ARMANI-2/ENGIC8 is a randomized, open-label, phase III trial evaluating a switch maintenance strategy in patients with previously untreated, locally advanced unresectable or metastatic, HER2-negative and PD-L1-positive gastroesophageal adenocarcinoma.
The combination of platinum- and fluoropyrimidine-based chemotherapy with an anti-PD-1 agent represents a first-line treatment option for patients with advanced HER2-negative, PD-L1-positive gastroesophageal adenocarcinoma. However, disease progression remains frequent and may lead to clinical deterioration, preventing a substantial proportion of patients from receiving subsequent anticancer treatment.
The phase III ARMANI trial demonstrated that, in patients with advanced HER2-negative gastric or gastroesophageal junction adenocarcinoma who achieved disease control after 3 months of first-line oxaliplatin- and fluoropyrimidine-based chemotherapy, switching to paclitaxel plus ramucirumab significantly improved progression-free survival and overall survival compared with continuation of the initial chemotherapy. These findings support the early introduction of a non-cross-resistant treatment before the development of chemotherapy-resistant disease and clinical deterioration.
ARMANI-2 builds on this strategy in the current immunotherapy-based treatment setting. In addition, VEGF/VEGFR blockade may have immunomodulatory effects that provide a biological rationale for combining ramucirumab with PD-1 blockade.
All eligible patients will receive a 12-week induction treatment with tislelizumab combined with platinum- and fluoropyrimidine-based chemotherapy (mFOLFOX6, CAPOX, or cisplatin plus fluorouracil). Patients who complete induction without disease progression or permanent treatment discontinuation will be randomized 1:1 to receive either switch maintenance with paclitaxel, ramucirumab, and tislelizumab (Arm A) or continuation of the chemotherapy 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 with continuation of chemotherapy and tislelizumab. Secondary objectives include overall survival, PFS2, tumor response and disease control, safety, health-related quality of life, and attrition to subsequent anticancer therapy. Exploratory analyses will investigate clinical and translational biomarkers potentially associated with treatment efficacy and early disease progression.
Able to provide written informed consent and can understand and agree to comply with the requirements of the study and the schedule of assessments.
Age ≥ 18 years on the day of signing the informed consent form.
Diagnosis of histologically confirmed gastroesophageal adenocarcinoma, either locally advanced unresectable or metastatic.
Locally assessed HER2-negative status and PD-L1 TAP score ≥5%.
HER2-positive disease as determined by local standards.
Active leptomeningeal disease or uncontrolled brain metastases. Patients with treated, asymptomatic and radiologically stable brain metastases may be eligible according to protocol-defined criteria.
Active autoimmune disease or history of autoimmune disease that may relapse, except for protocol-specified conditions.
Any active malignancy within 3 years before enrollment, except for the cancer under investigation and protocol-specified malignancies treated with curative intent.