Association of immune-related adverse events with early tumor shrinkage, depth of response, and survival outcomes in advanced gastric cancer treated with immune checkpoint inhibitors

Abstract

Immune-related adverse events (irAEs) have been associated with favorable outcomes in patients receiving immune checkpoint inhibitors (ICIs). However, evidence in gastric cancer remains limited, and the relationship between irAEs and quantitative measures of tumor response dynamics, including early tumor shrinkage (ETS) and depth of response (DpR), has not been elucidated. We investigated the association of irAEs with survival outcomes and tumor response dynamics in patients with advanced or recurrent gastric cancer treated with ICI-containing therapy. We retrospectively analyzed 49 consecutive patients with advanced or recurrent gastric cancer who received nivolumab- or pembrolizumab-containing therapy at a single institution. To minimize immortal time bias, predefined landmark analyses were performed at 8 and 12 weeks after treatment initiation, with the 12-week landmark analysis designated as the primary analysis. Overall survival (OS), progression-free survival (PFS), ETS, and DpR were evaluated according to irAE occurrence. Multivariable Cox proportional hazards models were used to identify independent prognostic factors. irAEs occurred in 21 patients (42.9%), including six patients with grade ≥ 3 events. In the 12-week landmark analysis, patients with irAEs demonstrated significantly improved OS (hazard ratio [HR], 0.37; 95% confidence interval [CI], 0.14–0.95; P  = 0.039) and PFS compared with those without irAEs. irAE occurrence remained an independent favorable prognostic factor for OS ( P  = 0.022) and PFS ( P  = 0.004) in multivariable analyses. Among patients with measurable lesions, exploratory analyses showed that ETS ≤ − 20% was associated with longer OS (HR, 0.19; 95% CI, 0.04–0.96; P  = 0.046) and PFS (HR, 0.37; 95% CI, 0.15–0.93; P  = 0.035). Furthermore, patients who developed irAEs showed greater early tumor shrinkage than those without (median − 27.6% versus − 10.7%; P  = 0.013), with a corresponding difference in depth of response. In patients with advanced or recurrent gastric cancer receiving ICI-containing therapy, irAE occurrence was independently associated with favorable survival outcomes. Exploratory analyses also demonstrated associations between irAE occurrence and greater ETS and DpR. These findings suggest that irAEs may be clinically observable indicators of enhanced antitumor immune activity during ICI-containing therapy.