First-line systemic therapy for advanced or metastatic esophageal squamous cell carcinoma: clinical implications for treatment selection after KEYNOTE-590, CheckMate 648, and RATIONALE-306.

First-line systemic therapy for unresectable advanced or metastatic esophageal squamous cell carcinoma (ESCC) has been reshaped by PD-1 blockade, but treatment selection remains complex because the pivotal trials differ in chemotherapy backbone and PD-L1 scoring methodology. KEYNOTE-590 enrolled both ESCC and adenocarcinoma and established pembrolizumab plus chemotherapy as a durable chemoimmunotherapy standard across histologic subtypes. CheckMate 648, focused on ESCC, showed that nivolumab plus chemotherapy and nivolumab plus ipilimumab both improve overall survival (OS), although the patterns of benefit are distinct: progression-free survival (PFS) benefit was observed with nivolumab plus chemotherapy but not with nivolumab plus ipilimumab. RATIONALE-306 subsequently added tislelizumab plus chemotherapy as another evidence-based first-line option in ESCC. Accordingly, clinically relevant treatment selection is better framed by the need for rapid disease control, tolerance for chemotherapy, toxicity profile, histology, and biomarker context than by a simple comparison of individual antibodies. Interpretation of PD-L1 also requires caution because KEYNOTE-590 used combined positive score (CPS), CheckMate 648 used tumor-cell PD-L1 expression, and RATIONALE-306 used Tumor Area Positivity (TAP). This review summarizes the evidence supporting current first-line treatment selection and its implications for daily clinical practice. Key issues addressed include practical distinctions between chemoimmunotherapy and dual immune checkpoint blockade, harmonization of PD-L1 assessment, platinum-backbone selection, and the optimization of treatment sequencing after first-line immunotherapy.