Assessment of the impact of proton pump inhibitor (PPI) exposure on survival outcomes in patients with gastric or gastroesophageal junction adenocarcinoma treated with zolbetuximab plus chemotherapy.

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349 Background: Concurrent use of PPIs has recently been associated with reduced progression-free survival (PFS) and overall survival (OS) among patients treated with immune checkpoint inhibitors (Ciappina G, et al. Cancers . 2025;17:2228). Zolbetuximab, a chimeric monoclonal antibody targeting the tight junction protein claudin 18.2, has been evaluated in combination with chemotherapy for the first-line treatment of locally advanced unresectable or metastatic (la/m) gastric or gastroesophageal junction (G/GEJ) adenocarcinoma in the phase 2 study FAST (NCT01630083) and the phase 3 studies SPOTLIGHT (NCT03504397) and GLOW (NCT03653507). Because the mechanism of action of zolbetuximab involves immune-mediated antitumor activity via antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity, we conducted the current analysis to investigate whether PPI exposure had an impact on efficacy outcomes for patients who received treatment in FAST, SPOTLIGHT, and GLOW. Methods: Patients in the FAST, SPOTLIGHT, and GLOW studies for whom PPI exposure was recorded were included in the analysis. In FAST, patients received either zolbetuximab plus chemotherapy (EOX) or EOX alone; in SPOTLIGHT and GLOW, patients received either zolbetuximab plus chemotherapy (mFOLFOX6 in SPOTLIGHT and CAPOX in GLOW) or placebo plus chemotherapy. Patients were considered to have PPI exposure if they received PPIs during study treatment. Multivariable Cox proportional hazards models were used to perform covariate analysis and interaction analysis for PFS and OS. Results: Data cutoff dates were January 31, 2019, for FAST; September 9, 2022, for SPOTLIGHT; and October 7, 2022, for GLOW. Among 1185 patients who received treatment in FAST, SPOTLIGHT, or GLOW and were included in the exposure-response dataset, 411 of 574 patients (71.6%) who received zolbetuximab plus chemotherapy (37/51 in FAST, 201/275 in SPOTLIGHT, and 173/248 in GLOW) and 403 of 611 patients (66.0%) who received chemotherapy alone or with placebo (52/84 in FAST, 187/278 in SPOTLIGHT, and 164/249 in GLOW) had recorded PPI exposure. No statistically significant effects of PPI exposure, either as a covariate or in interaction with average zolbetuximab concentration throughout treatment, on PFS and OS were observed. Conclusions: No significant impact of PPI exposure during study treatment on PFS or OS was observed in patients receiving zolbetuximab plus chemotherapy. These results suggest that the use of PPIs in conjunction with zolbetuximab plus chemotherapy does not have a negative effect on efficacy in la/m G/GEJ adenocarcinoma. Clinical trial information: NCT01630083 .

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