Introduction
Proton pump inhibitors (PPIs) are widely used and can significantly alter gastric acidity and gut microbiome composition. Growing evidence indicates that gut microbiome plays a key role in modulating response to cancer immunotherapy (IT), and that microbiome dysbiosis—potentially induced by concomitant medications such as PPIs—may impair treatment efficacy. In an exploratory analysis of an investigator-initiated clinical trial in patients with advanced hepatocellular carcinoma (HCC) treated in the second-line setting, we observed that PPI use was associated with decreased overall survival (OS). However, data in HCC, particularly in the first-line (1L) setting, remain limited.
Aims & Methods
We aimed to study the association between PPI use and 1) gut microbiome composition and 2) outcomes of patients with HCC treated with IT in the first-line (1L) setting. The study included patients from three different cohorts: 1) a prospective and multicenter Spanish cohort of patients treated with IT in 1L (RETO); 2) IMbrave 150 and 3) GO30140 trial (atezolizumab and bevacizumab). Data of cohort 2 and 3 were obtained from the Vivili platform. PPI exposure in the previous 2 months was prospectively registered in the RETO cohort (never, occasionally or always); in cohort 2 and 3 it was retrieved and defined as having at least one PPI prescription lasting ≥30 days within the 30-day window surrounding the inclusion date. In the RETO cohort, longitudinal stool samples were collected at baseline, month 1 and month 3 of treatment with IT. Microbiome analysis was performed by shotgun metagenomics sequencing. Machine-learning approaches and SHAP values were used to determine the relative contribution of microbiome features. OS was the primary endpoint. Cox regression models with inverse probability of treatment weighting (IPTW) were used in cohort 2 and 3 to assess associations between clinical variables, PPI exposure and OS.
Results
In total, 453 patients were included: 391 treated with IT in 1L (143 from IMbrave150; 131 from GO30140; 67 with atezolizumab-bevacizumab and 50 with tremelimumab-durvalumab from the RETO cohort). PPI use was associated with changes in the composition of microbiome in the RETO cohort. Increased alpha diversity was observed at species level (p-value for Chao1 and Shannon indexes were 0.07 and 0.091, respectively). Differential abundance across multiple bacterial families and species was also identified, including specific species of the oral microbiota (ie higher abundance of Streptocuoccus salivaris, Streptococcus parasanguinis, Coprobacter fastidiosus and Bifidobacterium dentium).
PPI use (n=56/274) was associated to a non-statistically significant worse OS in PPIs-exposed (HR: 1.19, 95% CI 0.75 to 1.87) in patients from cohorts 2 and 3 after IPTW.
Conclusion
PPI use is associated with increased alpha diversity and “oralization” of the gut microbiome composition in patients with HCC treated with IT. However, PPI use is not associated with a significantly reduced efficacy of IT in patients with HCC treated in 1L setting.
Disclosure
Conflict of Interest: MSZ: received consultancy/advisory fee from Captor Therapeutics, speaker fees from Bayer, AstraZeneca and Roche and travel grants from Bayer, BTG, Eisai and Roche; AM: None; MV: Advisory boards, conferences and congress and travel registration Roche and AstraZeneca; NLl: received consultancy fees from Bayer, Universal DX and AstraZeneca, travel funding from Bayer and congress registration from Eisai; GI: received travel grants from Bayer and received speaker fees from ROCHE; MF: received speaking fees from AstraZeneca; FT: DSMB fees from Argenx BV, Archivel and Connecta, and consultancy fees from Archivel, UniversalDX (diagnostics), LEO Pharma, Ferrer and Boehringer Ingelheim, all outside the submitted work; JRG: Educational and scientific outreach lectures from Novartis, Chiesi, Novo Nordisk, Sanofi Adventis, Boehringer Ingelheim, Lilly, Vifor-Fresenius and Grünenthal and DSMB fees from CZ Vaccines, all outside the submitted work; JB: Consultancy: AbbVie, Adaptimmune, Arqule, Astra-Medimmune, Basilea, Bayer-Shering Pharma, Bio-Alliance, BMS, BTG- Biocompatibles, Eisai, Gilead, IKF, Incyte, Ipsen, Kowa, Lilly, MSD, Nerviano, Novartis, Polaris, Quirem, Roche, Sirtex, Sanofi, Terumo. Paid conferences: Bayer, BTG, Ipsen, Astra-Zeneca, Roche. CCP: received consultancy and speaker fees from Roche. MR: received consultancy/advisory fees from Bayer, BMS, Roche, Ipsen, AstraZeneca, Boston Scientific, Abbive, Lilly, GENEOS, Merck, Guerbet, Engitix Therapeutics and UniversalDx, Parabilis Medicines; lecture fees from Bayer, BMS, Gilead, AstraZeneca Roche, Guerbet and Lilly; research grants (to the Institution) from Bayer, and Ipsen Educational Suport (to the institution): Bayer, AstraZenca, Eisai-Merck MSD, Boston Scientific, Ciscar Medical, Eventy C3 LLC and travel support from AstraZeneca, Rocher, Bayer, BMS, Eli Lilly and IPSEN.