2033MO - The impact of proton pump inhibitor (PPI) exposure before immune checkpoint inhibitor (ICI) therapy on overall survival (OS): A population-based study

Background

PPIs have been previously associated with potentially negative impacts on ICIs outcomes due to changes in the gut microbiome. However, many studies were smaller studies with heterogeneity in study design, exposure windows and populations. Here, we performed a population-level retrospective cohort study evaluating the impact of PPI exposure prior to ICI on OS.

Methods

A cohort of cancer patients ≥ 65 years of age receiving ICIs from 06/2012 to 10/2018 in Ontario, Canada was identified from population-level administrative data and deterministically linked with databases to obtain socio-demographics, co-variates and PPI prescription claims. Multivariable cox-proportional hazard models evaluated the impact of PPI exposure both within 1 year and 60 days prior to starting ICI on OS, adjusted for age, gender, body mass index, comorbidities, autoimmune history, hospitalization in the past year and treatment facility level at start of ICI therapy.

Results

Among 2737 patients, median age 73; 43% received Nivolumab, 41% Pembrolizumab and 13% Ipilimumab; 53% had lung cancer, 34% melanoma. Median PPI exposure for patients receiving PPI within 1 year (45%) and 60 days (26%) prior to ICI were 31 weeks (SD=19) and 10 weeks (SD=4) respectively; the most common PPI prescribed over 1 year was Pantoprazole (30%). Median OS estimate was 306 days. Any PPI exposure within 1 year (aHR=1.21 95% CI [1.09-1.33] p<0.001) or 60 days prior to ICI (aHR=1.26 95% CI [1.13-1.40] p<0.001) was associated with worse OS. A dose effect was seen based on weeks of PPI exposure 1 year (aHR=1.00 per week [1.00-1.01],p=0.05) and 60 days (aHR=1.01 per week [1.00-1.02] p=0.009) prior to ICI. PPI drug analysis only identified Pantoprazole exposure within 1 year (aHR=1.27 [1.14-1.41] p<0.001) and 60 days before ICI (aHR=1.34 [1.19-1.52] p<0.001) as being associated with worse OS. Subgroup analysis showed similar results for melanoma and patients receiving Pembrolizumab or Ipilimumab, and for Pantoprazole with lung cancer.

Conclusions

Exposure to PPIs prior to ICI therapy is associated with worse OS. Interventions aimed at altering the gut microbiome may be required to help improve outcomes for patients on ICIs with prior PPI exposure.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

ASCO/Conquer Cancer Foundation, Canadian Association of Medical Oncologists.

Disclosure

G. Liu: Financial Interests, Personal, Advisory Board: AstraZeneca, Takeda, Novartis, Lilly, Pfizer, Merck, EMD Serono, Jazz, Bristol Myers Squibb; Financial Interests, Institutional, Advisory Board: Boehringer Ingelheim, Takeda, AstraZeneca, EMD Serono. P.L. Bedard: Financial Interests, Institutional, Local PI: AstraZeneca, Bicara, BMS, Amgen, Novartis, Genentech/Roche, Sanofi, Merck, Pfizer, Zymeworks, Nektar Therapeutics, Lilly, SeaGen, Medicenna; Financial Interests, Institutional, Research Grant: Pfizer; Financial Interests, Institutional, Funding: Servier; Non-Financial Interests, Member of Board of Directors, Executive Board Member: Breast International Group; Non-Financial Interests, Leadership Role, Chair: AACR Project GENIE; Non-Financial Interests, Leadership Role, Past Chair IND CommitteeMember, Breast Site Steering Committee: Canadian Clinical Trials Group; Non-Financial Interests, Advisory Role: SeaGen, Lilly, Amgen, Merck, BMS, Pfizer, Gilead. All other authors have declared no conflicts of interest.