Re-challenge with immune checkpoint inhibitors as second-line treatment in advanced esophageal squamous cell...

To evaluate the feasibility and efficacy of immune checkpoint inhibitor (ICI) rechallenge as second-line therapy in advanced esophageal squamous cell carcinoma (ESCC) patients who had progressed after first-line ICI-based treatment.

This retrospective multicenter study analyzed 171 advanced ESCC patients who progressed after first-line ICI-based therapy and were subsequently re-treated with ICIs between 2021 and 2024. Rechallenge was defined as re-administration of the same or a different ICI agent. Patients were stratified by first-line treatment duration (≥180 vs. <180 days). Primary outcomes included progression-free survival during second-line treatment (PFS2) and overall survival (OS). Secondary outcomes included objective response rate (ORR), disease control rate (DCR), durable clinical benefit (DCB), and immune-related adverse events (irAEs).

Patients who had a first-line treatment duration of ≥180 days had significantly longer PFS2 (5.70 vs. 3.47 months, P<0.001) and OS (14.77 vs. 12.92 months, P = 0.008). Among second-line strategies, immunotherapy alone provided the longest PFS2, while ICI plus chemotherapy resulted in the shortest (P<0.001). PD-L1 expression ≥1% was paradoxically associated with shorter PFS2. IrAEs during second-line treatment were not associated with improved efficacy.

ICI rechallenge is a feasible and effective option for selected ESCC patients, particularly those with ≥180 days of benefit from first-line ICI therapy. Immunotherapy alone or combined with antiangiogenic agents may be preferable over combination with chemotherapy. Further prospective studies are needed to identify predictive factors and optimize rechallenge strategies.