Baseline co-medications may alter the anti-tumoural effect of checkpoint inhibitors as well as the risk of immune-related adverse events

Kostine, Marie; Mauric, Eleonora; Tison, Alice; Barnetche, Thomas; Barré, Aurélien; Nikolski, Macha; Rouxel, L.; Dutriaux, Caroline; Dousset, L.; Prey, S.; Beylot‐Barry, M.; Sénéschal, Julien; Veillon, Rémi; Vergnenègre, Charlotte; Daste, Amaury; Domblides, Charlotte; Sionneau, Baptiste; Gross‐Goupil, Marine; Ravaud, Alain; Forcade, Édouard; Schaeverbeke, Thierry; Acronim, Fhu

doi:10.1016/j.ejca.2021.08.036

Cited by 62 publications

(64 citation statements)

References 42 publications

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“…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 .…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2022

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Background: Proton pump inhibitors (PPIs) have been shown to regulate the gut microbiome and affect the response to immune checkpoint inhibitors (ICIs). Contradictory results on survival have been observed in patients concomitantly treated with ICIs and PPIs. We performed a systematic review and meta-analysis to determine the association between PPI use and survival outcomes in ICI-treated cancer patients. Methods: EMBASE, MEDLINE/PubMed, Cochrane Library databases, and major oncology conference proceedings were searched. Studies comparing overall survival (OS) and progression-free survival (PFS) between PPI-treated and PPI-free groups of ICI-treated cancer patients were included. Data regarding study and patient characteristics, ICI and PPI treatments, and survival outcomes were extracted. Hazard ratios (HRs) with 95% confidence interval (CI) were pooled using random effects models. Subgroup meta-analyses and meta-regressions were performed to explore possible factors of heterogeneity among the studies. Results: A total of 33 studies were included, comprising 7383 ICI- and PPI-treated patients and 8574 ICI-treated and PPI-free patients. The pooled HR was 1.31 (95% CI, 1.19–1.44; p < 0.001) for OS and 1.30 (95% CI, 1.17–1.46; p < 0.001) for PFS, indicating a significant negative association between PPI use and survival in ICI-treated patients. Subgroup meta-analyses by factors including cancer type, ICI type, and time window of PPI use revealed that ICI and PPI use impacted survival in patients with non-small cell lung or urothelial cancer, patients treated with anti-PD-1/PD-L1 antibodies, and patients receiving PPI as baseline treatment or 60 days before ICI treatment initiation. Conclusions: PPI use in patients treated with ICIs was associated with shorter OS and PFS, especially in several specific subgroups of cancer patients. PPIs should be strictly controlled and appear to not impact survival if given temporarily after ICI initiation. These observations could provide the basis for clinical guidelines for concomitant PPI and ICI use.

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Section: Resultsmentioning

confidence: 99%

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

et al. 2022

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“…A total of 513 (21.5%) patients were with concomitant use of statin. Four studies reported the association between concomitant statin and survival outcomes with univariate analyses [ 15 , 23 , 26 , 28 ], while the other four studies reported with multivariate analyses [ 24 , 25 , 27 , 29 ]. Variables including demographic features, cancer characteristics, and smoking history were adjusted in the multivariate models.…”

Section: Resultsmentioning

confidence: 99%

“…The 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase inhibitors, also named as statins, are well-applied lipid-lowering medications [ 14 ]. Statins are commonly prescribed for patients with atherosclerosis and cardiovascular diseases, and about one-fifth of cancer patients receiving ICIs are also on statins [ 15 ]. Accumulating evidence shows that statins may also exert anticancer efficacy via multiple pharmacological mechanisms such as antiproliferation, anti-inflammation, proapoptosis, and anti-invasion [ 16 , 17 ].…”

Section: Introductionmentioning

confidence: 99%

“…Accordingly, results of recent observational studies evaluating the influence of concomitant statin use on survival of NSCLC patients treated with ICIs were not consistent [ 15 , 23 – 28 ]. Some studies suggested that concomitant statin may improve the survival of these patients [ 23 , 25 , 28 ], while others did not show a significant influence [ 15 , 24 , 26 , 27 , 29 ]. Therefore, this meta-analysis was conducted to systematically evaluate the effect of concomitant statins on the therapeutic efficacy of ICIs in patients with NSCLC.…”

Section: Introductionmentioning

confidence: 99%

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Concomitant Statins and the Survival of Patients with Non-Small-Cell Lung Cancer Treated with Immune Checkpoint Inhibitors: A Meta-Analysis

Zhang

Wang

Tian

et al. 2022

International Journal of Clinical Practice

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Statins are suggested to improve cancer survival by possible anti-inflammatory effect. However, it remains unclear if concomitant use of statins could improve the efficacy of immune checkpoint inhibitors (ICIs) in patients with non-small-cell lung cancer (NSCLC). Accordingly, a meta-analysis was performed to systematically evaluate the effect of concomitant statins in NSCLC patients receiving ICIs. Relevant studies were obtained by literature search in PubMed, Embase, and Web of Science databases. A conservative random-effect model was used to combine the results. Eight cohorts including 2382 patients were included. The programmed death-1/ligand-1 inhibitors were used in seven studies; while the cytotoxic T-lymphocyte-associated protein 4 inhibitors were used in the other study. It was shown that concomitant use of statin did not significantly affect the progression-free survival (PFS, hazard ratio (HR): 0.86, 95% confidence interval (CI): 0.70 to 1.07, P = 0.17 ; I2 = 62%) or overall survival (OS, HR: 0.86, 95% CI: 0.74 to 1.01, P = 0.07 ; I2 = 29%) of NSCLC patients receiving ICIs. Subgroup analyses showed consistent results in studies with univariate or multivariate analytic models ( P for subgroup analysis = 0.97 and 0.38 for the outcome of PFS and OS, respectively). In conclusion, concomitant use of statin seemed to have no significant influence on the survival of patients with NSCLC who were treated with ICIs.

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“…The authors analysed the influence of comedications (including PPIs) on the anti-tumour effect and safety of these CPI. PPIs were prescribed in 38% of these patients; the median OS of patients receiving PPIs was 9 months versus 26.5 months in those not receiving PPIs (HR: 1.70, 95%CI: 1.40–2.08) [ 64 ].…”

Section: Ppis and Oncologic Treatment Efficacymentioning

confidence: 99%

Long-Term Use of Proton Pump Inhibitors in Cancer Patients: An Opinion Paper

Raoul

Edeline

Simmet

et al. 2022

Cancers

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Multikinase inhibitors (MKIs), and particularly tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (CPIs), are currently some of the major breakthroughs in cancer treatment. Proton pump inhibitors (PPIs) revolutionised the treatment of acid-related diseases, but are frequently overused for epigastric pain or heartburn. However, long-term acid suppression from using PPIs may lead to safety concerns, and could have a greater impact in cancer patients undergoing therapy, like bone fractures, renal toxicities, enteric infections, and micronutrient deficiencies (iron and magnesium). Moreover, acid suppression may also affect the pharmacokinetics of drugs (at least during acid suppression) and decrease the absorption of many molecularly-targeted anticancer therapies, which are mostly weak bases with pH-dependent absorption. This type of drug-drug interaction may have detrimental effects on efficacy, with major clinical impacts described for some orally administrated targeted therapies (erlotinib, gefitinib, pazopanib, palbociclib), and conflicting results with many others, including capecitabine. Furthermore, the long-term use of PPIs results in severe alterations to the gut microbiome and recent retrospective analyses have shown that the benefit of using CPIs was suppressed in patients treated with PPIs. These very expensive drugs are of great importance because of their efficacy. As the use of PPIs is not essential, we must apply the precautionary principle. All these data should encourage medical oncologists to refrain from prescribing PPIs, explaining to patients the risks of interaction in order to prevent inappropriate prescription by another physician.

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Baseline co-medications may alter the anti-tumoural effect of checkpoint inhibitors as well as the risk of immune-related adverse events

Cited by 62 publications

References 42 publications

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

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

Concomitant Statins and the Survival of Patients with Non-Small-Cell Lung Cancer Treated with Immune Checkpoint Inhibitors: A Meta-Analysis

Long-Term Use of Proton Pump Inhibitors in Cancer Patients: An Opinion Paper

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