Background: PD-1 inhibitor pembrolizumab in combination with the RTK inhibitor lenvatinib has demonstrated antitumor activity and acceptable safety in advanced gastroesophageal adenocarcinoma. Pembrolizumab + lenvatinib + platinum-doublet chemotherapy also showed acceptable safety in metastatic NSCLC in the phase 3 LEAP-006 study. LEAP-015 (NCT04662710) is a randomized, 2-part, phase 3 trial evaluating the efficacy and safety of pembrolizumab + lenvatinib + chemotherapy as first-line therapy in advanced/metastatic gastroesophageal adenocarcinoma. Methods: Key eligibility includes untreated locally advanced unresectable or metastatic gastroesophageal adenocarcinoma that is not HER2–positive, measurable disease per RECIST v1.1, ECOG performance status ≤1, and a tumor tissue sample for biomarker analysis. For part 1, safety run-in, ≥12 patients will be treated for induction with IV pembrolizumab 400 mg Q6W (×2) + oral lenvatinib 8 mg QD + investigator’s choice of chemotherapy (CAPOX Q3W ×4 [oral capecitabine 1000 mg/m² BID for 14 days + IV oxaliplatin 130 mg/m²] or mFOLFOX6 Q2W ×6 [bolus IV 5-FU 400 mg/m² + continuous IV 5-FU 2400 mg/m² + IV leucovorin 400 mg/m² or levoleucovorin 200 mg/m² + IV oxaliplatin 85 mg/m² ]) and for consolidation with pembrolizumab 400 mg Q6W for ≤16 doses + lenvatinib 20 mg QD; dose-limiting toxicities will be evaluated for 21 days. For part 2, main study, patients will be randomly assigned 1:1 to induction with pembrolizumab + lenvatinib + chemotherapy (CAPOX or mFOLFOX6) followed by consolidation with pembrolizumab + lenvatinib using the same dosing schedule as in part 1 or chemotherapy alone (CAPOX or mFOLFOX6 for maximum cycles allowed per local standards). Randomization will be stratified by region (East Asia vs North America and Western Europe vs rest of world), ECOG performance status (0 vs 1), and intended chemotherapy (CAPOX vs mFOLFOX6). Treatment will continue until confirmed disease progression, unacceptable toxicity, intercurrent illness that prevents further administration of treatment, patient/physician decision to withdraw, noncompliance, receipt of 18 administrations of study medication, achievement of complete response, or administrative reasons requiring cessation of treatment. Tumor imaging assessment will be performed Q6W. In part 1, the primary end point is safety and tolerability in all patients. In part 2, dual primary end points are OS and PFS (per RECIST v1.1 assessed by BICR) in patients with PD-L1 combined positive score (CPS) ≥1 and in all patients; secondary end points include objective response rate and duration of response (per RECIST v1.1 assessed by BICR) in patients with PD-L1 CPS ≥1 and in all patients, and safety and tolerability in all patients. Recruitment is ongoing. Clinical trial information: NCT04662710.