Impact of Antibiotics and Proton Pump Inhibitors on Efficacy and Tolerance of Anti-PD-1 Immune Checkpoint Inhibitors

Abstract

BackgroundThe use of antibiotics (ATB) and proton-pump inhibitors (PPI) alters the composition and diversity of the gut microbiota, which can influence the immune system, consequently interfering with response to anti-PD1 immune checkpoint inhibitors (ICI). We assessed the impact of ATB and/or PPI use on the efficacy and safety of ICI.MethodsTwo hundred twelve patients treated with anti-PD1 ICI for non-small cell lung carcinoma, melanoma, upper airway & digestive tract carcinoma or renal cell carcinoma were retrospectively included. Patients having received ATB within 60 days before ICI initiation were included in the ATB+ group. Patients having received PPI within 30 days before ICI initiation were included in the PPI+ group. Four groups were thus considered: ATB-/PPI-, ATB+/PPI-, ATB-/PPI+, ATB+/PPI+. Response rate was assessed by RECIST v1.1. Overall survival (OS), progression-free survival (PFS) and adverse events, recorded using Common Terminology Criteria for Adverse Events Version 5, were compared using inverse probability of treatment weighting to account for selection bias.ResultsPFS at 6 months was 56.7 %, 95%CI (49.6%; 63.2%) and 47.2 %, 95%CI (39.8%;54.1%) at 12 months. OS was 81.6%, 95%CI (75.6%; 86.2%) at 6 months, and 69.4%, 95%CI (61.9%;75.7%) at 12 months. Compared to ATB-/PPI- group, PFS was lower for the ATB+/PPI- group [Hazard ratio (HR) 1.90, 95%CI (1.41;2.57)] and the ATB-/PPI+ group [HR 1.51, 95%CI (1.11;2.05)], and lowest in the ATB+/PPI+ group [HR 3.65, 95%CI (2.75;4.84)]. For OS, the use of ATB alone or PPI alone or in combination was a risk factor for death, with each increasing HR values by a similar magnitude, and the combination of ATB and PPI did not increase risk further. AEs were observed in 78 cases (36.8%) with no significant impact of ATB or PPI use.ConclusionsThis study reveals that ATB and/or PPI use can alter response to anti-PD1 ICI, and the prognosis of cancer patients. The microbiota mechanisms involved in the response to ICI should be investigated to optimize patient management.

Association of proton pump inhibitor use with survival outcomes in cancer patients treated with immune checkpoint inhibitors: a systematic review and meta-analysis

“…Finally, 33 studies, of which 24 were peer-reviewed journal publications and 9 were conference abstracts, were included in the systematic review and meta-analysis. 12 , 13 , 19 – 49 The flow diagram of identifying the eligible studies is shown in Figure 1 .…”

Polydextrose Alleviates Adipose Tissue Inflammation and Modulates the Gut Microbiota in High-Fat Diet-Fed Mice

“…FMT from the obesity-associated human gut microbiota to mice can induce vascular dysfunction and glucose intolerance, and FMT from lean donors to patients with obesity can promote metabolic benefits (Mocanu et al, 2021;Russo et al, 2021). Recent studies over the past decade have revealed that many environmental factors, including diet, antibiotic exposure, energy intake and exercise, can dramatically influence the gut microbiota (Du et al, 2021;Giordan et al, 2021;Shi et al, 2021). Dietary fiber has been shown to improve obesity and is considered a potential therapy because it increases microbial fermentation of SCFAs (Schäfer et al, 2021;Thomson et al, 2021).…”

Impact of Proton Pump Inhibitors and Histamine-2-Receptor Antagonists on Non-Small Cell Lung Cancer Immunotherapy: A Systematic Review and Meta-Analysis

“…Antacid agents such as proton pump inhibitors (PPIs) and histamine-2-receptor antagonists (H2RAs) are commonly prescribed for extended periods in NSCLC patients, and these drugs have been suggested to modify the activity of anticancer therapies through several mechanisms, including gut microbiome changes [20]. However, available literature reports controversial results, with some studies highlighting a trend towards lower ICI activity and worse clinical outcomes in patients receiving antacids and immunotherapy, and other trials reporting no effect or even longer survival in subjects treated with concomitant PPIs or H2RAs [21,22]. Based on these premises, we performed a systematic review and meta-analysis to investigate the impact of antacids on NSCLC patients treated with ICIs.…”