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.
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 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
Single group
Durvalumab
DrugIn the preoperative treatment phase, patients will receive 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 addition, they will receive up to 4 treatments of durvalumab (1,500 mg) administrated by infusion on the first day of every second two-week cycle (Q4W). Four to eight weeks after the last dose of preoperative treatment, patients will undergo surgical resection. Study specifications for surgical resection are consistent with national guidelines. Surgical approaches will be tailored to the individual patient according to local standards with the goal of achieving R0-resection of the primary tumor. Four to twelve weeks after surgery, patients will receive durvalumab (1,500 mg IV, Q4W) monotherapy for a maximum of 10 cycles (14 cycles of durvalumab in total).
Pathological complete response (pCR)
Pathological complete response (pCR) rate as assessed locally, corresponding to the ypT0N0M0 stage category. pCR is defined as the proportion of patients with pathological complete remission in the post-surgery specimen, meaning complete absence of viable tumor cells in the primary tumor and lymph nodes and no evidence of metastatic disease upon pathological examination. For example, a patient with ypT0N0 but with pathologically confirmed peritoneal involvement containing viable tumor cells will not be considered to have achieved pCR.
Event-free survival (EFS) plus EFS-rate at 1 year
Event-free survival (EFS) plus EFS-rate at 1 year, defined as the time from enrollment until the date of one of the following events (whichever occurs first): progression acc. RECIST 1.1 that precludes surgery or requires non-protocol therapy during the neoadjuvant period; progression acc. RECIST 1.1 or recurrence during the adjuvant period; non-RECIST progression that precludes surgery or requires non-protocol therapy during the neoadjuvant period or discovered during surgery; progression/recurrence confirmed by biopsy post-surgery; or death due to any cause. Patients without an event at the time of data cut-off will be censored at the date of last disease assessment.
Event-free survival (EFS) plus EFS-rate at 2 years
Event-free survival (EFS) plus EFS-rate at 2 years, defined as the time from enrollment until the date of one of the following events (whichever occurs first): progression acc. RECIST 1.1 that precludes surgery or requires non-protocol therapy during the neoadjuvant period; progression acc. RECIST 1.1 or recurrence during the adjuvant period; non-RECIST progression that precludes surgery or requires non-protocol therapy during the neoadjuvant period or discovered during surgery; progression/recurrence confirmed by biopsy post-surgery; or death due to any cause. Patients without an event at the time of data cut-off will be censored at the date of last disease assessment.
Rate of patients who undergo surgery (with or without resection)
Number of patients who were surgically resected.
R0 resection rate
R0 resection rate, defined as proportion of patients in whom the surgical margin is microscopically negative for residual tumor
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Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest
Lead sponsor
AstraZeneca
Collaborator
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