This trial is designed to evaluate a total neoadjuvant approach using D-FLOT as the new standard backbone in patients with resectable esophagogastric adenocarcinoma. It addresses major limitations of current treatment paradigms, builds directly on the strong clinical signal from the MATTERHORN trial, and offers a rational, biologically sound framework for future therapy intensification and innovation.

By moving systemic therapy entirely into the preoperative phase, we aim to:

• Improve patient outcomes through better adherence and deeper response
• Minimize postoperative therapy-related dropout
• Create a platform for rational post-surgical drug testing and individualized treatment escalation The trial will provide pivotal evidence to guide the next generation of curative-intent treatment strategies for EGA.

The present clinical trial is a prospective, investigator-initiated, single-arm, open-label, multicenter, multi-national phase II trial. Patients with locally advanced, cT2-4 (any cN, M0) or any cT (cN+, M0), gastric, esophagogastric junction (type 1-3) or lower esophageal adenocarcinoma which are considered medically and technically resectable are eligible and will undergo baseline assessment. All patients will receive treatment consisting of up to eight 2-week cycles of FLOT chemotherapy (docetaxel 50 mg/m² IV, oxaliplatin 85 mg/m² IV, folinic acid 200 mg/m² IV, 5-FU 2,600 mg/m² IV; given on day 1 of each 2-weeks cycle [Q2W]) in combination with up to four 4-week cycles immunotherapy with durvalumab (1,500 mg IV, given on day 1 of each 4-weeks cycle [Q4W]). Four to eight weeks after last dose of preoperative treatment, patients will undergo surgical resection (tailored to the individual patient, according to local standards). Afterwards, patients will enter the maintenance phase receiving durvalumab monotherapy (1,500 mg IV, Q4W) for up to 10 cycles.

Inclusion Criteria:

• Patient* has given written informed consent

• Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up

• Patient is ≥ 18 years of age at time of signing the written informed consent

• Patient has histologically proven locally advanced (cT2-4, any cN, M0 OR any cT, cN+, M0 stage) gastric, esophagogastric junction (type 1-3) or lower esophageal adenocarcinoma that is considered medically and technically resectable

• Patient has a known PD-L1 status according to standardized TAP scoring (by local testing), any PD-L1 status is eligible

• Patient has a ECOG performance status 0 or 1

• Patient must have a life expectancy of at least 12 weeks

• Patient has adequate blood count, liver-enzymes, and renal function:

  1. ANC ≥ 1.0x109 cells/L without the use of hematopoietic growth factors
  2. Platelet count ≥ 75 x 109/L (>75,000 per mm3)**
  3. Hemoglobin ≥ 9 g/dL**
  4. Serum total bilirubin ≤ 1.5x institutional upper normal limit (ULN)
  5. AST (SGOT)/ALT (SGPT) ≤ 2.5 x institutional ULN
  6. Patients not receiving therapeutic anticoagulation must have an INR ≤ 1.5 ULN and aPTT ≤ 1.5 ULN. The use of full dose anticoagulants is allowed as long as the INR or PTT is within therapeutic limits (according to the medical standard in the institution) and the patient has been on a stable dose for anticoagulants for at least three weeks at the time of inclusion.
  7. Serum Creatinine ≤ 1.5 x ULN and a calculated creatinine clearance rate > 40 mL /min.

• Patient has a body weight > 30 kg

• Female patients defined as women of childbearing potential (WOCBP) must agree to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods that result in a failure rate of <1% per year during the treatment period and for 3 months after last dose of durvalumab or 6 months after last dose of chemotherapy, whatever is later

• Male patients with WOCBP partners must agree to remain abstinent (refrain from heterosexual intercourse) or use barrier contraceptive during the treatment period as well as up to 3 months after last dose of durvalumab or up to 6 months after last dose of chemotherapy, whatever is later. Male patients must refrain from donating sperm during this same period

Exclusion Criteria:

• Patient received previous (radio)chemotherapy or checkpoint inhibition for the same condition or within the past five years for any other cancerous condition

• Patient received prior partial or complete esophagogastric tumor resection

• Patient has known hypersensitivity to any component of the durvalumab formulation as well as a known history of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion protein and/or any known contraindication (including hypersensitivity) to one of the study drugs

• Patient has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease

• Patient has lung-specific intercurrent clinically significant illnesses including, but not limited to, any underlying pulmonary disorder (e.g., pulmonary emboli within three months of the study enrolment, severe asthma, severe COPD, restrictive lung disease, relevant pleural effusion etc.)

• Patient received a prior complete pneumonectomy

• Patient has inadequate cardiac function (LVEF value < 50 %) as determined by echocardiography

• Patient has a known complete absence of dihydropyrimidine dehydrogenase (DPD) activity

• Patient received treatment with brivudine, sorivudine or their chemically related analogues within 28 days prior to stud enrollment

• Patients has pernicious anemia or other megaloblastic anemia due to vitamin B12 deficiency

• Patient has a medical history of myocardial infarction (MI) within 6 months before enrollment, symptomatic congestive heart failure (CHF) (New York Heart Association Class II to IV). Subjects with troponin levels above ULN at screening (as defined by the manufacturer), and without any MI related symptoms should have a cardiologic consultation during screening to rule out MI

• Patient has a corrected QT interval (QTc) prolongation to > 470 ms (females) or >450 ms (males) based on average of the screening triplicate ECG

• Patient has a history of malignancy other than EGA except for:

  1. Malignancy treated with curative intent and cured with no known active disease ≥ 3 years before the first dose of study treatment and of low potential risk for recurrence.
  2. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease.
  3. Adequately treated carcinoma in situ without evidence of disease

• Patient has an uncontrolled infection requiring IV antibiotics, antivirals or antifungals within 14 days prior to enrolment

• Patient has active HBV infection, which is characterized by positive HBV surface antigen (HBsAg) and/or positive HBc antibodies (anti-HBcAb) with detectable HBV DNA (≥ 10 IU/mL or above the limit of detection per local laboratory standard), unless the participant is treated with antiviral therapy, as per institutional practice. The HBV antiviral therapy must be initiated prior to randomization, and participants must remain on antiviral therapy for the study duration and for 6 months after the last dose of response (e.g., reduction HBV DNA levels) prior to starting intervention.

Note: Patients who test positive for HBsAg or anti-HBc with undetectable HBV DNA (< 10 IU/mL or under the limit of detection per local laboratory standard) do not require antiviral therapy prior to enrollment. These patients are eligible and will be tested at every cycle to monitor HBV DNA levels and initiate antiviral therapy if HBV DNA is detected (≥ 10 IU/mL or above the limit of detection per local laboratory standard). The HBV DNA detectable patients must initiate and remain on antiviral therapy for the trial duration and for 6 months after the last dose of durvalumab

• Patient has active HCV infection (as characterized by the presence of detectable HCV RNA and anti-HCV antibody [anti-HCV]) unless the patient is managed per local institutional practice for the trial and for 6 months after the last dose of durvalumab

• Patient has any co-infection with HBV and HDV (HDV-positive infection is indicated by the presence of anti-HDV antibodies)

• Patient has active tuberculosis infection (clinical evaluation that may include clinical history, physical examination, and radiographic findings, or tuberculosis testing in line with local practice)

• Patient has known HIV infection that is not well controlled. All of the following criteria are required to define an HIV infection that is well controlled:

  1. Undetectable viral RNA
  2. CD4+ count ≥ 350 cells/mm3
  3. No history of acquired immune deficiency syndrome-defining opportunistic infection within the past 12 months, and stable for at least 4 weeks on the same anti-HIV medications (meaning there are no expected further changes in that time to the number or type of antiretroviral drugs in the regimen).

If an HIV infection meets the above criteria, monitoring of viral RNA load and CD4+ count is recommended. Patient must be tested for HIV if acceptable by local regulations or an institutional IRB/IEC.

• Patient has active or history of autoimmune disease including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener's granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis. The following are exceptions to this criterion:

  1. Patients with vitiligo or alopecia
  2. Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement
  3. Any chronic skin condition that does not require systemic therapy
  4. Patients without active disease in the last 5 years may be included but only after consultation with the study physician
  5. Patients with celiac disease controlled by diet alone

• Patient currently or priorly used immunosuppressive medication within 14 days before the first dose of durvalumab. The following are exceptions to this criterion:

  1. Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection)
  2. Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent
  3. Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication)

• Patient received live, attenuated vaccine within 30 days prior initiation of study drug

• Patient has any other serious concomitant or medical condition that, in the opinion of the investigator, presents a high risk of complications to the patient or reduces the likelihood of clinical effect

• Patient participated in another interventional clinical study within 28 days prior to study enrollment or participation in a clinical study at the same time as this study, unless it is an observational/ non-interventional study or during the follow-up period of an interventional study

• Patient has taken an investigational drug within 28 days prior to initiation of study drug

• Female patients, who are pregnant or breast feeding or planning to become pregnant within 6 months after the end of treatment. Female patients of childbearing potential must have a negative serum pregnancy test result within 7 days prior to initiation of study treatment

No IPD will be shared