Abstract
Purpose
This study aimed to examine the prognostic impact of concomitant pH-regulating drug use in patients with epidermal growth factor receptor (EGFR)-mutation-positive non-small-cell lung cancer (NSCLC) receiving EGFR-tyrosine kinase inhibitors (TKIs).
Methods
We conducted a nationwide retrospective cohort study and reviewed clinical data of consecutive patients with NSCLC treated with the first-line EGFR-TKIs in 46 hospitals between April 2010 and March 2020. Cox regression analyses were conducted to examine the differences in overall survival (OS) between patients treated with and without concomitant pH-regulating drugs, including potassium-competitive acid blockers (P-CABs), proton pump inhibitors (PPIs), and H2-receptor antagonists (H2RAs).
Results
A total of 758 patients were included in the final dataset, of which 307 (40%) were administered concomitant pH-regulating drugs while receiving frontline EGFR-TKIs. After adjusting for basic patient characteristics, patients administered gefitinib, erlotinib, afatinib, and osimertinib with concomitant pH-regulating drugs had lower OS than those without concomitant pH-regulating drugs, with hazard ratios of 1.74 (with a 95% confidence interval of 1.34–2.27), 1.33 (0.80–2.22), 1.73 (0.89–3.36), and 5.04 (1.38–18.44), respectively. The 2-year OS rates of patients receiving gefitinib with or without concomitant pH-regulating drugs were 65.4 and 77.5%, those for erlotinib were 55.8 and 66.6%, and those for afatinib were 63.2 and 76.9%, respectively. The 1-year OS rates of patients receiving osimertinib with or without concomitant pH-regulating drugs were 88.1% and 96.9%, respectively.
Conclusion
In addition to the first-generation EGFR-TKIs, the second- and third-generation EGFR-TKIs also resulted in OS deterioration in patients with EGFR mutation-positive NSCLC when used concurrently with pH-regulating drugs.
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References
Hayashi H, Nadal E, Gray JE, Ardizzoni A, Caria N, Puri T, Grohe C (2022) Overall treatment strategy for patients with metastatic NSCLC with activating EGFR mutations. Clin Lung Cancer 23:e69–e82. https://doi.org/10.1016/j.cllc.2021.10.009
Sequist LV, Yang JC, Yamamoto N, O’Byrne K, Hirsh V, Mok T, Geater SL, Orlov S, Tsai CM, Boyer M, Su WC, Bennouna J, Kato T, Gorbunova V, Lee KH, Shah R, Massey D, Zazulina V, Shahidi M, Schuler M (2013) Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol 31:3327–3334. https://doi.org/10.1200/JCO.2012.44.2806
Wu YL, Zhou C, Hu CP, Feng J, Lu S, Huang Y, Li W, Hou M, Shi JH, Lee KY, Xu CR, Massey D, Kim M, Shi Y, Geater SL (2014) Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX-Lung 6): an open-label, randomised phase 3 trial. Lancet Oncol 15:213–222. https://doi.org/10.1016/S1470-2045(13)70604-1
Yang JC, Sequist LV, Geater SL, Tsai CM, Mok TS, Schuler M, Yamamoto N, Yu CJ, Ou SH, Zhou C, Massey D, Zazulina V, Wu YL (2015) Clinical activity of afatinib in patients with advanced non-small-cell lung cancer harbouring uncommon EGFR mutations: a combined post-hoc analysis of LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6. Lancet Oncol 16:830–838. https://doi.org/10.1016/S1470-2045(15)00026-1
Park K, Tan EH, O’Byrne K, Zhang L, Boyer M, Mok T, Hirsh V, Yang JC, Lee KH, Lu S, Shi Y, Kim SW, Laskin J, Kim DW, Arvis CD, Kölbeck K, Laurie SA, Tsai CM, Shahidi M, Kim M, Massey D, Zazulina V, Paz-Ares L (2016) Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7): a phase 2B, open-label, randomised controlled trial. Lancet Oncol 17:577–589. https://doi.org/10.1016/S1470-2045(16)30033-X
Paz-Ares L, Tan EH, O’Byrne K, Zhang L, Hirsh V, Boyer M, Yang JC, Mok T, Lee KH, Lu S, Shi Y, Lee DH, Laskin J, Kim DW, Laurie SA, Kölbeck K, Fan J, Dodd N, Märten A, Park K (2017) Afatinib versus gefitinib in patients with EGFR mutation-positive advanced non-small-cell lung cancer: overall survival data from the phase IIb LUX-Lung 7 trial. Ann Oncol 28:270–277. https://doi.org/10.1093/annonc/mdw611
Ramalingam SS, Vansteenkiste J, Planchard D, Cho BC, Gray JE, Ohe Y, Zhou C, Reungwetwattana T, Cheng Y, Chewaskulyong B, Shah R, Cobo M, Lee KH, Cheema P, Tiseo M, John T, Lin MC, Imamura F, Kurata T, Todd A, Hodge R, Saggese M, Rukazenkov Y, Soria JC, Investigators FLAURA (2020) Overall survival with osimertinib in untreated, EGFR-mutated advanced NSCLC. N Engl J Med 382:41–50. https://doi.org/10.1056/NEJMoa1913662
Cho BC, Chewaskulyong B, Lee KH, Dechaphunkul A, Sriuranpong V, Imamura F, Nogami N, Kurata T, Okamoto I, Zhou C, Cheng Y, Cho EK, Voon PJ, Lee JS, Mann H, Saggese M, Reungwetwattana T, Ramalingam SS, Ohe Y (2019) Osimertinib versus standard of care EGFR TKI as first-line treatment in patients with EGFRm advanced NSCLC: FLAURA Asian subset. J Thorac Oncol 14:99–106. https://doi.org/10.1016/j.jtho.2018.09.004
Chu MP, Ghosh S, Chambers CR, Basappa N, Butts CA, Chu Q, Fenton D, Joy AA, Sangha R, Smylie M, Sawyer MB (2015) Gastric acid suppression is associated with decreased erlotinib efficacy in non-small-cell lung cancer. Clin Lung Cancer 16:33–39. https://doi.org/10.1016/j.cllc.2014.07.005
Lam LH, Capparelli EV, Kurzrock R (2016) Association of concurrent acid-suppression therapy with survival outcomes and adverse event incidence in oncology patients receiving erlotinib. Cancer Chemother Pharmacol 78:427–432. https://doi.org/10.1007/s00280-016-3087-6
Chen YM, Lai CH, Chang HC, Chao TY, Tseng CC, Fang WF, Wang CC, Chung YH, Wang YH, Su MC, Liu SF, Huang KT, Chen HC, Chang YC, Lin MC (2016) pH-regulating drug use and de novo brain metastases in patients with epidermal growth factor receptor-mutant non-small cell lung cancer who were treated using first-line first-generation epidermal growth factor receptor tyrosine kinase inhibitors. PLoS One 11:e0149722. https://doi.org/10.1371/journal.pone.0149722
Fang YH, Yang YH, Hsieh MJ, Hung MS, Lin YC (2019) Concurrent proton-pump inhibitors increase risk of death for lung cancer patients receiving 1st-line gefitinib treatment—a nationwide population-based study. Cancer Manag Res 11:8539–8546. https://doi.org/10.2147/CMAR.S222278
Lee CH, Shen MC, Tsai MJ, Chang JS, Huang YB, Yang YH, Hsieh KP (2022) Proton pump inhibitors reduce the survival of advanced lung cancer patients with therapy of gefitinib or erlotinib. Sci Rep 12:7002. https://doi.org/10.1038/s41598-022-10938-x
Xu ZY, Li JL (2019) Comparative review of drug–drug interactions with epidermal growth factor receptor tyrosine kinase inhibitors for the treatment of non-small-cell lung cancer. Onco Targets Ther 12:5467–5484. https://doi.org/10.2147/OTT.S194870
Nakao K, Kobuchi S, Marutani S, Iwazaki A, Tamiya A, Isa S, Okishio K, Kanazu M, Tamiya M, Hirashima T, Imai K, Sakaeda T, Atagi S (2019) Population pharmacokinetics of afatinib and exposure-safety relationships in Japanese patients with EGFR mutation-positive non-small cell lung cancer. Sci Rep 9:18202. https://doi.org/10.1038/s41598-019-54804-9
Vishwanathan K, Dickinson PA, Bui K, Cassier PA, Greystoke A, Lisbon E, Moreno V, So K, Thomas K, Weilert D, Yap TA, Plummer R (2018) The effect of food or omeprazole on the pharmacokinetics of osimertinib in patients with non-small-cell lung cancer and in healthy volunteers. J Clin Pharmacol 58:474–484. https://doi.org/10.1002/jcph.1035
Ho MC, Chung YS, Lin YC, Hung MS, Fang YH (2022) Combination use of first-line afatinib and proton-pump inhibitors reduces overall survival among patients with EGFFR mutant lung cancer. Onco Targets Ther 15:1573–1582. https://doi.org/10.2147/OTT.S387165
Uryu K, Imamura Y, Shimoyama R, Mase T, Fujimura Y, Hayashi M, Ohtaki M, Otani K, Hibino M, Horiuchi S, Fukui T, Fukai R, Chihara Y, Iwase A, Yamada N, Tamura Y, Harada H, Shinozaki N, Tsuya A, Fukuoka M, Minami H (2023) Stepwise prolongation of overall survival from first to third generation EGFR-TKIs for EGFR mutation-positive non-small-cell lung cancer: the Tokushukai REAl-world Data project (TREAD 01). Jpn J Clin Oncol 54(3):319–328. https://doi.org/10.1093/jjco/hyad162
Shimoyama R, Imamura Y, Uryu K, Mase T, Fujimura Y, Hayashi M, Ohtaki M, Ohtani K, Shinozaki N, Minami H (2022) Real-world outcomes of systemic therapy in Japanese patients with cancer (Tokushukai REAl-World Data project: TREAD): study protocol for a nationwide cohort study. Healthcare (Basel, Switzerland) 10:2146. https://doi.org/10.3390/healthcare10112146
National Cancer Registry (Ministry of Health, Labour and Welfare), tabulated by Cancer Information Service, National Cancer Center, Japan. https://ganjoho.jp/reg_stat/statistics/data/dl/en.html. Accessed 28 Feb 2023
Akaike H (1973) Information theory and an extension of the maximum likelihood principle. Institute of Statistical Mathematics, pp 199–213
Saito Y, Takekuma Y, Kobayashi M, Shinagawa N, Shimizu Y, Kinoshita I, Dosaka-Akita H, Iseki K, Sugawara M (2021) Impact of histamine type-2 receptor antagonists on the anticancer efficacy of gefitinib in patients with non-small cell lung cancer. Eur J Clin Pharmacol 77:381–388. https://doi.org/10.1007/s00228-020-03013-9
Su VY, Yang KY, Huang TY, Hsu CC, Chen YM, Yen JC, Chou YC, Chang YL, He CH (2020) The efficacy of first-line tyrosine kinase inhibitors combined with co-medications in Asian patients with EGFR mutation non-small cell lung cancer. Sci Rep 10:14965. https://doi.org/10.1038/s41598-020-71583-w
Zenke Y, Yoh K, Matsumoto S, Umemura S, Niho S, Ohmatsu H, Goto K, Ohe Y (2016) Clinical impact of gastric acid-suppressing medication use on the efficacy of erlotinib and gefitinib in patients with advanced non-small-cell lung cancer harboring EGFR mutations. Clin Lung Cancer 17:412–418. https://doi.org/10.1016/j.cllc.2016.01.006
Li J, Nickens D, Wilner K, Tan W (2021) Evaluation of the effect of proton pump inhibitors on the efficacy of dacomitinib and gefitinib in patients with advanced non-small cell lung cancer and EGFR-activating mutations. Oncol Ther 9:525–539. https://doi.org/10.1007/s40487-021-00156-2
Sachs G, Shin JM, Vagin O, Lambrecht N, Yakubov I, Munson K (2007) The gastric H, K ATPase as a drug target: past, present, and future. J Clin Gastroenterol 41(Suppl 2):S226–S242. https://doi.org/10.1097/MCG.0b013e31803233b7
Asano S (2011) Molecular basis of gastric acid secretion in parietal cells. Membrane 36:278–285. https://doi.org/10.5360/membrane.36.278
Roche VF (2006) The chemically elegant proton pump inhibitors. Am J Pharm Educ 70:101. https://doi.org/10.5688/aj7005101
Yun CH, Boggon TJ, Li Y, Woo MS, Greulich H, Meyerson M, Eck MJ (2007) Structures of lung cancer-derived EGFR mutants and inhibitor complexes: mechanism of activation and insights into differential inhibitor sensitivity. Cancer Cell 11:217–227. https://doi.org/10.1016/j.ccr.2006.12.017
Stamos J, Sliwkowski MX, Eigenbrot C (2002) Structure of the epidermal growth factor receptor kinase domain alone and in complex with a 4-anilinoquinazoline inhibitor. J Biol Chem 277:46265–46272. https://doi.org/10.1074/jbc.M207135200
Shi K, Wang G, Pei J, Zhang J, Wang J, Ouyang L, Wang Y, Li W (2022) Emerging strategies to overcome resistance to third-generation EGFR inhibitors. J Hematol Oncol 15:94. https://doi.org/10.1186/s13045-022-01311-6
Ward RA, Anderton MJ, Ashton S, Bethel PA, Box M, Butterworth S, Colclough N, Chorley CG, Chuaqui C, Cross DA, Dakin LA, Debreczeni JÉ, Eberlein C, Finlay MR, Hill GB, Grist M, Klinowska TC, Lane C, Martin S, Orme JP, Smith P, Wang F, Waring MJ (2013) Structure- and reactivity-based development of covalent inhibitors of the activating and gatekeeper mutant forms of the epidermal growth factor receptor (EGFR). J Med Chem 56:7025–7048. https://doi.org/10.1021/jm400822z
Cross DA, Ashton SE, Ghiorghiu S, Eberlein C, Nebhan CA, Spitzler PJ, Orme JP, Finlay MR, Ward RA, Mellor MJ, Hughes G, Rahi A, Jacobs VN, Red Brewer M, Ichihara E, Sun J, Jin H, Ballard P, Al-Kadhimi K, Rowlinson R, Klinowska T, Richmond GH, Cantarini M, Kim DW, Ranson MR, Pao W (2014) AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. Cancer Discov 4:1046–1061. https://doi.org/10.1158/2159-8290.CD-14-0337
Durant GJ, Emmett JC, Ganellin CR, Miles PD, Parsons ME, Prain HD, White GR (1977) Cyanoguanidine-thiourea equivalence in the development of the histamine H2-receptor antagonist, cimetidine. J Med Chem 20:901–906. https://doi.org/10.1021/jm00217a007
van Vugt-Lussenburg BMA, Capinha L, Reinen J, Rooseboom M, Kranendonk M, Onderwater RCA, Jennings P (2022) ‘Commandeuring’ xenobiotic metabolism: advances in understanding xenobiotic metabolism. Chem Res Toxicol 35:1184–1201. https://doi.org/10.1021/acs.chemrestox.2c00067
Figala V, Klemm K, Kohl B, Krüger U, Rainer G, Schaefer H, Senn-Bilfinger J, Sturm E (1986) Acid activation of (H+-K+)-ATPase inhibiting 2-(2-pyridylmethyl-sulphinyl) benzimidazoles: isolation and characterisation of the thiophilic “active principle” and its reactions. J Chem Soc Chem Commun 2:125–127. https://doi.org/10.1039/C39860000125
Yamakawa T (1993) H+/K+-ATPase inhibitors. J Synth Org Chem Jpn 51:89–96. https://doi.org/10.5059/yukigoseikyokaishi.51.86
Dénès F, Pichowicz M, Povie G, Renaud P (2014) Thiyl radicals in organic synthesis. Chem Rev 114:2587–2693. https://doi.org/10.1021/cr400441m
Shin JM, Kim N (2013) Pharmacokinetics and pharmacodynamics of the proton pump inhibitors. J Neurogastroenterol Motil 19:25–35. https://doi.org/10.5056/jnm.2013.19.1.25
Moayyedi P, Eikelboom JW, Bosch J, Connolly SJ, Dyal L, Shestakovska O, Leong D, Anand SS, Störk S, Branch KRH, Bhatt DL, Verhamme PB, O’Donnell M, Maggioni AP, Lonn EM, Piegas LS, Ertl G, Keltai M, Bruns NC, Muehlhofer E, Dagenais GR, Kim JH, Hori M, Steg PG, Hart RG, Diaz R, Alings M, Widimsky P, Avezum A, Probstfield J, Zhu J, Liang Y, Lopez-Jaramillo P, Kakkar AK, Parkhomenko AN, Ryden L, Pogosova N, Dans AL, Lanas F, Commerford PJ, Torp-Pedersen C, Guzik TJ, Vinereanu D, Tonkin AM, Lewis BS, Felix C, Yusoff K, Metsarinne KP, Fox KAA, Yusuf S (2019) Safety of proton pump inhibitors based on a large, multi-year, randomised trial of patients receiving rivaroxaban or aspirin. Gastroenterology 157:682–691.e2. https://doi.org/10.1053/j.gastro.2019.05.056
Watanabe K, Shimodaira Y, Takahashi S, Fukuda S, Koizumi S, Matsuhashi T, Iijima K (2021) Potent acid suppression with vonoprazan vs proton pump inhibitors does not have higher association with Clostridioides difficile infection. Am J Gastroenterol 116:1632–1637. https://doi.org/10.14309/ajg.0000000000001309
Freedberg DE, Toussaint NC, Chen SP, Ratner AJ, Whittier S, Wang TC, Wang HH, Abrams JA (2015) Proton pump inhibitors alter specific taxa in the human gastrointestinal microbiome: a crossover trial. Gastroenterology 149:883–885.e9. https://doi.org/10.1053/j.gastro.2015.06.043
Hafiz RA, Wong C, Paynter S, David M, Peeters G (2018) The risk of community-acquired enteric infection in proton pump inhibitor therapy: systematic review and meta-analysis. Ann Pharmacother 52:613–622. https://doi.org/10.1177/1060028018760569
Bavishi C, Dupont HL (2011) Systematic review: the use of proton pump inhibitors and increased susceptibility to enteric infection. Aliment Pharmacol Ther 34:1269–1281. https://doi.org/10.1111/j.1365-2036.2011.04874.x
Xun X, Yin Q, Fu Y, He X, Dong Z (2022) Proton pump inhibitors and the risk of community-acquired pneumonia: an updated meta-analysis. Ann Pharmacother 56:524–532. https://doi.org/10.1177/10600280211039240
Acknowledgements
We gratefully acknowledge the invaluable contributions and dedications of both past and present members of the Tokushukai Respiratory and Intensive Care Division. Their unwavering commitment to excellence played a pivotal role in the success of this study. We extend our deepest appreciation to everyone for their expertise, support, and collaborative spirit that significantly enhanced the quality of our work. This work would not have been possible without the collective effort of this team.
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This study received no specific grants from any funding agency in the public, commercial, or not-for-profit sectors.
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KU, YI, and KO made substantial contributions to the study design and conception; RS, YF, and MH were responsible for data acquisition; KU, RS and YI interpreted the data and drafted the manuscript; TM, MO, MH, HS, YF, RF, YC, AI, NY, YT, HH, NS, TS, AT, MF and HM provided advice on research design and aided in the critical interpretation of this research for critical content; NS and HM comprehensively reviewed and approved the final version of this manuscript. All authors have read and approved the final version of the manuscript. Declaration of Generative AI and AI-assisted technologies in the writing process None declared.
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The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. The authors declare no actual or potential conflict of interest. Some authors have received research funding, honoraria, or scholarship donations from various pharmaceutical companies and other organizations outside of the submitted work, none of which construe actual or potential conflicts of interest. KU has received speaker and consultant honoraria from Chugai, Astra Zeneca, Boehringer-Ingelheim Japan, Bristol Myers Squibb, and Nipponkayaku. YI has received speaker bureau fees/honoraria from Bayer, Bristol-Myers Squibb, Daiichi-Sankyo, Pfizer, and Ono Pharm outside of the submitted work. RS has received speaker and consultant honoraria from Daiichi-Sankyo, Ono Parm, Taiho Parm, and Chugai. TF has received speaker and consultant honoraria from Astra Zeneca, Boehringer-Ingelheim Japan, and Chugai Pharmaceutical Co Ltd. HM has received speakers’ bureau fees/honoraria from Daiichi-Sankyo and Ono Pharm; research funding from Astellas-Amgen Biopharma, Bayer, Bristol-Myers Squibb, Chugai, Daiichi-Sankyo, Incite, Novartis, Ono Pharm, Pfizer, and Rakuten Medical; and scholarship donations from Bayer, Chugai, Daiichi-Sankyo, Eisai, Kyowa-Kirin, Lilly, Ono Pharmaceutical, Pfizer, Taiho Pharma, and Takeda outside the submitted work. These organizations had no role in the design, conduct, or reporting of the study.
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Uryu, K., Imamura, Y., Shimoyama, R. et al. Prognostic impact of concomitant pH-regulating drugs in patients with non-small cell lung cancer receiving epidermal growth factor receptor tyrosine kinase inhibitors: the Tokushukai REAl-world Data project 01-S1. Cancer Chemother Pharmacol (2024). https://doi.org/10.1007/s00280-024-04666-4
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DOI: https://doi.org/10.1007/s00280-024-04666-4