Timing and intensity of proton pump inhibitor exposure hampers overall survival in patients with metastatic non-small cell lung cancer treated with immune checkpoint inhibitors : a retrospective cohort study

Japelj, Nuša (author), Horvat, Nejc (author), Jazbar, Janja (author), Kos, Mitja (author), Pelicon, Veronika (author), Knez, Lea (author)

Introduction: Proton pump inhibitor (PPI) use has been associated with reduced immune checkpoint inhibitor (ICI) efficacy in metastatic non-small cell lung cancer (mNSCLC) with evidence limited to their use during a short time period around ICI initiation. This study evaluated the associations between the timing and intensity of PPI exposure up to one year before ICI initiation and overall survival (OS) in mNSCLC patients treated with ICIs. Methods: This retrospective cohort study included consecutive mNSCLC patients treated with ICIs within routine clinical practice. Patients were grouped by the timing of PPI exposure from 365 days before to 30 days after (−365 to +30 days) ICI initiation: (1) no PPIs within −365 to +30 days; (2) PPIs only within −365 to −31 days; and (3) PPIs also within ±30 days of ICI initiation. The intensity of PPI exposure was quantified with the total defined daily doses (DDDs). OS was estimated using Kaplan–Meier methods, and associations between PPI exposure and OS were analyzed using Cox proportional hazards models. Results: Of 391 patients included (median age 64.7 years, 58.6% male), 73.4% had access to PPI within −365 to +30 days of ICI initiation. PPI exposure within ±30 days (220 patients) was associated with reduced median OS (mOS) compared with no PPI exposure between −365 and +30 days of ICI initiation (mOS 15.4 vs 21.9 months; adjusted hazard ratio [aHR] 1.373, 95% CI 1.007–1.873, p = 0.045). High-intensity PPI exposure within −365 to +30 days of ICI initiation (DDD > 159; 108 patients) was also associated with reduced mOS compared with no PPI exposure in this period (mOS 13.4 vs 21.9 months; aHR 1.454, 95% CI 1.023–2.067, p = 0.037). Discussion: PPI use around ICI initiation as well as PPI treatment intensity over a wider period was associated with reduced OS. Efforts should be made to streamline PPI use.

• Language: English
• Keywords: carcinoma, non-small-cell lung, immune checkpoint inhibitors, proton pump inhibitors, survival analysis, gastrointestinal microbiome
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: FFA - Faculty of Pharmacy
• Publication status: Published
• Publication version: Version of Record
• Year: 2026
• Number of pages: Str. 1-13
• Numbering: Vol. 17, art, 1682723
• PID: 20.500.12556/RUL-179608
• UDC: 616.24-006
• ISSN on article: 1664-3224
• DOI: 10.3389/fimmu.2026.1682723
• COBISS.SI-ID: 266366979
• Publication date in RUL: 18.02.2026

Record is a part of a journal

• Title: Frontiers in immunology
• Shortened title: Front. immunol.
• Publisher: Frontiers Media
• ISSN: 1664-3224
• COBISS.SI-ID: 30774233

Licences

• License: CC BY 4.0, Creative Commons Attribution 4.0 International
• Link: http://creativecommons.org/licenses/by/4.0/
• Description: This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.

Secondary language

• Language: Slovenian
• Keywords: karcinom, nedrobnocelična pljuča, zaviralci imunskih kontrolnih točk, zaviralci protonske črpalke, analiza preživetja, gastrointestinalni mikrobiom, rak (medicina), nedrobnocelični pljučni rak

Projects

• Funder: ARIS - Slovenian Research and Innovation Agency
• Project number: P1-0189
• Name: Farmacevtska tehnologija: od dostavnih sistemov učinkovin do terapijskih izidov zdravil pri otrocih in starostnikih

• Funder: ARIS - Slovenian Research and Innovation Agency
• Project number: P3-0360
• Name: Celostna obravnava alergijskih bolezni in astme v Sloveniji: od epidemiologije do genetike