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Incidence of serious adverse events caused by tyrosine kinase inhibitor treatment following immune checkpoint inhibitor therapy in advanced NSCLC patients with oncogenic driver alterations

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Abstract

Background

Sequential tyrosine kinase inhibitors (TKIs) following immune checkpoint inhibitors (ICIs) increases the incidence of serious adverse events (SAEs). However, the factors and the types of TKIs that affect the incidence of SAEs remain unknown.

Methods

We retrospectively reviewed advanced non-small cell lung cancer (NSCLC) patients who received sequential TKIs following ICIs between November 2015 and April 2021. All AEs were evaluated using Common Terminology Criteria for Adverse Events (CTCAE) ver 5.0.

Results

Among 1,638 NSCLC patients who received ICIs, 63 patients received sequential TKIs following ICIs. The types of TKIs included EGFR-TKIs in 48 patients, ALK-TKIs in 10 patients, and others in 5 patients. The median dosing interval was 57 days (range: 7–698). Eighteen (28.6%) patients developed SAEs (Grade 3/4 or hospitalized). The incidence of SAEs and withdrawal of TKIs due to AEs were significantly higher in patients (n = 40) who initiated TKI treatment within 3 months after ICIs than in patients (n = 23) who initiated TKI treatment 3 months after ICIs (SAEs, 40.0% vs. 4.3%, p < 0.01; withdrawal rate: 57.5% vs. 21.7%, p < 0.01). There was no significant difference in the incidence of SAEs and withdrawal rate due to AEs between EGFR-TKIs and other TKIs (SAE, 22.9% vs. 40.0%, p = 0.20; withdrawal rate: 41.7% vs. 53.3%, p = 0.55).

Conclusion

The dosing interval from last ICI to the initiation of TKI treatment can affects the incidence of SAEs and the withdrawal rate due to AEs regardless of the types of TKIs.

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Data availability

Data are available on reasonable request.

Abbreviations

ABCP:

Atezolizumab, bevacizumab, carboplatin, and paclitaxel

ALK:

Anaplastic lymphoma kinase

CTCAE:

Common Terminology Criteria for Adverse Events

Dab/Tra:

Dabrafenib/trametinib

ECOG:

Eastern Cooperative Oncology Group

EGFR:

Epidermal growth factor receptor

HER2:

Human epidermal growth factor receptor 2

ICI:

Immune checkpoint inhibitor

ILD:

Interstitial lung disease

MAPK:

Mitogen-activated protein kinase

MET:

C-Met

NE:

Not estimable

NRG1:

Neuregulin 1

NSCLC:

Non-small cell lung cancer

PD-1:

Programmed cell death 1

PD-L1:

Programmed death-ligand 1

PS:

Performance status

ROS1:

C-ros oncogene 1

SAE:

Serious adverse event

TKI:

Tyrosine kinase inhibitor

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Funding

The study did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Author information

Authors and Affiliations

  1. Department of Thoracic Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-Ku, Tokyo, 104-0045, Japan

    Yukiko Shimoda, Tatsuya Yoshida, Jun Miyakoshi, Masahiro Torasawa, Akiko Tateishi, Yuji Matsumoto, Ken Masuda, Yuki Shinno, Yusuke Okuma, Yasushi Goto, Hidehito Horinouchi, Noboru Yamamoto & Yuichiro Ohe

  2. Department of Experimental Therapeutics, National Cancer Center Hospital, 5-1-1, Tsukiji, Chuo-Ku, Tokyo, 104-0045, Japan

    Tatsuya Yoshida & Noboru Yamamoto

Authors
  1. Yukiko Shimoda
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Contributions

YS and TY designed the study. YS collected the clinical data. YS performed statistical data analyses, interpretation of the results, and writing of the manuscript. YS and TY drafted the manuscript. All authors read the manuscript and approved the final version.

Corresponding author

Correspondence to Tatsuya Yoshida.

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Conflict of interest

Dr. Yoshida received grants and personal fees from AstraZeneca and Bristol-Myers Squibb; grants from AbbVie, MSD, Ono Pharmaceutical, and Takeda Pharmaceutical; and personal fees from Chugai and Novartis. Dr. Matsumoto received grants from Grant-in-Aid for Scientific Research on Innovative Areas, Hitachi High-Technologies, Hitachi, Ltd., and National Cancer Center Research and Development Fund and received personal fees from AMCO INC., AstraZeneca, COOK, and Olympus. Dr. Masuda received personal fees from Chugai and AstraZeneca. Dr. Shinno received personal fees from Pfizer, AstraZeneca, and Chugai Pharmaceutical and received grants from Japan Clinical Research Operations K.K., Janssen Pharmaceutical K.K., and Ono Pharmaceutical. Dr. Okuma received grants from AbbVie. Dr. Goto received grants and personal fees from Bristol-Myers Squibb, Daiichi- Sankyo, Eli Lilly, Guardant Health, MSD, Novartis, Ono Pharmaceutical, Pfizer, and Taiho Pharmaceutical; grants from Kyorin; and personal fees from AstraZeneca, Boehringer Ingelheim, Chugai, and Illumina. Dr. Horinouchi received grants and personal fees from AstraZeneca, BMS, Chugai, Eli Lilly, MSD, Taiho Pharmaceutical, and Ono Pharmaceutical and received grants from Astellas, Genomic Health, and Merck Serono. Dr. Yamamoto received grants and personal fees from BMS, Boehringer Ingelheim, Chugai, Eisai, Eli Lilly, Ono Pharmaceutical, Pfizer, and Takeda Pharmaceutical; grants from Astellas, Bayer, Chiome Bioscience Inc., Daiichi-Sankyo, GSK, Janssen Pharma, Kyowa-Hakko kirin, MSD, Merck, Novartis, Otsuka, Taiho Pharmaceutical, Quintiles, and Sumitomo Dainippon; and received personal fees from AstraZeneca, Otsuka, Cimic, and Sysmex. Dr. Ohe received grants and personal fees from AstraZeneca, Bristol-Myers Squibb, Chugai, Eli Lilly, Janssen Pharma, Kyorin, MSD, Nippon Kayaku, Novartis, Ono Pharmaceutical, Pfizer, Taiho Pharmaceutical, and Takeda Pharmaceutical; grants from Kissei; and personal fees from Boehringer Ingelheim, and Celtrion. The remaining authors declare no competing interests.

Ethical approval

The present study with human samples has been approved by the Ethics Committee of the National Cancer Center Hospital, Tokyo, Japan (2019-123).

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Shimoda, Y., Yoshida, T., Miyakoshi, J. et al. Incidence of serious adverse events caused by tyrosine kinase inhibitor treatment following immune checkpoint inhibitor therapy in advanced NSCLC patients with oncogenic driver alterations. Cancer Immunol Immunother 72, 2613–2621 (2023). https://doi.org/10.1007/s00262-023-03429-z

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