Early tumor shrinkage during first-line immune checkpoint inhibitor–based chemotherapy is associated with progression-free survival in measurable unresectable gastric cancer

Abstract Background Early tumor shrinkage (ETS) has been proposed as an early indicator of treatment efficacy in advanced gastric cancer. However, its prognostic relevance during first-line immune checkpoint inhibitor (ICI)-based chemotherapy remains insufficiently characterized. Methods This retrospective single-center study included 162 patients with previously untreated unresectable advanced gastric or gastroesophageal junction adenocarcinoma who received first-line ICI-based chemotherapy between November 2021 and July 2025. ETS was defined as a ≥ 20% reduction in the sum of target lesion diameters at the first radiological assessment and was evaluated in patients with measurable disease according to RECIST version 1.1. To account for the post-baseline assessment of ETS, survival analyses were performed using a fixed Day-90 landmark. The association between ETS and progression-free survival (PFS) was evaluated using multivariable Cox proportional hazards analysis. Results Ninety patients had measurable disease and constituted the ETS cohort. Best overall response was complete response in 11 patients (12.2%), partial response in 75 (83.3%), stable disease in 2 (2.2%), and progressive disease in 2 (2.2%), yielding an objective response rate of 95.6%. ETS was observed in 70 patients (77.8%). At the Day-90 landmark, ETS-positive patients had longer overall survival (HR 0.369, 95% CI 0.181–0.752; p = 0.006) and PFS (HR 0.395, 95% CI 0.206–0.755; p = 0.005) than ETS-negative patients. In the primary multivariable PFS model ( n = 84; 51 events), ETS remained associated with favorable PFS (HR 0.382, 95% CI 0.197–0.740; p = 0.004). A continuous analysis of tumor shrinkage showed a consistent association with PFS (HR 0.876 per 10-percentage-point greater reduction, 95% CI 0.777–0.987; p = 0.030). Conclusions ETS was associated with favorable subsequent PFS in patients with measurable unresectable advanced gastric or gastroesophageal junction adenocarcinoma treated with first-line ICI-based chemotherapy. ETS may represent a potential on-treatment prognostic marker of early treatment sensitivity in this setting. External validation is required before its clinical utility can be established.