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Clinical Efficacy and Safety of First- or Second-Generation EGFR-TKIs after Osimertinib Resistance for EGFR Mutated Lung Cancer: A Prospective Exploratory Study

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Abstract

Background

Osimertinib monotherapy is a common treatment for epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC); however, standard treatment strategies for acquired resistance to this drug have not been established. In addition, the clinical significance of first-generation (1G) or second-generation (2G) EGFR-tyrosine kinase inhibitors (TKI) in patients with EGFR-mutant NSCLC and osimertinib resistance has not yet been fully evaluated.

Objective

We aimed to conduct a prospective multicenter observational study to evaluate the efficacy and safety of 1G and 2G EGFR-TKIs after the development of osimertinib resistance.

Methods

Patients with EGFR-mutant NSCLC who received 1G or 2G EGFR-TKIs after developing resistance to osimertinib monotherapy were prospectively assessed at eight institutions in Japan. The primary endpoint was progression-free survival (PFS).

Results

A total of 29 patients with advanced or recurrent EGFR-mutant NSCLC were analyzed. The objective response and disease control rates were 6.9% (2/29) and 58.6% (17/29), respectively. The median PFS was 1.9 months [95% confidence interval (CI): 1.3–5.3]. There was no significant difference in PFS between the 1G and 2G EGFR-TKI groups (3.7 versus 1.5 months, log-rank test p = 0.20). However, patients with normal cytokeratin 19 fragment (CYFRA 21-1) and pro-gastrin-releasing peptide (ProGRP) levels experienced longer PFS than those with elevated CYFRA 21-1 and/or ProGRP (5.5 versus 1.3 months, log-rank test p < 0.001).

Conclusion

Administration of 1G or 2G EGFR-TKIs after the development of osimertinib resistance has limited efficacy in patients with EGFR-mutant NSCLC. Moreover, normal CYFRA 21-1 and ProGRP levels could be promising indicators for 1G and 2G EGFR-TKI administration after osimertinib resistance development.

Trial Registration Number

UMIN000044049.

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Acknowledgments

The authors sincerely appreciate the contributions of all the physicians and patients who participated in this study.

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Authors and Affiliations

  1. Department of Pulmonary Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kajii-cho, Kamigyo-ku, Kyoto, Japan

    Kenji Morimoto, Tadaaki Yamada, Yuki Katayama, Masahiro Iwasaku, Shinsaku Tokuda & Koichi Takayama

  2. Department of Respiratory Medicine, Japanese Red Cross Kyoto Daini Hospital, Kyoto, Japan

    Takayuki Takeda & Yusuke Kunimatsu

  3. Department of Respiratory Medicine, Japanese Red Cross Kyoto Daiichi Hospital, Kyoto, Japan

    Shinsuke Shiotsu

  4. Department of Pulmonary Medicine, Kyoto Chubu Medical Center, Kyoto, Japan

    Koji Date

  5. Department of Pulmonary Medicine, Rakuwakai Otowa Hospital, Kyoto, Japan

    Nobuyo Tamiya

  6. Department of Respiratory Medicine, Fujita Health University School of Medicine, Aichi, Japan

    Yasuhiro Goto

  7. Department of Respiratory Medicine, Omi Medical Center, Shiga, Japan

    Hibiki Kanda

  8. Department of Respiratory Medicine, Uji-Tokushukai Medical Center, Kyoto, Japan

    Yusuke Chihara

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  1. Kenji Morimoto
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Corresponding author

Correspondence to Tadaaki Yamada.

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Funding

No external funding was used in the preparation of this manuscript.

Conflicts of Interest

Tadaaki Yamada received grants from Pfizer, Ono Pharmaceutical, Janssen Pharmaceutical, AstraZeneca, and Takeda Pharmaceutical as well as personal fees from Eli Lilly. Koichi Takayama received grants from Chugai Pharmaceutical and Ono Pharmaceutical as well as personal fees from AstraZeneca, Chugai Pharmaceutical, MSD, Eli Lilly, Boehringer Ingelheim, and Daiichi Sankyo. Kenji Morimoto, Takayuki Takeda, Shinsuke Shiotsu, Koji Date, Nobuyo Tamiya, Yasuhiro Goto, Hibiki Kanda, Yusuke Chihara, Yusuke Kunimatsu, Yuki Katayama, Masahiro Iwasaku, and Shinsaku Tokuda declare that they have no conflicts of interest that might be relevant to the contents of this manuscript.

Availability of Data and Material

The datasets generated during the current study are not publicly available because of ethical constraints. However, they are available from the corresponding author upon reasonable request.

Ethics Approval

This study was approved by the Institutional Review Board of Kyoto Prefectural University of Medicine (ERB-C- 1731) and each participating hospital, registered at the University Medical Hospital Information Network (UMIN) Clinical Trials Registry (UMIN000044049), and performed in accordance with the Declaration of Helsinki.

Consent to Participate

All patients provided written informed consent prior to participation in this prospective study. In addition, opt-out informed consent was provided at each hospital where the trial was conducted.

Code Availability

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Author Contributions

TY was responsible for conceptualization, methodology, formal analysis, writing-original draft preparation, writing-review and editing, and supervision, KM for methodology, investigation, formal analysis, writing-original draft preparation, writing-review and editing, project administration, and data curation; TT for methodology; Shinsuke Shiotsu for investigation; Koji Date for investigation; Nobuyo Tamiya for investigation; YG for investigation; Hibiki Kanda for investigation; YC for investigation; YK for investigation; YK for project administration and data curation; MI for project administration and data curation; ST for project administration and data curation; and KT for writing-original draft preparation, writing-review and editing, and supervision.

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Morimoto, K., Yamada, T., Takeda, T. et al. Clinical Efficacy and Safety of First- or Second-Generation EGFR-TKIs after Osimertinib Resistance for EGFR Mutated Lung Cancer: A Prospective Exploratory Study. Targ Oncol 18, 657–665 (2023). https://doi.org/10.1007/s11523-023-00991-5

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