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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

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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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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.

Funding

This study received no specific grants from any funding agency in the public, commercial, or not-for-profit sectors.

Author information

Authors and Affiliations

  1. Department of Medical Oncology, Yao Tokushukai General Hospital, 1-17, Wakakusa-Cho, Yao-Shi, Osaka, 581-0011, Japan

    Kiyoaki Uryu

  2. Department of Medical Oncology and Haematology, Kobe University Graduate School of Medicine, 7-5-1, Kusunoki-Cho, Chuo-Ku, Kobe, Hyougo, 650-0017, Japan

    Yoshinori Imamura & Hironobu Minami

  3. Department of General Surgery, Shonan Kamakura General Hospital, 1370-1, Okamoto, Kamakura, Kanagawa, 247-8533, Japan

    Rai Shimoyama & Nobuaki Shinozaki

  4. Department of Breast Surgery, Ogaki Tokushukai Hospital, 6-85-1, Hayashi-Cho, Ogaki-Shi, Gifu, 503-0015, Japan

    Takahiro Mase

  5. Tokushukai Information System Inc., 1-3-1-800, Umeda, Kita-Ku, Osaka, 530-0001, Japan

    Yoshiaki Fujimura

  6. Mirai Iryo Research Centre Inc., 1-8-7, Kojimachi, Chiyoda-Ku, Tokyo, 102-0083, Japan

    Maki Hayashi

  7. deCult Co., Ltd., 2-7-9, Miyajimaguchiue, Hatsukaichi-Shi, Hiroshima, 739-0413, Japan

    Megu Ohtaki & Keiko Otani

  8. Department of Respiratory Medicine, Shonan Fujisawa Tokushukai Hospital, 1-5-1, Tsujidokandai, Fujisawa-Shi, Kanagawa, 251-0041, Japan

    Makoto Hibino & Shigeto Horiuchi

  9. Department of Respiratory Medicine, Shonan Kamakura General Hospital, 1370-1, Okamoto, Kamakura, Kanagawa, 247-8533, Japan

    Tomoya Fukui

  10. Department of General Thoracic Surgery, Shonan Kamakura General Hospital, 1370-1, Okamoto, Kamakura, Kanagawa, 247-8533, Japan

    Ryuta Fukai

  11. Department of Respiratory Medicine, Uji Tokushukai Medical Centre, 145, Ishibashi, Makishima-Cho, Uji-Shi, Kyoto, 611-0041, Japan

    Yusuke Chihara

  12. Department of Respiratory Medicine, Chibanishi General Hospital, 107-1, Kanegasaku, Matsudo-Shi, Chiba, 270-2251, Japan

    Akihiko Iwase

  13. Department of General Thoracic Surgery, Chibanishi General Hospital, 107-1, Kanegasaku, Matsudo-Shi, Chiba, 270-2251, Japan

    Noriko Yamada

  14. Department of General Internal Medicine, Oosumi Kanoya Hospital, Shinkawa-Cho, Kanoya-Shi, Kagoshima, 6081-1893-0015, Japan

    Yukihiro Tamura

  15. Department of Respiratory Medicine, Yao Tokushukai General Hospital, 1-17, Wakakusa-Cho, Yao-Shi, Osaka, 581-0011, Japan

    Hiromasa Harada

  16. General Incorporated Association Tokushukai, 1-3-1, Kudanminami, Chiyoda-Ku, Tokyo, 102-0074, Japan

    Nobuaki Shinozaki

  17. SiHsReact Co., Ltd., 284-1, Mikami, Yasu-Shi, Shiga, 520-2323, Japan

    Toyoshi Shimada

  18. Department of Medical Oncology, Izumi City General Hospital, 4-5-1, Wake-Cho, Izumi, Osaka, 594-0073, Japan

    Asuka Tsuya & Masahiro Fukuoka

  19. Cancer Centre, Kobe University Hospital, 7-5-1, Kusunoki-Cho, Chuo-Ku, Kobe, Hyougo, 650-0017, Japan

    Hironobu Minami

Authors
  1. Kiyoaki Uryu
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  2. Yoshinori Imamura
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  3. Rai Shimoyama
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  4. Takahiro Mase
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  5. Yoshiaki Fujimura
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  6. Maki Hayashi
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  7. Megu Ohtaki
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  8. Keiko Otani
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  9. Makoto Hibino
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  10. Shigeto Horiuchi
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  11. Tomoya Fukui
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  12. Ryuta Fukai
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  13. Yusuke Chihara
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  14. Akihiko Iwase
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  15. Noriko Yamada
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  16. Yukihiro Tamura
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  17. Hiromasa Harada
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  18. Nobuaki Shinozaki
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  19. Toyoshi Shimada
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  20. Asuka Tsuya
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  21. Masahiro Fukuoka
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  22. Hironobu Minami
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Contributions

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.

Corresponding author

Correspondence to Yoshinori Imamura.

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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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