Acquired resistance to first-line immune checkpoint inhibitors in esophageal squamous cell carcinoma: progression patterns and prognostic implications

Background: Despite the survival benefit of first-line immune checkpoint inhibitor (ICI)-based therapy in advanced esophageal squamous cell carcinoma (ESCC), acquired resistance (AR) remains a major clinical challenge, and its progression patterns and prognostic significance are poorly defined. This study aimed to characterize progression patterns and sites at AR after first-line ICI-based therapy in ESCC and to evaluate their associations with clinical outcomes. Methods: We retrospectively identified patients with metastatic or unresectable locally advanced ESCC who underwent first-line ICI-based therapy at the First Affiliated Hospital of Zhengzhou University and Anyang Cancer Hospital (September 2023-January 2026). Initial clinical benefit was defined as complete response, partial response, or stable disease lasting ≥6 months; AR was defined as subsequent disease progression or death. Progression was classified as oligoprogression (≤2 sites) or polymetastatic progression (≥3 sites). Overall survival (OS) was estimated using the Kaplan-Meier method and analyzed with Cox models. Results: Among 1,537 patients treated with ICIs, 106 patients with ESCC who developed AR were included. Oligoprogression was the most common AR pattern (85/106, 80.2%), whereas 21 (19.8%) had polymetastatic progression. Polymetastatic progression was associated with worse OS than oligoprogression (HR = 1.97, 95% CI 1.12-3.47; p = 0.016). Conclusions: Oligoprogression was the dominant pattern of AR, and lymph nodes were the most frequent progression sites. Polymetastatic progression was associated with poorer OS.