Efficacy and Safety of Concomitant Proton Pump Inhibitor and Nivolumab in Renal Cell Carcinoma: Results of the GETUG-AFU 26 NIVOREN Multicenter Phase II Study


      • The GETUG-AFU 26 NIVOREN trial enrolled 729 mRCC patients of whom 27.7% were PPI users.
      • PPI use did not correlate with PFS or OS (HR = 0.89, 95% CI 0.74-1.08 and HR = 1.24; 95% CI, 0.98-1.58, respectively).
      • Nivolumab-related adverse events of any grade occurred similarly among PPI users and non-users (61.2% vs. 62%).
      • Grade 3-5 nivolumab-related adverse events were more common among PPI users (25.5% vs. 15.3%).



      Proton pump inhibitors (PPI) may influence the gut microbiome and thus impact the effectiveness of immune checkpoint inhibitors (ICI). The effect of PPIs on the outcomes of ICI has not been fully explored and investigated in metastatic renal cell carcinoma (mRCC).


      This retrospective analysis used prospectively collected data from the GETUG-AFU 26 NIVOREN (NCT03013335) phase II study which enrolled 729 mRCC patients of whom 720 were treated with nivolumab. The main objective of this analysis was to evaluate the impact of PPI on the efficacy and safety outcomes of mRCC patients. PPI use was defined as PPI administration on the day of ICI initiation.


      Of the 707 patients with mRCC analyzed in this study, 196 (27.7%) were PPI users. The majority of PPI users were males (80.6%), had an ECOG performance status of 0-1 (78.9%) and a nephrectomy (82.1%). Almost two-thirds of the patients had a favorable and intermediate IMDC risk category and 52% received nivolumab in the third line and beyond. PPI use did not correlate with PFS or OS (HR = 0.89, 95% CI 0.74-1.08 and HR = 1.24; 95% CI, 0.98-1.58, respectively). Grade 3-5 nivolumab-related adverse events were more common among PPI users (25.5% vs. 15.3%).


      This real-world study suggests that PPI use in patients with mRCC does not impact the efficacy outcomes but may influence the safety of nivolumab which warrants further investigations.


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      1. Cancer today [Internet]. [cited 2021 Jan 23]. Available at:

      2. Kidney and Renal Pelvis Cancer — Cancer Stat Facts [Internet]. [cited 2021 Jan 23]. Available at:

        • Choueiri TK
        • Motzer RJ.
        Systemic therapy for metastatic renal-cell carcinoma.
        N Engl J Med. 2017; 376: 354-366
        • Rassy E
        • Flippot R
        • Albiges L.
        Tyrosine kinase inhibitors and immunotherapy combinations in renal cell carcinoma.
        Ther Adv Med Oncol. 2020; 121758835920907504
        • de Velasco G
        • Bex A
        • Albiges L
        • et al.
        Sequencing and combination of systemic therapy in metastatic renal cell carcinoma.
        Eur Urol Oncol. 2019; 2: 505-514
        • Escudier B
        • Sharma P
        • McDermott DF
        • et al.
        CheckMate 025 randomized phase 3 study: outcomes by key baseline factors and prior therapy for nivolumab versus everolimus in advanced renal cell carcinoma.
        Eur Urol. 2017; 72: 962-971
        • Rini BI
        • Plimack ER
        • Stus V
        • et al.
        Pembrolizumab plus Axitinib versus sunitinib for advanced renal-cell carcinoma.
        N Engl J Med. 2019; 380: 1116-1127
        • Motzer RJ
        • Rini BI
        • McDermott DF
        • et al.
        Nivolumab plus ipilimumab versus sunitinib in first-line treatment for advanced renal cell carcinoma: extended follow-up of efficacy and safety results from a randomised, controlled, phase 3 trial.
        Lancet Oncol. 2019; 20: 1370-1385
        • Motzer RJ
        • Penkov K
        • Haanen J
        • et al.
        Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma.
        N Engl J Med. 2019; 380: 1103-1115
        • Xu JX
        • Maher VE
        • Zhang L
        • et al.
        FDA approval summary: nivolumab in advanced renal cell carcinoma after anti-angiogenic therapy and exploratory predictive biomarker analysis.
        Oncologist. 2017; 22: 311-317
        • Motzer RJ
        • Escudier B
        • McDermott DF
        • et al.
        Nivolumab versus everolimus in advanced renal-cell carcinoma.
        N Engl J Med. 2015; 373: 1803-1813
        • Routy B
        • Le Chatelier E
        • Derosa L
        • et al.
        Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors.
        Science. 2018; 359: 91-97
        • Gopalakrishnan V
        • Spencer CN
        • Nezi L
        • et al.
        Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients.
        Science. 2018; 359: 97-103
        • Elkrief A
        • Derosa L
        • Zitvogel L
        • Kroemer G
        • Routy B.
        The intimate relationship between gut microbiota and cancer immunotherapy.
        Gut Microbes. 2019; 10: 424-428
        • Derosa L
        • Routy B
        • Fidelle M
        • et al.
        Gut bacteria composition drives primary resistance to cancer immunotherapy in renal cell carcinoma patients.
        Eur Urol. 2020; 78: 195-206
        • Derosa L
        • Hellmann MD
        • Spaziano M
        • et al.
        Negative association of antibiotics on clinical activity of immune checkpoint inhibitors in patients with advanced renal cell and non-small-cell lung cancer.
        Ann Oncol Off J Eur Soc Med Oncol. 2018; 29: 1437-1444
        • Imhann F
        • Bonder MJ
        • Vich Vila A
        • et al.
        Proton pump inhibitors affect the gut microbiome.
        Gut. 2016; 65: 740-748
        • Huber V
        • Camisaschi C
        • Berzi A
        • et al.
        Cancer acidity: an ultimate frontier of tumor immune escape and a novel target of immunomodulation.
        Semin Cancer Biol. 2017; 43: 74-89
        • Nayan M
        • Juurlink DN
        • Austin PC
        • et al.
        Medication use and kidney cancer risk: a population-based study.
        Eur J Cancer Oxf Engl 1990. 2017; 83: 203-210
        • Lalani AKA
        • McKay RR
        • Lin X
        • Simantov R
        • Kaymakcalan MD
        • Choueiri TK.
        Proton pump inhibitors and survival outcomes in patients with metastatic renal cell carcinoma.
        Clin Genitourin Cancer. 2017; 15: 724-732
        • Mollica V
        • Santoni M
        • Matrana MR
        • et al.
        Concomitant proton pump inhibitors and outcome of patients treated with nivolumab alone or plus ipilimumab for advanced renal cell carcinoma.
        Target Oncol. 2021; 11
        • Flippot R
        • Dalban C
        • Laguerre B
        • et al.
        Safety and efficacy of nivolumab in brain metastases from renal cell carcinoma: results of the GETUG-AFU 26 NIVOREN multicenter phase ii study.
        J Clin Oncol Off J Am Soc Clin Oncol. 2019; 37: 2008-2016
        • Jackson MA
        • Verdi S
        • Maxan ME
        • et al.
        Gut microbiota associations with common diseases and prescription medications in a population-based cohort.
        Nat Commun. 2018; 9: 2655
        • Maier L
        • Pruteanu M
        • Kuhn M
        • et al.
        Extensive impact of non-antibiotic drugs on human gut bacteria.
        Nature. 2018; 555: 623-628
        • Le Bastard Q
        • Al-Ghalith GA
        • Grégoire M
        • et al.
        Systematic review: human gut dysbiosis induced by non-antibiotic prescription medications.
        Aliment Pharmacol Ther. 2018; 47: 332-345
        • Zhou H
        • Mascelli MA.
        Mechanisms of monoclonal antibody-drug interactions.
        Annu Rev Pharmacol Toxicol. 2011; 51: 359-372
        • Kamath AV.
        Translational pharmacokinetics and pharmacodynamics of monoclonal antibodies.
        Drug Discov Today Technol. 2016; 21-22: 75-83
        • Li M
        • Zeng C
        • Yao J
        • Ge Y
        • An G.
        The association between proton pump inhibitors use and clinical outcome of patients receiving immune checkpoint inhibitors therapy.
        Int Immunopharmacol. 2020; 88106972
        • Nguyen QP
        • Nomura M
        • Matsumoto S
        • Muto M.
        MO3-10-1 - The effect of proton pump inhibitors on the efficacy of nivolumab monotherapy in different types of cancer.
        Ann Oncol. 2019; 30: vi115
        • Trabolsi A
        • Winter M
        • Rodriguez E.
        Proton pump inhibitors and response to immune check-point inhibitors: single center study.
        J Clin Oncol. 2019; 37: e14092
        • Iglesias-Santamaría A.
        Impact of antibiotic use and other concomitant medications on the efficacy of immune checkpoint inhibitors in patients with advanced cancer.
        Clin Transl Oncol. 2020; 22: 1481-1490
        • Cortellini A
        • Tucci M
        • Adamo V
        • et al.
        Integrated analysis of concomitant medications and oncological outcomes from PD-1/PD-L1 checkpoint inhibitors in clinical practice.
        J Immunother Cancer. 2020; 8e001361
        • Failing JJ
        • Finnes HD
        • Kottschade LA
        • Allred JB
        • Markovic SN.
        Effects of commonly used chronic medications on the outcomes of ipilimumab therapy in patients with metastatic melanoma.
        Melanoma Res. 2016; 26: 609-615
        • Mukherjee S
        • Ibrahimi S
        • Khalid B
        • Roman D
        • Zhao D
        • Aljumaily R.
        Do proton pump inhibitors modulate the efficacy of anti-PD-1/PD-L1 therapy? A retrospective study.
        J Oncol. 2019; 25: 762-764
        • Gupta S
        • Short SAP
        • Sise ME
        • et al.
        Acute kidney injury in patients treated with immune checkpoint inhibitors.
        J Immunother Cancer. 2021; 9e003467
        • Svaton M
        • Zemanova M
        • Zemanova P
        • et al.
        Impact of concomitant medication administered at the time of initiation of nivolumab therapy on outcome in non-small cell lung cancer.
        Anticancer Res. 2020; 40: 2209-2217
        • Afzal MZ
        • Shirai K.
        What impact do the proton pump inhibitors have on the efficacy of immune check point inhibitors in metastatic malignant melanoma?.
        J Clin Oncol. 2019; 37: e21040
        • Hopkins AM
        • Kichenadasse G
        • Karapetis CS
        • Rowland A
        • Sorich MJ.
        Concomitant proton pump inhibitor use and survival in urothelial carcinoma treated with atezolizumab.
        Clin Cancer. 2020; 26: 5487-5493
        • Chalabi M
        • Cardona A
        • Nagarkar DR
        • et al.
        Efficacy of chemotherapy and atezolizumab in patients with non-small-cell lung cancer receiving antibiotics and proton pump inhibitors: pooled post hoc analyses of the OAK and POPLAR trials.
        Ann Oncol. 2020; 31: 525-531
        • Homicsko K
        • Richtig G
        • Tuchmann F
        • et al.
        Proton pump inhibitors negatively impact survival of PD-1 inhibitor based therapies in metastatic melanoma patients.
        Ann Oncol. 2018; 29: x40