Efficacy of first-line atezolizumab combination therapy in patients with non-small cell lung cancer receiving proton pump inhibitors: post hoc analysis of IMpower150

Proton pump inhibitors (PPIs) are commonly used concomitant to cancer treatment and they induce gut microbiota changes. It’s increasingly apparent that gut dysbiosis can reduce the effectiveness of immune checkpoint inhibitors (ICI). However, little is known on PPI effects on outcomes with ICIs.

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Before this study

Gut dysbiosis caused by proton pump inhibitors (PPIs) is hypothesised to influence antitumour immune activity and clinical responses to immune checkpoint inhibitors (ICIs). Recent meta-analyses suggest proton pump inhibitors (PPIs) may be associated with poor prognosis in patients treated with ICIs1,2. However, research is largely based on small single-arm data, leading to conflicting results and an inability to inform whether PPIs specifically impact ICI efficacy or if they just represent poor prognosis. Information on treatment efficacy (rather than just prognosis) is critical to informing clinical decisions, and randomised control trials (RCTs) are the gold standard for valid estimation of treatment efficacy. For this study, PubMed and Google Scholar were searched to identify studies which have utilised ‘randomised data’ to evaluate if ‘PPI’ use were predictive of ‘ICI’ ‘efficacy’ versus comparator anticancer treatments. While many single-arm studies were found, only two studies evaluating whether PPIs were associated with modified efficacy of ICIs versus comparator treatments in RCT data were identified. These post hoc analyses indicated that PPI use was trending towards a decrease in the magnitude of ICI benefit versus comparator chemotherapies3,4. However, the subgroup analyses were in (1) a later line advanced urothelial cancer cohort treated with atezolizumab monotherapy3, and (2) a platinum-resistant advanced non-small cell lung cancer (NSCLC) cohort treated with atezolizumab monotherapy4. A limitation of the studies is they provide little insights on the associations of PPIs with treatment efficacy in patients initiating contemporary chemo-immunotherapy combinations in the first-line setting.

Value of the study

The present analysis is the first study to evaluate the association between PPI use and survival outcomes in patients with chemotherapy-naïve, metastatic non-squamous NSCLC initiating a contemporary chemo-immunotherapy combination5. Specifically, the study was a post hoc analysis of individual-participant data from the IMpower150 (NCT02366143)6,7, where patients were randomised to atezolizumab plus carboplatin plus paclitaxel (ACP), versus bevacizumab plus carboplatin plus paclitaxel (BCP), versus atezolizumab plus BCP (ABCP). The study demonstrated that PPI use was an independent prognostic factor of worse survival outcomes when treated with atezolizumab plus carboplatin plus paclitaxel (±bevacizumab) therapy, which was not observed with BCP therapy. Further, the post hoc analysis identified a statistical decrease in the magnitude of atezolizumab benefit (ACP/ABCP arms vs BCP) in PPI users.

Implications

Available evidence from three RCTs indicates that PPI use may be a potential marker of reduced atezolizumab efficacy3-5. Given approximately 30% of cancer patients use PPIs, there is an urgent need to confirm these findings in RCTs of other ICIs and to develop guidelines on the appropriate use of PPIs in patients considering ICIs. Research also needs to enlighten to whether PPI are having causative effects or whether ICI treatment efficacy is impaired in patients with gastrointestinal diseases, needing PPIs, which are associated with gut dysbiosis8,9.

References

  1. Li C, Xia Z, Li A, Meng J. The effect of proton pump inhibitor uses on outcomes for cancer patients treated with immune checkpoint inhibitors: a meta-analysis. Annals of translational medicine 2020; 8(24): 1655-1655; doi 10.21037/atm-20-7498.
  2. 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; e-pub ahead of print 2020/11/14; doi 10.1016/j.intimp.2020.106972.
  3. 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(20): 5487-5493; e-pub ahead of print 2020/09/17; doi 10.1158/1078-0432.Ccr-20-1876.
  4. 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(4): 525-531; e-pub ahead of print 2020/03/03; doi 10.1016/j.annonc.2020.01.006.
  5. Hopkins AM, Kichenadasse G, McKinnon RA, Abuhelwa AY, Logan JM, Badaoui S 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. British Journal of Cancer 2021.
  6. 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(5): 387-401; e-pub ahead of print 2019/03/30; doi 10.1016/s2213-2600(19)30084-0.
  7. 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(24): 2288-2301; e-pub ahead of print 2018/06/05; doi 10.1056/NEJMoa1716948.
  8. Haworth JJ, Boyle N, Vales A, Hobson AR. The prevalence of intestinal dysbiosis in patients referred for antireflux surgery. Surgical Endoscopy 2021; doi 10.1007/s00464-020-08229-5.
  9. Saffouri GB, Shields-Cutler RR, Chen J, Yang Y, Lekatz HR, Hale VL et al. Small intestinal microbial dysbiosis underlies symptoms associated with functional gastrointestinal disorders. Nature Communications 2019; 10(1): 2012; doi 10.1038/s41467-019-09964-7.

Ashley Hopkins

Senior Research Fellow, Flinders University