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Prospective evaluation of the relationship between response and exposure of total and unbound erlotinib in non-small cell lung cancer patients

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Abstract

Purpose

To evaluate the relationship between treatment efficacy and exposure of total and unbound erlotinib in patients with non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR)-activating mutations.

Patients and Methods

EGFR-tyrosine kinase inhibitor naïve NSCLC patients were enrolled, and erlotinib was started at 150 mg/day. Total and unbound exposure of erlotinib were prospectively evaluated.

Results

Of the 70 enrolled patients, 61 had EGFR-activating mutations (30 patients with exon 19 deletions, 31 patients with L858R). The median area under the concentration-time curve from 0 to 24 h (AUC0-24) of total and unbound erlotinib on day 1 was 37,004 ng·h/mL (range, 9683–63,257 ng·h/mL) and 2338 ng·h/mL (581–5904 ng·h/mL), respectively. The median progression-free survival (PFS) was 10.9 months, and PFS did not differ between each tertile of total and unbound AUC0-24 on day 1 in 59 patients with EGFR-activating mutations. The worst grade of skin toxicities was significantly correlated with total trough concentration at steady state (Ctrough,ss) at each visit for 3 months after the initiation of erlotinib treatment (P < 0.0001). Total and unbound Ctrough,ss on day 7–15 in 20 patients whose dose was reduced due to intolerable toxicities was significantly higher than those in 48 patients whose dose was unchanged for 3 months (P = 0.0046, 0.0008).

Conclusion

The lack of relationship between efficacy and exposure of total and unbound erlotinib demonstrates that the standard dose of 150 mg/day is sufficient for the treatment of NSCLC harboring EGFR-activating mutations, despite wide inter-individual variability in exposure and dose reduction.

Clinical trials registration number: UMIN000012862.

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Data availability

The datasets generated and analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

We thank all the patients who participated in this study and their families. We also thank Ms. Mie Yamada, Ms. Chiemi Asano, and Ms. Miho Watanabe (Division of Thoracic Oncology, Shizuoka Cancer Center) for study management; Ms. Yumiko Iwamoto, Ms. Miyuki Sugiyama, and Ms. Satomi Koizumi (Nursing Department, Shizuoka Cancer Center) for blood sampling; and Dr. Ryo Ko, Dr. Norimitsu Kasahara, Dr. Haruki Kobayashi, and Dr. Takumi Fujiwara (Division of Thoracic Oncology, Shizuoka Cancer Center) for their contributions to this study.

Funding

This work was supported by JSPS KAKENHI Grant Number JP16K09568.

Author information

Authors and Affiliations

  1. Department of Clinical Pharmacokinetics and Pharmacodynamics, Keio University School of Medicine, Tokyo, Japan

    Hirotsugu Kenmotsu, Chiyo K. Imamura, Takahisa Kawamura & Yusuke Tanigawara

  2. Division of Thoracic Oncology, Shizuoka Cancer Center, Shizuoka, Japan

    Hirotsugu Kenmotsu, Takahisa Kawamura, Shota Omori, Kazuhisa Nakashima, Kazushige Wakuda, Akira Ono, Tetsuhiko Taira, Tateaki Naito, Haruyasu Murakami & Toshiaki Takahashi

  3. Advanced Cancer Translational Research Institute, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142-8555, Japan

    Chiyo K. Imamura

  4. Division of Cardiology, Shizuoka Cancer Center, Shizuoka, Japan

    Takuya Oyakawa

  5. Third Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan

    Nobuyuki Yamamoto

Authors
  1. Hirotsugu Kenmotsu
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  2. Chiyo K. Imamura
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  3. Takahisa Kawamura
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  4. Takuya Oyakawa
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  5. Shota Omori
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  6. Kazuhisa Nakashima
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  7. Kazushige Wakuda
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  8. Akira Ono
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  9. Tetsuhiko Taira
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  10. Tateaki Naito
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  11. Haruyasu Murakami
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  12. Nobuyuki Yamamoto
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  13. Toshiaki Takahashi
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  14. Yusuke Tanigawara
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Corresponding author

Correspondence to Chiyo K. Imamura.

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Competing interests

Dr. Kenmotsu reported of grants and personal fees from Chugai Pharmaceutical Co., Ltd., during the conduct of the study; personal fees from Ono Pharmaceutical Co., Ltd., grants and personal fees from Nippon Boeringer Ingelheim Co., Ltd, personal fees from Eli Lilly Japan K.K., personal fees from Kyowa Kirin Co., Ltd., personal fees from Bristol-Myers Squibb K.K., personal fees from MSD K.K., grants and personal fees from Novartis Pharma K.K., personal fees from Daiichi Sankyo Co., Ltd., grants and personal fees from AstraZeneca K.K., personal fees from Pfizer Japan Inc., and personal fees from Taiho Pharmaceutical Co., Ltd., outside the submitted work. Dr. Imamura reported personal fees from Chugai Pharmaceutical Co., Ltd. and grants from Otsuka Pharmaceutical Co., Ltd. outside the submitted work. Dr. Kawamura reported personal fees from AstraZeneca K.K. outside the submitted work. Dr. Omori reported personal fees from Chugai Pharmaceutical Co., Ltd., personal fees from Daiichi Sankyo Co., Ltd., personal fees from Ono Pharmaceutical Co., Ltd., personal fees from Novartis Pharma K.K., personal fees from MSD K.K., and personal fees from AstraZeneca K.K. outside the submitted work. Dr. Nakashima reported personal fees from Taiho Phamaceutical Co., Ltd., personal fees from Chugai Pharmaceutical Co., Ltd., personal fees from AstraZeneca K.K., personal fees from Nippon Boehringer Ingelheim Co., Ltd., and personal fees from Nippon Kayaku Co., Ltd. outside the submitted work. Dr. Wakuda reported grants and personal fees from Chugai Pharmaceutical Co., Ltd., personal fees from Taiho Pharmaceutical Co., Ltd., personal fees from Nippon Boehringer Ingelheim Co., Ltd., personal fees from Eli Lilly Japan K.K., personal fees from Ono Pharmaceutical Co., Ltd., personal fees from MSD K.K., grants and personal fees from AstrazZeneca K.K., grants from Novartis Pharma K.K., and grants from AbbVie GK outside the submitted work. Dr. Ono reported personal fees from AstraZeneca K.K., personal fees from Ono Pharmaceutical Co., Ltd., personal fees from Chugai Pharmaceutical Co., Ltd., and personal fees from Novartis Pharma K.K. outside the submitted work. Dr. Taira reported personal fees from Kyowa Kirin Co., Ltd., personal fees from Chugai Pharmaceutical Co., Ltd., personal fees from Eli Lilly Japan K.K., personal fees from Taiho Pharmaceutical Co., Ltd., and personal fees from Daiichi Sankyo Co., Ltd. outside the submitted work. Dr. Naito reported personal fees from Ono Pharmaceutical Co., Ltd. outside the submitted work. Dr. Murakami reported grants and personal fees from AstraZeneca K.K., Pfizer Japan Inc., personal fees from Eli Lilly Japan K.K., grants and personal fees from Chugai Pharmaceutical Co., Ltd., grants and personal fees from Taiho Pharmaceutical Co., Ltd., grants from AbbVie GK, grants and personal fees from Daiichi Sankyo Co., Ltd., grants from IQVIA Japan K.K., personal fees from Bristol-Myers Squibb K.K., personal fees from Ono Pharmaceutical Co., Ltd., personal fees from MSD K.K., personal fees from Takeda Pharmaceutical Co., Ltd., personal fees from Nippon Boehringer Ingelheim Co., Ltd., and personal fees from Novartis Pharma K.K. outside the submitted work. Dr. Yamamoto reported grants and personal fees from MSD K.K., grants and personal fees from AstraZeneca K.K., grants and personal fees from Ono Pharmaceutocal Co., Ltd., personal fees from Thermo Fisher Scientific K.K., grants and personal fees from Daiichi Sankyo Co., Ltd., grants and personal fees from Taiho Pharmaceutical Co., Ltd., grants and personal fees from Takeda Pharmaceutical Co., Ltd., grants and personal fees from Chugai Pharmaceutical Co., Ltd., grants and personal fees from Eli Lilly Japan K.K., grants and personal fees from Nippon Boehringer-Ingelheim Co., Ltd., grants and personal fees from Novartis Pharma K.K., grants and personal fees from Pfizer Japan Inc., personal fees from Bristol-Myers Squibb K.K., personal fees from Life Technologies Japan Ltd., personal fees from Nippon Kayaku Co., Ltd., personal fees from Merck Biopharma Co., Ltd., grants from Astellas Pharma Inc., grants from Tsumura & Co., grants from Shionogi & Co., Ltd., grants from AbbVie GK., grants from Amgen Inc., grants from Kyorin Pharmaceutical Co., Ltd., grants from Eisai Co., Ltd., grants from Terumo Medical Co., grants from Toppan IncInc., and grants from Tosoh Co. outside the submitted work. Dr. Takahashi reported grants and personal fees from AstraZeneca K.K., grants and personal fees from Chugai Pharmaceutical Co., Ltd., grants and personal fees from Eli Lilly Japan K.K., grants and personal fees from Ono Pharmaceutical Co., Ltd., grants and personal fees from MSD K.K., grants and personal fees from Pfizer Japan Inc., personal fees from Nippon Boehringer Ingelheim Co. Ltd., and personal fees from Roche Diagnostics K.K. outside the submitted work. Dr. Tanigawara reported personal fees from Chugai Pharmaceutical Co., Ltd., grants from Millennium Pharmaceuticals Inc., and grants from Taiho Pharmaceutical Co. Ltd. outside the submitted work. All remaining authors have declared no conflicts of interest.

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280_2022_4452_MOESM1_ESM.pdf

Fig. S1 Association between AUC0-24 on day 1 and each concentration at the sampling point. (A) Administration after 2 h (C2), (B) after 4 h (C4), (C) after 6 h (C6), (D) after 12 h (C12), (E) after 24 h (C24), (F) trough concentration at steady state (Ctrough,ss) on day 7–15. Fig. S2 Correlation between the degree of unbound fraction and plasma protein level. (A) AAG α1-acid glycoprotein, (B) ALB Albumin Supplementary file1 (PDF 154 KB)

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Kenmotsu, H., Imamura, C.K., Kawamura, T. et al. Prospective evaluation of the relationship between response and exposure of total and unbound erlotinib in non-small cell lung cancer patients. Cancer Chemother Pharmacol 90, 115–123 (2022). https://doi.org/10.1007/s00280-022-04452-0

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  • DOI: https://doi.org/10.1007/s00280-022-04452-0

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