The goal of this clinical trial is to evaluate the addition of ivonescimab to standard chemotherapy in patients with advanced or metastatic gastric and gastroesophageal adenocarcinoma. The main question it aims to answer is : Does the addition of ivonescimab increase the response to treatment ? Participants will visit the clinic every 2 weeks for checkups, treatment administration and tests for collection of adverse events.

Phase 2, multicenter, two-cohort, non-randomized, open-label trial to evaluate the efficacy of ivonescimab in combination with chemotherapy in patients with advanced or metastatic gastric and esophageal adenocarcinoma, with and without actionable biomarker (HER2/PD-L1/claudin18.2).

Inclusion Criteria:

1. Signed a written informed consent form prior to any trial specific procedures. Note: If the patient is physically unable to provide their written consent, a trusted person of their choice, independent of the Investigator or the Sponsor, can confirm the patients consent in writing.
2. Histologically or cytologically proven gastric cancer (GC) or esophagogastric junction cancer adenocarcinoma (EGJC)
3. Metastatic or locally advanced non resectable (stage IV) disease.
4. Presence of at least one measurable lesion as assessed by the investigator according to RECIST v1.1.
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
6. Age ≥18 years.
7. For patients without actionable biomarker (HER2 and Claudin 18.2-negative) except for PD-L1, no prior treatment for advanced disease (cohort 1). For patients with at least one of the following actionable biomarker (PD-L1 CPS≥1, and/or HER2-positive, and/or Claudin 18.2-positive), who had received only one prior line of treatment for advanced disease (cohort 2).
8. Adequate hematological function: absolute neutrophil count (ANC) ≥1.5 × 10⁹/L, platelet count ≥100 × 10⁹/L, and hemoglobin ≥9 g/dL. Note: Blood transfusion or growth factor therapy should not be performed within 7 days prior to the screening hematology analysis.
9. Adequate renal function: estimated creatinine clearance ≥50 mL/min according to the Cockcroft-Gault formula, or estimated glomerular filtration rate (eGFR) value ≥50 mL/min using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation, and urine protein < 2+ or 24-hour urine protein quantification < 1.0 g.
10. Adequate liver function: total bilirubin level ≤1.5 × the upper limit of normal (ULN) range (≤3 x ULN for patients with liver metastases or confirmed/suspected Gilbert syndrome), and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels ≤2.5 × ULN (AST and ALT ≤5 x ULN when documented liver metastasis).
11. Coagulation: prothrombin time (PT) or international normalized ratio (INR) ≤ 1.5 x ULN, and partial prothrombin time (PTT) or activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN (unless abnormalities are unrelated to coagulopathy).This applies only to patients who are not on therapeutic anti-coagulation. Patients receiving therapeutic anti-coagulation should be on a stable dose.
12. Women of childbearing potential (WOCBP) having sex with an unsterilized male partner and unsterilized males having sex with a female partner of childbearing potential, must agree to use an effective method of contraception for the duration of trial participation and as required after completing study treatment (120 days after the last dose of ivonescimab). Men must also agree to not donate sperm and women must agree to not donate oocytes during the specified period.
13. WOCBP must have a negative serum pregnancy test performed within 3 days before inclusion and a negative urine pregnancy test on the day of first dose, prior to treatment administration.
14. Willing and able to comply with the protocol for the duration of the study including scheduled visits, treatment plan, laboratory tests, and other study procedures
15. Affiliation to the Social Security System (or equivalent)

Exclusion Criteria:

1. Previous or concurrent cancer that is distinct in primary site or histology from gastroesophageal cancer within 2 years prior to study inclusion, except for curatively treated cervical cancer in situ, non-melanoma skin cancer and superficial bladder tumors [Ta (non-invasive tumor), Tis (carcinoma in situ) and T1 (lamina propria invasion)].

2. Patients with high microsatellite instability (MSI-H) or mismatched repair disease (dMMR) tumor.

3. Enteral intake < 1500 kcal /d and or a weight loss > 15% of total body weight within the 6 months

4. Toxicities from previous treatment not resolved to grade ≤ 1 (according to the version 5.0 of the National Cancer Institute - Common terminology criteria for adverse events [NCI-CTCAE v5.0]) before treatment start with the exception of alopecia.

5. Major surgical procedures or serious trauma within 4 weeks prior to treatment start, or plans for major surgery within 4 weeks after the first dose (as determined by the investigator). Minor local procedures (excluding central venous catheterization and port implantation) within 3 days prior to treatment start.

6. History of bleeding tendencies or coagulopathy and/or clinically significant bleeding symptoms or risk within 4 weeks prior to inclusion, including but not limited to:

   1. Hemoptysis (defined as coughing up ≥ 0.5 teaspoon of fresh blood or small blood clots), Note: transient hemoptysis associated with diagnostic bronchoscopy is allowed.
   2. Nasal bleeding /epistaxis (bloody nasal discharge is allowed),
   3. Current use of prophylactic or full-dose anticoagulants or anti-platelet agents for therapeutic purposes that is not stable prior to treatment start is not allowed. The use of full-dose anticoagulants is permitted as long as the international normalized ratio (INR) or activated partial thromboplastin time (aPTT) is within therapeutic limits according to the medical standard of the enrolling institution.

7. Poorly controlled hypertension with repeated systolic blood pressure ≥ 150 mmHg or diastolic blood pressure ≥ 100 mmHg after oral antihypertensive therapy.

8. History of major diseases before inclusion, specifically:

   1. Unstable angina, myocardial infarction, congestive heart failure (New York Heart Association classification ≥ grade 2) or unstable vascular disease (eg, aortic aneurysm at risk of rupture, Moyamoya disease) that required hospitalization within 12 months prior to inclusion, or other cardiac impairment that may affect the safety evaluation of the study drug (eg, poorly controlled arrhythmias, myocardial ischemia),
   2. History of esophageal gastric varices, severe ulcers, wounds that do not heal, abdominal fistula, intra-abdominal abscesses, or acute gastrointestinal bleeding within 6 months before inclusion,
   3. History of any grade arterial thromboembolic event, venous thromboembolic event of Grade 3 and above as specified in NCI-CTCAE v5.0, transient ischemic attack, cerebrovascular accident, hypertensive crisis, or hypertensive encephalopathy within 12 months prior to inclusion,
   4. Acute exacerbation of chronic obstructive pulmonary disease within 4 weeks before inclusion,
   5. History of perforation of the gastrointestinal tract and/or fistula, history of gastrointestinal obstruction (including incomplete intestinal obstruction requiring parenteral nutrition), extensive bowel resection (partial colectomy or extensive small bowel resection) within 6 months prior to inclusion.

9. Imaging during the screening period shows that the patient has:

   1. Radiologically documented evidence of major blood vessel invasion or encasement by cancer,
   2. Radiographic evidence of intra-tumor cavitation.
   3. Evidence of higher bleeding risk on prostheses

10. Any immunosuppressive therapy during more than 7 days (i.e. corticosteroids >10mg or equivalent dose) within 14 days before the planned start of study therapy. Physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency is not considered as a form of systemic treatment.

11. Active autoimmune disease that has required a systemic treatment in past 2 years (i.e. corticosteroids or immunosuppressive drugs). Replacement therapy (e.g. thyroxine, insulin) is allowed active or history of autoimmune disease or immune deficiency, including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, or multiple sclerosis, with the following exceptions:

    1. Patients with a history of autoimmune-related hypothyroidism who are on thyroid replacement hormone are eligible for the study,
    2. Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen are eligible for the study,
    3. Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis are excluded) are eligible for the study provided all of following conditions are met:

    I. Rash must cover < 10% of body surface area, II. Disease is well controlled at baseline and requires only low-potency topical corticosteroids, III. No occurrence of acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high potency or oral corticosteroids within the previous 12 months.

12. Prior allogeneic bone marrow transplantation or prior solid organ transplantation.

13. Known history of, or any evidence of, interstitial lung disease.

14. Patient with non-controlled human immunodeficiency virus (HIV) (positive HIV 1/2 antibodies) infection (patient with undetectable viral load (HIV RNA PCR) and CD4 above 350 either spontaneously or on stable anti-viral regimen).

15. Chronic hepatitis B or C infection (if hepatitis status cannot be obtained from medical records, re-testing is required)

16. In case of planned treatment with fluorouracil, proven complete deficiency of dihydropyrimidine dehydrogenase (DPD).

17. Any condition which in the Investigator's opinion makes it undesirable for the subject to participate in the trial or which would jeopardize compliance with the protocol.

18. Pregnant or breast-feeding females.

19. Participation in another therapeutic trial within the 30 days prior to entering the study. Participation in an observational trial would be acceptable.

20. Patients unwilling or unable to comply with the medical follow-up required by the trial because of geographic, familial, social, or psychological reasons.

21. Individuals deprived of liberty or placed under protective custody or guardianship

Individual Participant Data will not be shared at an individual level. Those data will be part of the study database including all enrolled patients.