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

Kiyoaki Uryu; Yoshinori Imamura; Rai Shimoyama; Takahiro Mase; Yoshiaki Fujimura; Maki Hayashi; Megu Ohtaki; Keiko Otani; Makoto Hibino; Shigeto Horiuchi; Tomoya Fukui; Ryuta Fukai; Yusuke Chihara; Akihiko Iwase; Noriko Yamada; Yukihiro Tamura; Hiromasa Harada; Nobuaki Shinozaki; Toyoshi Shimada; Asuka Tsuya; Masahiro Fukuoka; Hironobu Minami

doi:10.1007/s00280-024-04666-4

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 Apr 8. doi: 10.1007/s00280-024-04666-4. Online ahead of print.

Authors

Kiyoaki Uryu¹, Yoshinori Imamura², Rai Shimoyama³, Takahiro Mase⁴, Yoshiaki Fujimura⁵, Maki Hayashi⁶, Megu Ohtaki⁷, Keiko Otani⁷, Makoto Hibino⁸, Shigeto Horiuchi⁸, Tomoya Fukui⁹, Ryuta Fukai¹⁰, Yusuke Chihara¹¹, Akihiko Iwase¹², Noriko Yamada¹³, Yukihiro Tamura¹⁴, Hiromasa Harada¹⁵, Nobuaki Shinozaki^{3

16}, Toyoshi Shimada¹⁷, Asuka Tsuya¹⁸, Masahiro Fukuoka¹⁸, Hironobu Minami^{19

20}

Affiliations

¹ Department of Medical Oncology, Yao Tokushukai General Hospital, 1-17, Wakakusa-Cho, Yao-Shi, Osaka, 581-0011, Japan.
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. yimamura@med.kobe-u.ac.jp.
³ Department of General Surgery, Shonan Kamakura General Hospital, 1370-1, Okamoto, Kamakura, Kanagawa, 247-8533, Japan.
⁴ Department of Breast Surgery, Ogaki Tokushukai Hospital, 6-85-1, Hayashi-Cho, Ogaki-Shi, Gifu, 503-0015, Japan.
⁵ Tokushukai Information System Inc., 1-3-1-800, Umeda, Kita-Ku, Osaka, 530-0001, Japan.
⁶ Mirai Iryo Research Centre Inc., 1-8-7, Kojimachi, Chiyoda-Ku, Tokyo, 102-0083, Japan.
⁷ deCult Co., Ltd., 2-7-9, Miyajimaguchiue, Hatsukaichi-Shi, Hiroshima, 739-0413, Japan.
⁸ Department of Respiratory Medicine, Shonan Fujisawa Tokushukai Hospital, 1-5-1, Tsujidokandai, Fujisawa-Shi, Kanagawa, 251-0041, Japan.
⁹ Department of Respiratory Medicine, Shonan Kamakura General Hospital, 1370-1, Okamoto, Kamakura, Kanagawa, 247-8533, Japan.
¹⁰ Department of General Thoracic Surgery, Shonan Kamakura General Hospital, 1370-1, Okamoto, Kamakura, Kanagawa, 247-8533, Japan.
¹¹ Department of Respiratory Medicine, Uji Tokushukai Medical Centre, 145, Ishibashi, Makishima-Cho, Uji-Shi, Kyoto, 611-0041, Japan.
¹² Department of Respiratory Medicine, Chibanishi General Hospital, 107-1, Kanegasaku, Matsudo-Shi, Chiba, 270-2251, Japan.
¹³ Department of General Thoracic Surgery, Chibanishi General Hospital, 107-1, Kanegasaku, Matsudo-Shi, Chiba, 270-2251, Japan.
¹⁴ Department of General Internal Medicine, Oosumi Kanoya Hospital, Shinkawa-Cho, Kanoya-Shi, Kagoshima, 6081-1893-0015, Japan.
¹⁵ Department of Respiratory Medicine, Yao Tokushukai General Hospital, 1-17, Wakakusa-Cho, Yao-Shi, Osaka, 581-0011, Japan.
¹⁶ General Incorporated Association Tokushukai, 1-3-1, Kudanminami, Chiyoda-Ku, Tokyo, 102-0074, Japan.
¹⁷ SiHsReact Co., Ltd., 284-1, Mikami, Yasu-Shi, Shiga, 520-2323, Japan.
¹⁸ Department of Medical Oncology, Izumi City General Hospital, 4-5-1, Wake-Cho, Izumi, Osaka, 594-0073, Japan.
¹⁹ Department of Medical Oncology and Haematology, Kobe University Graduate School of Medicine, 7-5-1, Kusunoki-Cho, Chuo-Ku, Kobe, Hyougo, 650-0017, Japan.
²⁰ Cancer Centre, Kobe University Hospital, 7-5-1, Kusunoki-Cho, Chuo-Ku, Kobe, Hyougo, 650-0017, Japan.

PMID: 38584202
DOI: 10.1007/s00280-024-04666-4

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.

Keywords: Drug interaction; Epidermal growth factor receptor tyrosine kinase inhibitor; Non-small cell lung cancer; Osimertinib; Proton pump inhibitor; pH-regulating drug.