Line of therapy and proton pump inhibitor use as prognostic factors in advanced soft tissue sarcoma treated with immunotherapy.

Abstract

e23573 Background: With the expanding use of immune checkpoint inhibitors (ICI) in selected soft tissue sarcoma (STS) subtypes, clinical factors associated with outcomes at ICI initiation remain poorly defined. Proton pump inhibitor (PPI) exposure has been associated with inferior ICI outcomes in other malignancies, while line of therapy may reflect both disease biology and prior treatment resistance. We evaluated the association of PPI use and line of systemic therapy at ICI initiation with overall survival (OS) and progression-free survival (PFS) in patients with advanced STS treated in routine clinical practice. Methods: Patients with advanced STS treated with ICI at The Ohio State University from 2015–2023 were identified from a retrospective sarcoma immunotherapy database. Advanced disease was defined as stage IV disease or receipt of ≥3rd-line systemic therapy. Variables of interest included PPI use at ICI initiation (yes/no) and line of systemic therapy at ICI initiation (1st, 2nd, ≥3rd). OS and PFS were estimated using Kaplan–Meier methods and compared by log-rank tests. Cox proportional hazards models adjusted for age and ECOG performance status were used to evaluate associations between line of therapy and survival outcomes, reported as hazard ratios (HR) with 95% confidence intervals. Results: A total of 192 patients were included; 49 (26%) were receiving PPI therapy at ICI initiation. No significant differences in OS (P = 0.42) or PFS (P = 0.83) were observed based on PPI use. Most patients received ICI in the ≥3rd line (n = 99; 1st line n = 40, 2nd line n = 52). Compared with first-line ICI, OS was significantly worse for ≥3rd-line ICI (HR 2.0, P = 0.001), but not for second-line ICI (HR 1.03, P = 0.92). PFS was also significantly worse for ≥3rd-line ICI (HR 3.36, P = 0.0002), with no difference between first- and second-line treatment (P = 0.80). Conclusions: In patients with advanced STS treated with ICI, later line of therapy at treatment initiation was associated with significantly worse OS and PFS, while concurrent PPI use was not associated with adverse outcomes. Line of therapy may serve as a pragmatic prognostic marker in STS immunotherapy studies and should be considered in stratification and interpretation of future trials. Prospective studies are needed to identify biologic correlates of resistance beyond clinical surrogates.