Paclitaxel, Ramucirumab and Tislelizumab Switch Maintenance in Advanced HER2-negative and PD-L1 TAP Score of 5 or More Advanced Gastroesophageal Adenocarcinoma

ARMANI‐2/ENGIC8 is a randomized, open‐label, phase III trial evaluating a switchmaintenance strategy in patients with previously untreated, locally advanced unresectableor metastatic, HER2‐negative and PD‐L1‐positive gastroesophageal adenocarcinoma.The combination of platinum‐ and fluoropyrimidine‐based chemotherapy with an anti‐PD‐1agent represents a first‐line treatment option for patients with advanced HER2‐negative,PD‐L1‐positive gastroesophageal adenocarcinoma. However, disease progression remainsfrequent and may lead to clinical deterioration, preventing a substantial proportion ofpatients from receiving subsequent anticancer treatment.The phase III ARMANI trial demonstrated that, in patients with advanced HER2‐negativegastric or gastroesophageal junction adenocarcinoma who achieved disease control after 3months of first‐line oxaliplatin‐ and fluoropyrimidine‐based chemotherapy, switching topaclitaxel plus ramucirumab significantly improved progression‐free survival and overallsurvival compared with continuation of the initial chemotherapy. These findings supportthe early introduction of a non‐cross‐resistant treatment before the development ofchemotherapy‐resistant disease and clinical deterioration.ARMANI‐2 builds on this strategy in the current immunotherapy‐based treatment setting. Inaddition, VEGF/VEGFR blockade may have immunomodulatory effects that provide a biologicalrationale for combining ramucirumab with PD‐1 blockade.All eligible patients will receive a 12‐week induction treatment with tislelizumabcombined with platinum‐ and fluoropyrimidine‐based chemotherapy (mFOLFOX6, CAPOX, orcisplatin plus fluorouracil). Patients who complete induction without disease progressionor permanent treatment discontinuation will be randomized 1:1 to receive either switchmaintenance with paclitaxel, ramucirumab, and tislelizumab (Arm A) or continuation of thechemotherapy regimen used during induction in combination with tislelizumab (Arm B).The primary objective is to determine whether switch maintenance with paclitaxel,ramucirumab, and tislelizumab improves progression‐free survival compared withcontinuation of chemotherapy and tislelizumab. Secondary objectives include overallsurvival, PFS2, tumor response and disease control, safety, health‐related quality oflife, and attrition to subsequent anticancer therapy. Exploratory analyses willinvestigate clinical and translational biomarkers potentially associated with treatmentefficacy and early disease progression.