Associations between dysbiosis-inducing drugs, overall survival and tumor response in patients treated with immune checkpoint inhibitors

Gaucher, L; Adda, Leslie; Séjourné, Alice; Joachim, Camille; Chaby, G.; Poulet, Claire; Liabeuf, Sophie; Gras‐Champel, Valérie; Masmoudi, Kamel; Houessinon, Aline; Bennis, Youssef; Batteux, Benjamin

doi:10.1177/17588359211000591

Cited by 34 publications

(33 citation statements)

References 63 publications

(146 reference statements)

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“…reported a significant improvement in clinical response in patients taking metformin plus ICI therapy (ORR = 47.1% with vs . 24.5% without, p = 0.02) but this benefit did not equate to longer OS or PFS ( 40 ). Three studies reported a trend towards improved ICI efficacy with metformin but was not statistically significant ( 8 , 20 , 24 ).…”

Section: Resultsmentioning

confidence: 99%

Concomitant Medication Effects on Immune Checkpoint Inhibitor Efficacy and Toxicity

Sieber

Strauss

et al. 2022

Front. Oncol.

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There are multiple approved indications for immune checkpoint inhibitors (ICI) in patients with advanced solid tumors. Polypharmacy, defined as the use of ≥ 5 medications, is common among cancer patients. The impact of these non-oncologic medications on ICI efficacy or the development of side effects, specifically immune related adverse events (irAEs), is unclear. Recent clinical studies investigating the connection between concomitant medications and ICI efficacy have produced conflicting results. A systematic literature search was performed on PubMed to identify published clinical studies evaluating the impact of metformin, angiotensin-converting-enzyme inhibitor (ACEi), angiotensin receptor blockers (ARBs) and aspirin on ICI outcomes and toxicity in patients with advanced solid tumors. Clinical outcomes assessed included overall response rate, progression free survival, overall patient survival and the development of adverse events, specifically irAEs. A total of 10 retrospective studies were identified. Most studies reported a small percentage (range 8% to 42%) of their study population taking the concomitant medications of interest. Collectively, the studies did not identify a significant impact on ICI efficacy with concomitant medication use. In addition, the impact on irAEs was rarely reported in these studies but no significant group effect on reported toxicities or irAEs was found. This review provides a comprehensive analysis of current clinical studies and illustrates potential alterations in the tumor microenvironment induced by the medications. Given the high occurrence of polypharmacy among patients with advanced cancer, gaining a better understanding of the impact of non-oncologic medications on immunotherapy is necessary to improve ICI efficacy and reduce toxicity.

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Section: Resultsmentioning

confidence: 99%

Concomitant Medication Effects on Immune Checkpoint Inhibitor Efficacy and Toxicity

Sieber

Strauss

et al. 2022

Front. Oncol.

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“…However, these meta-analyses included only five and seven studies. Since then, many studies have continued to explore this DDI, and Table 5 summarizes the latest ones ( Mukherjee et al, 2018 ; Zhao et al, 2019 ; Chalabi et al, 2020 ; Cortellini et al, 2020 ; Hopkins et al, 2020 ; Iglesias-Santamaría, 2020 ; Buti et al, 2021 ; Cortellini et al, 2021 ; Gaucher et al, 2021 ; Jun et al, 2021 ; Rounis et al, 2021 ; Ruiz-Bañobre et al, 2021 ). Robust recommendations for PPI use cannot be inferred given the retrospective nature of the currently available evidence, but caution should be exercised with ICIs ( Rossi et al, 2019 ; Hussain et al, 2021 ).…”

Section: Resultsmentioning

confidence: 99%

Proton Pump Inhibitors and Cancer: Current State of Play

2022

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Background: Proton pump inhibitors (PPIs) are one of the most widely used drugs worldwide and are overprescribed in patients with cancer; there is increasing evidence of their effects on cancer development and survival. The objective of this narrative review is to comprehensively identify cancer medications that have clinically meaningful drug–drug interactions (DDIs) with PPIs, including loss of efficacy or adverse effects, and to explore the association between PPIs and cancer.Methods: A PubMed search of English language studies published from 1 January 2016, to 1 June 2021 was conducted. The search terms included “proton pump inhibitors,” “cancer,” “chemotherapy,” “immunotherapy,” “hormonotherapies,” “targeted therapies,” “tyrosine kinase inhibitors,” and “gut microbiome”. Recent and relevant clinical trials, meta-analyses, and reviews were included.Results: PPIs may have pro-tumor activity by increasing plasma gastrin levels or anti-tumor activity by inhibiting V-ATPases. However, their impact on cancer survival remains unclear. PPIs may decrease the efficacy of some antineoplastic agents through direct DDIs (e.g., some tyrosine kinase inhibitors, capecitabine, irinotecan, methotrexate). More complex DDIs seem to exist for immunotherapies with indirect interactions through the microbiome. PPIs worsen hypomagnesemia, bone loss, iron, and vitamin B12 deficiencies but may have a protective effect on the renal system.Discussion/Conclusions: PPIs may interact with the cancer microbiome and the efficacy of various antineoplastic agents, although only a few DDIs involving PPIs are clinically significant. Further pharmaco-epidemiological studies are warranted, but physicians should be aware of the potential consequences of PPI use, which should be dose appropriate and prescribed according to guidelines.

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“…Recent studies have suggested that exposure to corticosteroids, antibiotics, and PPI leads to progressively poorer outcomes after ICI therapy. 22 , 23 Conversely, a meta‐analysis that included 1167 patients with cancer examined the effect of PPI on the survival of patients with cancer treated with ICIs; this study showed that the concomitant use of PPI did not significantly affect OS (HR: 0.996; 95% CI [0.486, 1.447]) or PFS (HR: 0.858; 95% CI [0.388, 1.328]). 24 These contentious outcomes stem mainly from the indirect analysis of the effects of dysbiosis‐inducing drugs on oncological outcomes.…”

Section: Discussionmentioning

confidence: 99%

Prognostic impact of proton pump inhibitors for immunotherapy in advanced urothelial carcinoma

et al. 2021

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Objective To evaluate the effects of the concomitant use of proton pump inhibitors (PPIs) and/or antibiotics (Abs) on oncological outcomes in patients with advanced urothelial carcinoma. Patients and methods We retrospectively evaluated 155 patients with advanced urothelial carcinoma who were treated with immune checkpoint inhibitors (ICIs) between August 2015 and April 2021. The concomitant use of PPI or Abs was defined as any PPI or Abs administered within 30 days before ICI initiation and during ICI therapy. The primary outcomes were the effect of PPI and/or Abs use on the objective response rate (ORR) and immune‐related adverse events (irAEs). The secondary outcomes were the effects of PPI and/or Abs use on progression‐free survival (PFS) and overall survival (OS) after ICI therapy analyzed using the inverse probability of treatment weighting‐adjusted Cox regression analysis. Results Of the 155 patients enrolled in the study, 99 (64%) were PPI users and 56 (36%) Abs users. PPI users were associated with a significantly poorer ORR than non‐PPI users (41% vs. 20%, respectively), whereas Abs use was not significantly associated with changes in ORR. The rate of irAEs was not significantly associated with the use of PPIs or Abs. Multivariate inverse probability of treatment weighting‐adjusted Cox regression analysis revealed significantly poorer PFS and OS in PPI users than in non‐PPI users, whereas Abs use was not associated with poorer outcomes. Conclusion The concomitant use of PPI may adversely affect oncological outcomes in patients with locally advanced or metastatic urothelial carcinoma treated with ICI therapy.

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Associations between dysbiosis-inducing drugs, overall survival and tumor response in patients treated with immune checkpoint inhibitors

Cited by 34 publications

References 63 publications

Concomitant Medication Effects on Immune Checkpoint Inhibitor Efficacy and Toxicity

Concomitant Medication Effects on Immune Checkpoint Inhibitor Efficacy and Toxicity

Proton Pump Inhibitors and Cancer: Current State of Play

Prognostic impact of proton pump inhibitors for immunotherapy in advanced urothelial carcinoma

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