disease (ILD)

• Participants with an active, known or suspected autoimmune disease. Participantswith type I diabetes mellitus, hypothyroidism only requiring hormone replacement,skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemictreatment, or conditions not expected to recur in the absence of an external triggerare permitted to enroll.

• Patient has any other concurrent severe and/or uncontrolled medical condition thatwould, in the investigator's judgment contraindicate patient participation in theclinical study.

• Use of other investigational drugs within 30 days of enrollment.

• Patient is enrolled in any other clinical protocol or investigational trial thatwill interfere with the primary endpoint of the current study.

• Patients who in the investigators' opinion may be unwilling, unable or unlikely tocomply with requirements of the study protocol.

• Breast feeding, known pregnancy, positive serum pregnancy test or unwillingness touse a reliable method of birth control, during therapy and for 3 months followingthe last dose of study treatment.

• Treatment within 4 weeks with DPD inhibitors, including sorivudine or its chemicallyrelated analogues such as brivudine.

• Pre-existing motor or sensory neurotoxicity greater than CTCAE grade 1.

• History of organ transplant, including allogeneic stem cell transplantation.

• Receiving probiotics as of the first dose of study treatment.