Tislelizumab plus chemotherapy versus placebo plus chemotherapy as first-line therapy in patients with locally advanced unresectable or metastatic gastric or gastroesophageal junction (G/GEJ) adenocarcinoma.

TPS458 Background: First-line standard of care in patients with locally advanced or metastatic G/GEJ adenocarcinoma is fluoropyrimidine- and platinum (plat)-based combination chemotherapy. Despite improved chemotherapy regimens, outcomes remain poor and survival is low. Tislelizumab, an investigational humanized IgG4 monoclonal antibody with high affinity and binding specificity for PD-1, was engineered to minimize binding of FcγR on macrophages in order to abrogate antibody-dependent phagocytosis, a mechanism of T-cell clearance and potential resistance to anti-PD-1 therapy. Previous reports from early phase studies suggested tislelizumab, as a single agent and combined with chemotherapy, was generally well tolerated and had antitumor activity in patients with advanced solid tumors, including G/GEJ cancer. Methods: This randomized, placebo-controlled phase 3 study (NCT03777657) is designed to evaluate plat/fluoropyrimidine + tislelizumab vs plat/fluoropyrimidine + placebo as first-line therapy for patients with locally advanced or metastatic G/GEJ adenocarcinoma. Adult patients (n≈720) from ~160 centers will be randomized 1:1 to receive tislelizumab (200 mg IV Q3W) or placebo in combination with chemotherapy. Oxaliplatin (130 mg/m² IV Q3W) + capecitabine (1000 mg/m 2 orally BID for 2 weeks) or cisplatin (80 mg/m² IV Q3W) + 5-fluorouracil (800 mg/m 2 /day IV on Days 1-5 Q3W) will be used as backbone chemotherapy on an individual basis. Chemotherapy will be administered for up to 6 cycles; capecitabine maintenance therapy is optional for patients who received capecitabine and oxaliplatin. Progression-free and overall survival are primary endpoints of the study. Secondary endpoints will include overall response rate, quality-of-life outcomes, and the safety/tolerability profile of combination therapy. Exploratory endpoints include disease control rate, time to response, and an analysis of potential predictive biomarkers including PD-L1 expression; the VENTANA PD-L1 (SP263) assay will be used for PD-L1 expression analysis. This study is actively enrolling. Clinical trial information: NCT03777657.