Comedications with Immune Checkpoint Inhibitors: Involvement of the Microbiota, Impact on Efficacy and Practical Implications

Abstract

Immune checkpoint inhibitors (ICIs) have been a major breakthrough in solid oncology over the past decade. The immune system and the gut microbiota are involved in their complex mechanisms of action. However, drug interactions have been suspected of disrupting the fine equilibrium necessary for optimal ICI efficacy. Thus, clinicians are facing a great deal of sometimes contradictory information on comedications with ICIs and must at times oppose conflicting objectives between oncological response and comorbidities or complications. We compiled in this review published data on the role of the microbiota in ICI efficacy and the impact of comedications. We found mostly concordant results on detrimental action of concurrent corticosteroids, antibiotics, and proton pump inhibitors. The timeframe seems to be an important variable each time to preserve an initial immune priming at ICIs initiation. Other molecules have been associated with improved or impaired ICIs outcomes in pre-clinical models with discordant conclusions in retrospective clinical studies. We gathered the results of the main studies concerning metformin, aspirin, and non-steroidal anti-inflammatory drugs, beta blockers, renin-angiotensin-aldosterone system inhibitors, opioids, and statins. In conclusion, one should always assess the necessity of concomitant treatment according to evidence-based recommendations and discuss the possibility of postponing ICI initiation or switching strategies to preserve the critical window.

Impact of concurrent medications on clinical outcomes of cancer patients treated with immune checkpoint inhibitors: Analysis of Health Insurance Review and Assessment data

“…Evidence suggests that altered gut microbiota negatively impacts patient survival outcomes, primarily through acquired resistance mechanisms (Routy et al 2018). In particular, medications that affect the immune homeostasis and gut microbiota, such as antibiotics (ATBs), corticosteroids (CSs), proton-pump inhibitors (PPIs), and opioids, have been shown to affect the e cacy of ICIs (Colard-Thomas et al 2023;Hussain et al 2021;Sieber et al 2022).…”

“…Evidence suggests that altered gut microbiota negatively impacts patient survival outcomes, primarily through acquired resistance mechanisms (Routy et al 2018). In particular, medications that affect the immune homeostasis and gut microbiota, such as antibiotics (ATBs), corticosteroids (CSs), proton-pump inhibitors (PPIs), and opioids, have been shown to affect the e cacy of ICIs (Colard-Thomas et al 2023;Hussain et al 2021;Sieber et al 2022). However, the impact of concurrent medications on the treatment outcomes of ICI-treated patients with cancer is not demonstrated well in population-based studies, as most previous studies are small-scale retrospective analyses of patients in clinical trials or single-center studies.…”

Impact of concurrent medications on clinical outcomes of cancer patients treated with immune checkpoint inhibitors: analysis of Health Insurance Review and Assessment data

“…While ICI therapy has shown remarkable efficacy in subsets of patients, not all patients show a favorable response; thus, identifying the characteristics of patients who are likely to benefit from it (e.g., short treatment duration) is crucial. The gut microbiome has emerged as a potential factor contributing to the variability in ICI response (Colard-Thomas et al 2023 ; Gopalakrishnan et al 2018 ; Schirmer et al 2016 ). Several previous studies have explored the effects of concomitant medication use on ICI treatment outcomes and suggested complex associations between the gut microbiome and immunotherapy responses and generally accepted the negative impact of CSs, ATBs, PPIs, and opioids on ICI efficacy (Colard-Thomas et al 2023 ; Gaucher et al 2021 ; Kalfeist et al 2022 ; Weersma et al 2020 ).…”

“…The gut microbiome has emerged as a potential factor contributing to the variability in ICI response (Colard-Thomas et al 2023 ; Gopalakrishnan et al 2018 ; Schirmer et al 2016 ). Several previous studies have explored the effects of concomitant medication use on ICI treatment outcomes and suggested complex associations between the gut microbiome and immunotherapy responses and generally accepted the negative impact of CSs, ATBs, PPIs, and opioids on ICI efficacy (Colard-Thomas et al 2023 ; Gaucher et al 2021 ; Kalfeist et al 2022 ; Weersma et al 2020 ). Many studies have reported that ATBs directly disrupt the gut microbiome.…”

“…Evidence suggests that altered gut microbiota negatively impacts patient survival outcomes, primarily through acquired resistance mechanisms (Routy et al 2018 ). In particular, medications that affect the immune homeostasis and gut microbiota, such as antibiotics (ATBs), corticosteroids (CSs), proton-pump inhibitors (PPIs), and opioids, have been shown to affect the efficacy of ICIs (Colard-Thomas et al 2023 ; Hussain et al 2021 ; Sieber et al 2022 ).…”