Comparative effectiveness of first-line pembrolizumab plus chemotherapy, nivolumab plus chemotherapy, and nivolumab plus ipilimumab in metastatic esophageal squamous cell carcinoma: A propensity score-matched real-world analysis.

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Background: Pembrolizumab plus chemotherapy (KEYNOTE-590), nivolumab plus chemotherapy, and nivolumab plus ipilimumab (CheckMate 648) are approved first-line regimens for advanced esophageal squamous cell carcinoma (ESCC). No head-to-head trial or real-world study has directly compared them. We performed pairwise propensity score-matched (PSM) comparisons using a global federated electronic health record network. Methods: Adults with metastatic ESCC (ICD-10 C15 + C78/C79) receiving pembrolizumab+chemotherapy (A), nivolumab+chemotherapy (B), or nivolumab+ipilimumab (C) were identified from the TriNetX Global Collaborative Network (171 organizations). 1:1 nearest-neighbor PSM balanced demographics, Charlson comorbidities, and baseline labs. Outcomes included overall survival (OS) and safety events. Hazard ratios (HR) with 95% CI were estimated via Kaplan-Meier with log-rank testing. Results: Pre-match cohorts comprised 813 (A), 1424 (B), and 253 (C) patients. After PSM, balanced pairs were obtained for all comparisons (Table). OS was comparable between A and B (median 381 vs 360 days; HR 1.11; p=0.162). C showed significantly better OS than B (median 443 vs 303 days; HR 1.38; p=0.029) and trended toward better OS than A (median 411 vs 292 days; HR 0.76; p=0.069). Neutropenia was significantly higher with both chemo-containing regimens versus C (p≤0.011). No differences in colitis, hypothyroidism, or nausea/vomiting were observed. Conclusions: In this real-world PSM analysis, pembrolizumab+chemotherapy and nivolumab+chemotherapy showed comparable OS in first-line metastatic ESCC. Nivolumab+ipilimumab was associated with longer OS versus nivolumab+chemotherapy and markedly lower neutropenia versus both chemo-containing regimens, supporting the chemo-free regimen as a viable option particularly for patients at risk for hematologic toxicity.