Concomitant Proton Pump Inhibitors and Outcome of Patients Treated with Nivolumab Alone or Plus Ipilimumab for Advanced Renal Cell Carcinoma

Mollica, Veronica; Santoni, Matteo; Matrana, Marc; Basso, Umberto; Giorgi, Ugo De; Rizzo, Alessandro; Maruzzo, Marco; Marchetti, Andrea; Rosellini, Matteo; Bleve, Sara; Maslov, Diana; Tawagi, Karine; Philon, Ernest; Blake, Zoe; Massari, Francesco

doi:10.1007/s11523-021-00861-y

Cited by 63 publications

(56 citation statements)

References 38 publications

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“…Similar to antibiotics, PPIs were also found to significantly affect the composition of the gut microbiota and are negatively associated with ICI efficacy ( 23 , 34 , 35 ). However, there are some studies suggesting that PPI use was unrelated to ICI efficacy ( 14 , 28 ). Therefore, in this study, we performed an up-to-date meta-analysis to clarify the correlation between PPI use and ICI efficacy in advanced solid cancers.…”

Section: Discussionmentioning

confidence: 99%

“…Consistently, another retrospective study based on nationwide data has shown that concomitant PPI use was correlated with reduced OS in non-small cell lung cancer (NSCLC) patients treated with ICIs ( 13 ). However, a recent study has found that PPI use was not correlated with ORR, PFS, or OS in advanced renal cell carcinoma (RCC) patients treated with anti-PD-1 therapy alone or plus anti-CTLA-4 therapy ( 14 ). Furthermore, researchers have even found that PPI use was significantly correlated with prolonged median PFS in metastatic melanoma patients treated with ICI alone or combined ICIs ( 15 ).…”

Section: Introductionmentioning

confidence: 99%

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An Up-To-Date Investigation Into the Correlation Between Proton Pump Inhibitor Use and the Clinical Efficacy of Immune Checkpoint Inhibitors in Advanced Solid Cancers: A Systematic Review and Meta-Analysis

et al. 2022

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BackgroundAlthough immune checkpoint inhibitors (ICIs) have revolutionized the current anticancer therapies, a considerable proportion of patients are found to hardly benefit from these drugs. Accumulating studies have demonstrated that concomitant proton pump inhibitor (PPI) use may affect the clinical efficacy of ICIs; however, their results are inconsistent. In this study, based on updated evidence, we aimed to perform a meta-analysis to clarify the prognostic significance of PPI use in advanced solid cancer patients receiving ICI therapy.MethodsEligible literature was searched using PubMed, Cochrane Library, Web of Science, EMBASE, and other network resources before July 2021. Clinical outcome was evaluated using overall survival (OS) and progression-free survival (PFS). The correlation of PPI use with OS or PFS was determined based on hazard ratios (HRs) and 95% confidence intervals (CIs).ResultsA total of 17 studies enrolling 9,978 ICI-treated cancer patients were included in our meta-analysis. The global analysis demonstrated that PPI use was significantly correlated with worse OS [HR = 1.29 (1.10–1.50)] instead of PFS [HR = 1.19 (0.98–1.44)] in solid cancer patients receiving ICI therapy. In a subgroup analysis, the negative correlation of PPI use with ICI efficacy was significant in patients with non-small cell lung cancer [PFS, HR = 1.27 (1.10–1.47)] and urothelial carcinoma [OS, HR = 1.55 (1.31–1.84), PFS, HR = 1.52 (1.13–2.06)] and mixed cohorts containing multiple cancer types [OS, HR = 1.40 (1.16–1.69)], while an opposite result was observed in the PFS of patients with melanoma [HR = 0.48 (0.25–0.90)]. Moreover, the unfavorable prognostic impact of PPI use was also significant in patients over 65 years old [OS, HR = 1.28 (1.05–1.55), PFS, HR = 1.32 (1.12–1.56)] or those receiving anti-PD-1 [OS, HR = 1.37 (1.04–1.79)] or anti-PD-L1 therapies (OS, HR = 1.49 (1.30–1.69), PFS, HR = 1.34 (1.20–1.50). Finally, PPI use was significantly correlated with a worse prognosis in patients receiving PPIs 30 days before and/or after ICI initiation (OS, HR = 1.38 (1.18–1.62), PFS, HR = 1.23 (1.06–1.43)).ConclusionAlthough our global analysis revealed PPI use was not correlated with the PFS of ICI-treated patients, considering the results of our subgroup analysis, PPIs should be still cautiously used shortly before or during ICI therapy. Furthermore, more clinical validations and related mechanism investigations are of great necessity to clarify the clinical correlation of PPI use with ICI efficacy.Systematic Review Registration[https://www.crd.york.ac.uk/prospero/], PROSPERO [No. CRD42021243707].

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

An Up-To-Date Investigation Into the Correlation Between Proton Pump Inhibitor Use and the Clinical Efficacy of Immune Checkpoint Inhibitors in Advanced Solid Cancers: A Systematic Review and Meta-Analysis

et al. 2022

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“…Indeed, obesity and male sex were associated with the best IO effect [ 49 ]. In addition, with regard to drug interactions, no drug effects of widely used proton pump inhibitors were observed on the outcome of mRCC patients treated with ipilimumab plus nivolumab [ 50 ].…”

Section: Discussionmentioning

confidence: 99%

Role of the Systemic Immune-Inflammation Index in Patients with Metastatic Renal Cell Carcinoma Treated with First-Line Ipilimumab plus Nivolumab

Stühler¹,

Herrmann²,

Rausch³

et al. 2022

Cancers

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Background: The aim of this study was to evaluate the predictive and prognostic value of the systemic immune-inflammation index (SII) in patients with metastatic renal cell carcinoma (mRCC) treated with first-line ipilimumab plus nivolumab. Methods: This retrospective study included forty-nine mRCC patients treated with first-line ipilimumab plus nivolumab at the Department of Urology of the University of Tuebingen, Germany. SII was assessed before starting ipilimumab plus nivolumab therapy at the time of first imaging and at tumor progression. Optimal SII cut-off was stratified by ROC-analysis. Univariable and multivariable Cox regression analyses were used to evaluate the predictive and prognostic value of SII. Results: Optimal SII cut-off was 788. Twenty-nine/forty-nine patients had high SII (≥788) before initiation of ipilimumab plus nivolumab. High SII was an independent prognostic factor for worse progression-free (HR 2.70, p = 0.014) and overall survival (HR 10.53, p = 0.025). The clinical benefit rate was higher for patients with low SII if compared to high SII (80% vs. 32.1%). An increase in SII > 20% from baseline after twelve weeks of therapy was associated with progression at first imaging (p = 0.003). Conclusions: SII is both prognostic and predictive and could refine decision making in patients with unclear imaging on therapy with ipilimumab plus nivolumab.

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“…In this opinion paper, we have put emphasis on articles showing the potential negative impact of such combinations and particularly on unplanned retrospective analysis from prospective studies, because we can expect that no randomized trial can be and will be conducted on this topic; moreover, PPIs are symptomatic treatments that can be replaced without any major risk of interactions. There are articles that did not find clinical interactions, particularly with CPIs [ 70 , 71 , 72 ], but we think that the precautionary principle must be applied until there is demonstration of the absence of clinical interaction. It is certainly of major importance that patients can be helped to stop taking PPIs after four weeks of treatment, except in cases of severe oesophagitis, previous bleeding, or Barrett’s oesophagus, [ 73 ] and ideally that prescriptions of PPIs be avoided for heartburn or epigastralgia.…”

Section: Discussionmentioning

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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Concomitant Proton Pump Inhibitors and Outcome of Patients Treated with Nivolumab Alone or Plus Ipilimumab for Advanced Renal Cell Carcinoma

Cited by 63 publications

References 38 publications

An Up-To-Date Investigation Into the Correlation Between Proton Pump Inhibitor Use and the Clinical Efficacy of Immune Checkpoint Inhibitors in Advanced Solid Cancers: A Systematic Review and Meta-Analysis

An Up-To-Date Investigation Into the Correlation Between Proton Pump Inhibitor Use and the Clinical Efficacy of Immune Checkpoint Inhibitors in Advanced Solid Cancers: A Systematic Review and Meta-Analysis

Role of the Systemic Immune-Inflammation Index in Patients with Metastatic Renal Cell Carcinoma Treated with First-Line Ipilimumab plus Nivolumab

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

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