Proton pump inhibitors (PPIs) are commonly used concomitant to cancer treatment and they induce gut microbiota changes. It is increasingly apparent that gut dysbiosis can reduce the effectiveness of immune checkpoint inhibitors (ICI). However, little is known about PPI effects on outcomes with ICIs, particularly in combination, ICI approaches.
Post hoc, Cox proportional hazard analysis of phase III trial, IMpower150 was conducted to assess the association between PPI use and overall survival (OS) and progression-free survival (PFS) in chemotherapy-naive, metastatic non-squamous non-small cell lung cancer participants randomised atezolizumab plus carboplatin plus paclitaxel (ACP), bevacizumab plus carboplatin plus paclitaxel (BCP), or atezolizumab plus BCP (ABCP). PPI use was defined as any PPI administration between 30 days prior and 30 days after treatment initiation.
Of 1202 participants, 441 (37%) received a PPI. PPI use was independently associated with worse OS (n = 748; hazard ratio (HR) [95% confidence interval (CI)] = 1.53 [1.21–1.95], P < 0.001) and PFS (1.34 [1.12–1.61], P = 0.002) in the pooled atezolizumab arms (ACP plus ABCP). This association was not apparent for BCP (n = 368; OS 1.01 [0.73–1.39], P = 0.969; PFS 0.97 [0.76–1.25], P = 0.827). The observed OS treatment effect (HR 95% CI) of the atezolizumab (ACP plus ABCP) arms vs BCP was 1.03 (0.77–1.36) for PPI users compared to 0.68 (0.54–0.86) for non-users (P [interaction] = 0.028). A similar association was noted for ABCP vs BCP (PPI users 0.96 [0.68–1.35]; PPI non-users 0.66 [0.50–0.87]; P [interaction] = 0.095).
PPI use was a negative prognostic marker in patients treated with ACP or ABCP, but not BCP. The analysis suggests that PPIs negatively influence the magnitude of ICI efficacy.
This is a preview of subscription content, access via your institution
Subscribe to this journal
Receive 24 print issues and online access
$259.00 per year
only $10.79 per issue
Rent or buy this article
Get just this article for as long as you need it
Prices may be subject to local taxes which are calculated during checkout
Data were accessed according to Roche’s policy and process for clinical study data sharing and are available upon request at vivli.org.
Available upon request to the corresponding author.
Hanna NH, Schneider BJ, Temin S, Baker S Jr., Brahmer J, Ellis PM, et al. Therapy for stage IV non-small-cell lung cancer without driver alterations: ASCO and OH (CCO) Joint Guideline Update. J Clin Oncol. 2020;38:1608–32. https://doi.org/10.1200/jco.19.03022.
Hopkins AM, Rowland A, Kichenadasse G, Wiese MD, Gurney H, McKinnon RA, et al. Predicting response and toxicity to immune checkpoint inhibitors using routinely available blood and clinical markers. Br J Cancer. 2017;117:913–20. https://doi.org/10.1038/bjc.2017.274.
Hopkins AM, Kichenadasse G, Garrett-Mayer E, Karapetis CS, Rowland A, Sorich MJ. Development and validation of a prognostic model for patients with advanced lung cancer treated with the immune checkpoint inhibitor atezolizumab. Clin Cancer Res. 2020;26:3280–6. https://doi.org/10.1158/1078-0432.CCR-19-2968.
Kichenadasse G, Miners JO, Mangoni AA, Rowland A, Hopkins AM, Sorich MJ. Multiorgan immune-related adverse events during treatment with atezolizumab. J Natl Compr Canc Netw. 2020;18:1191–9. https://doi.org/10.6004/jnccn.2020.7567.
Chalabi M, Cardona A, Nagarkar DR, Dhawahir Scala A, Gandara DR, Rittmeyer A. 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;31:525–31. https://doi.org/10.1016/j.annonc.2020.01.006.
Bai R, Chen N, Li L, Du N, Bai L, Lv Z. et al. Mechanisms of cancer resistance to immunotherapy. Front Oncol. 2020;10:1290–1290. https://doi.org/10.3389/fonc.2020.01290.
Fares CM, Allen EMV, Drake CG, Allison JP, Hu-Lieskovan S. Mechanisms of resistance to immune checkpoint blockade: why does checkpoint inhibitor immunotherapy not work for all patients? Am Soc Clin Oncol Educ Book. 2019;147–64. https://doi.org/10.1200/edbk_240837.
Hopkins AM, Kichenadasse G, Karapetis CS, Rowland A, Sorich MJ. Concomitant antibiotic use and survival in urothelial carcinoma treated with atezolizumab. Eur Urol. 2020;78:540–3. https://doi.org/10.1016/j.eururo.2020.06.061.
Elkrief A, Derosa L, Kroemer G, Zitvogel L, Routy B. The negative impact of antibiotics on outcomes in cancer patients treated with immunotherapy: a new independent prognostic factor? Ann Oncol. 2019;30:1572–9. https://doi.org/10.1093/annonc/mdz206.
Kichenadasse G, Miners JO, Mangoni AA, Rowland A, Hopkins AM, Sorich MJ. Association between body mass index and overall survival with immune checkpoint inhibitor therapy for advanced non-small cell lung cancer. JAMA Oncol. 2020;6:512–8. https://doi.org/10.1001/jamaoncol.2019.5241.
Hopkins AM, Kichenadasse G, Abuhelwa AY, McKinnon RA, Rowland A, Sorich MJ. Value of the lung immune prognostic index in patients with non-small cell lung cancer initiating first-line atezolizumab combination therapy: subgroup analysis of the IMPOWER150 Trial. Cancers. 2021;13. https://doi.org/10.3390/cancers13051176.
Vivarelli S, Salemi R, Candido S, Falzone L, Santagati M, Stefani S, et al. Gut microbiota and cancer: from pathogenesis to therapy. Cancers. 2019;11:38. https://doi.org/10.3390/cancers11010038.
Routy B, Le Chatelier E, Derosa L, Duong CPM, Alou MT, Daillere R, et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science. 2018;359:91–97. https://doi.org/10.1126/science.aan3706.
Matson V, Fessler J, Bao R, Chongsuwat T, Zha Y, Alegre ML, et al. The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. Science. 2018;359:104–8. https://doi.org/10.1126/science.aao3290.
Gopalakrishnan V, Spencer CN, Nezi L, Reuben A, Andrews MC, Karpinets TV, et al. Gut microbiome modulates response to anti–PD-1 immunotherapy in melanoma patients. Science. 2018;359:97–103. https://doi.org/10.1126/science.aan4236.
Imhann F, Bonder MJ, Vich Vila A, Fu J, Mujagic Z, Vork L, et al. Proton pump inhibitors affect the gut microbiome. Gut. 2016;65:740–8. https://doi.org/10.1136/gutjnl-2015-310376.
Jackson MA, Goodrich JK, Maxan M-E, Freedberg DE, Abrams JA, Poole AC, et al. Proton pump inhibitors alter the composition of the gut microbiota. Gut. 2016;65:749–56. https://doi.org/10.1136/gutjnl-2015-310861.
Jackson MA, Verdi S, Maxan M-E, Shin CM, Zierer J, Bowyer RCE, et al. Gut microbiota associations with common diseases and prescription medications in a population-based cohort. Nat Commun. 2018;9:2655. https://doi.org/10.1038/s41467-018-05184-7.
Le Bastard Q, Al-Ghalith GA, Grégoire M, Chapelet G, Javaudin F, Dailly E, et al. Systematic review: human gut dysbiosis induced by non-antibiotic prescription medications. Aliment Pharm Ther. 2018;47:332–45. https://doi.org/10.1111/apt.14451.
Maier L, Pruteanu M, Kuhn M, Zeller G, Telzerow A, Anderson EE, et al. Extensive impact of non-antibiotic drugs on human gut bacteria. Nature. 2018;555:623. https://doi.org/10.1038/nature25979.
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;88:106972 https://doi.org/10.1016/j.intimp.2020.106972.
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 Res. 2020;26:5487–93. https://doi.org/10.1158/1078-0432.CCR-20-1876.
Reck M, Mok TSK, Nishio M, Jotte RM, Cappuzzo F, Orlandi F, et al. Atezolizumab plus bevacizumab and chemotherapy in non-small-cell lung cancer (IMpower150): key subgroup analyses of patients with EGFR mutations or baseline liver metastases in a randomised, open-label phase 3 trial. Lancet Respir Med. 2019;7:387–401. https://doi.org/10.1016/s2213-2600(19)30084-0.
Socinski MA, Jotte RM, Cappuzzo F, Orlandi F, Stroyakovskiy D, Nogami N, et al. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N. Engl J Med. 2018;378:2288–301. https://doi.org/10.1056/NEJMoa1716948.
Simon RM, Paik S, Hayes DF. Use of archived specimens in evaluation of prognostic and predictive biomarkers. J Natl Cancer Inst. 2009;101:1446–52. https://doi.org/10.1093/jnci/djp335.
Fais S. Evidence-based support for the use of proton pump inhibitors in cancer therapy. J Transl Med. 2015;13:368. https://doi.org/10.1186/s12967-015-0735-2.
Wang B-Y, Zhang J, Wang J-L, Sun S, Wang Z-H, Wang L-P, et al. Intermittent high dose proton pump inhibitor enhances the antitumor effects of chemotherapy in metastatic breast cancer. J Exp Clin Cancer Res. 2015;34:85–85. https://doi.org/10.1186/s13046-015-0194-x.
Cortellini A, Di Maio M, Nigro O, Leonetti A, Cortinovis DL, Aerts JG, et al. Differential influence of antibiotic therapy and other medications on oncological outcomes of patients with non-small cell lung cancer treated with first-line pembrolizumab versus cytotoxic chemotherapy. J J Immunother Cancer. 2021;9:e002421. https://doi.org/10.1136/jitc-2021-002421.
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 Pharm Pract. 2019;25:762–4. https://doi.org/10.1177/1078155218771152.
Homicsko K, Richtig G, Tuchmann F, Tsourti Z, Hanahan D, Coukos G, et al. Abstract LBA2: proton pump inhibitors negatively impact survival of PD-1 inhibitor based therapies in metastatic melanoma patients. Ann Oncol. 2018;29 Suppl 10. https://doi.org/10.1093/annonc/mdy511.001.
Trabolsi A, Winter M, Rodriguez E. Abstract e14092: proton pump inhibitors and response to immune check-point inhibitors: single center study. J Clin Oncol. 2019;37 Suppl 15. https://doi.org/10.1200/JCO.2019.37.15_suppl.e14092.
Afzal MZ, Shirai K. Abstract e21040: 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 Suppl 15. https://doi.org/10.1200/JCO.2019.37.15_suppl.e21040.
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;26:609–15. https://doi.org/10.1097/cmr.0000000000000299.
Wang R, Lagakos SW, Ware JH, Hunter DJ, Drazen JM. Statistics in medicine—reporting of subgroup analyses in clinical trials. N. Engl J Med. 2007;357:2189–94.https://doi.org/10.1056/NEJMsr077003
Forgacs I, Loganayagam A. Overprescribing proton pump inhibitors. BMJ. 2008;336:2–3. https://doi.org/10.1136/bmj.39406.449456.BE.
RAM, AR and MJS are supported by Beat Cancer Research Fellowships from Cancer Council South Australia. AMH is supported by a Postdoctoral Fellowship from the National Breast Cancer Foundation, Australia (PF-17-007). Data access and salary of AYA was supported by funding from an Australian, Tour de Cure Early Career Research Grant (RSP-155-18/19). The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit. This publication is based on research using data from Roche that has been made available through Vivli, Inc. Vivli has not contributed to or approved, and is not in any way responsible for the contents of this publication.
RAM, AR and MJS report investigator-initiated project grants from Pfizer, outside the submitted work. CSK reports advisory board roles with AstraZeneca, Merck Sharp & Dohme, Bristol-Myers Squibb and Roche, outside the submitted work. GK, AYA, AMH, SB and JML declare no competing interests.
Ethics approval and consent to participate
Secondary analysis of anonymized clinical trial data was confirmed negligible risk research by the Southern Adelaide Local Health Network, Office for Research and Ethics and was exempt from review.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Hopkins, A.M., Kichenadasse, G., McKinnon, R.A. et al. Efficacy of first-line atezolizumab combination therapy in patients with non-small cell lung cancer receiving proton pump inhibitors: post hoc analysis of IMpower150. Br J Cancer 126, 42–47 (2022). https://doi.org/10.1038/s41416-021-01606-4