Background: Recent data from the KEYNOTE-590 study demonstrated the superiority of pembrolizumab plus chemotherapy compared with chemotherapy as first-line treatment for unresectable locally advanced recurrent or metastatic adenocarcinoma or squamous cell carcinoma of the esophagus, or advanced/metastatic Siewert type 1 adenocarcinoma of the gastroesophageal junction. Prior data also suggest promising antitumor activity of lenvatinib plus pembrolizumab in advanced solid tumors. LEAP-014 (NCT04949256) is a randomized, 2-part, open-label, phase 3 study that will evaluate the efficacy and safety of first-line lenvatinib plus pembrolizumab plus chemotherapy versus pembrolizumab plus chemotherapy in patients with metastatic esophageal squamous cell carcinoma (ESCC). Methods: Key eligibility criteria include histologically or cytologically confirmed metastatic ESCC, measurable disease per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1), and Eastern Cooperative Oncology Group performance status 0 to 1. In part 1 (safety run-in), ̃6 patients will be treated for induction with intravenous (IV) pembrolizumab 400 mg every 6 weeks (Q6W) for 2 cycles plus oral lenvatinib 8 mg daily (QD) plus IV 5-fluorouracil (FU; 4000 mg/m² on days 1-5) plus IV cisplatin (80 mg/m²) (FP) for 4 cycles and treated for consolidation with pembrolizumab 400 mg Q6W for ≤16 doses plus lenvatinib 20 mg QD; patients will be closely monitored for 21 days after the first dose of study intervention for dose-limiting toxicities. In part 2 (main study), approximately 850 patients will be randomly assigned 1:1 to induction with pembrolizumab plus lenvatinib plus chemotherapy (FP or mFOLFOX6 [Q2W for 6 cycles {IV oxaliplatin 85 mg/m² plus bolus IV 5-FU 400 mg/m² plus continuous IV 5-FU 2400 mg/m² plus IV leucovorin 400 mg/m² or IV levoleucovorin 200 mg/m²}]) followed by consolidation with pembrolizumab plus lenvatinib (arm 1) or pembrolizumab plus chemotherapy (FP or mFOLFOX6; arm 2). Randomization will be stratified by PD-L1 combined positive score (CPS; ≥10 vs < 10), region (East Asia vs North America and Western Europe vs rest of world), and chemotherapy backbone (FP vs mFOLFOX6). Treatment will continue until disease progression, unacceptable toxicity, or withdrawal of consent. Tumor imaging assessment will be performed Q6W for ≤1 year and Q9W thereafter. In part 1, the primary end point is safety and tolerability. In part 2, the dual primary end points are overall survival and progression-free survival (per RECIST v1.1 assessed by blinded independent central review [BICR]); secondary end points include objective response rate and duration of response (per RECIST v1.1 assessed by BICR) and safety and tolerability. Enrollment in this trial is ongoing. Clinical trial information: NCT04949256.