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Impact of Dose-Effect in Smoking on the Effectiveness of Pembrolizumab in Patients with Metastatic Urothelial Carcinoma

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Abstract

Background

Subgroup analysis of KEYNOTE-045 suggested that cigarette smoking had a positive impact on the effectiveness of pembrolizumab in patients with advanced urothelial carcinoma (UC), whereas studies on other cancers treated with immune checkpoint inhibitors reported inconsistent results.

Objectives

This study aimed to examine the association between smoking-related factors and the effectiveness of pembrolizumab in patients with metastatic UC.

Patients and methods

This multicenter retrospective study was conducted using data from 95 patients with metastatic UC treated with pembrolizumab. The primary outcomes were progression and all-cause mortality. Time-to-event outcomes were compared with smoking history and lifetime smoking exposure at treatment initiation. Survival curves were compared using the log-rank test, with hazard ratios (HRs) estimated from Cox regression models. Cubic spline regression analysis was used to depict event hazards.

Results

We identified 32 (34.7%) patients with heavy smoking exposure (≥ 25 pack-years). Moreover, 19 (20.0%), 36 (37.9%), and 40 (42.1%) patients were current, former, and never smokers, respectively. Multivariable models showed that heavy smoking exposure was significantly associated with lower risk of progression (HR 0.58; 95% confidence interval (CI) 0.35–0.97; P = 0.047) and all-cause mortality (HR 0.30; 95% CI 0.11–0.82; P = 0.019). Cubic spline regression analyses revealed a dose-effect relationship. No significant association was observed between smoking history alone and effectiveness of pembrolizumab.

Conclusions

Lifetime smoking exposure plays a significant role in the effectiveness of pembrolizumab in patients with metastatic UC.

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Authors and Affiliations

  1. Department of Urology, The Jikei University School of Medicine, 3-25-8 Nishi-shimbashi, Minato-ku, Tokyo, 105-8461, Japan

    Wataru Fukuokaya, Takahiro Kimura, Takafumi Yanagisawa, Shoji Kimura, Shunsuke Tsuzuki, Yuhei Koike, Yuya Iwamoto, Yuki Enei, Masatoshi Tanaka, Fumihiko Urabe, Hajime Onuma, Mariko Honda, Jun Miki, Hirokazu Abe & Shin Egawa

  2. Department of Urology, Kameda Medical Center, 929 Higashi-cho, Kamogawa, Chiba, 296-8602, Japan

    Yuhei Koike & Hirokazu Abe

  3. Department of Medical Oncology, Kameda Medical Center, 929 Higashi-cho, Kamogawa, Chiba, 296-8602, Japan

    Yu Oyama

Authors
  1. Wataru Fukuokaya
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  2. Takahiro Kimura
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  3. Takafumi Yanagisawa
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  4. Shoji Kimura
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  5. Shunsuke Tsuzuki
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  6. Yuhei Koike
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  7. Yuya Iwamoto
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  8. Yuki Enei
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  9. Masatoshi Tanaka
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  10. Fumihiko Urabe
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  11. Hajime Onuma
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  12. Mariko Honda
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  13. Jun Miki
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  14. Yu Oyama
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  15. Hirokazu Abe
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  16. Shin Egawa
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Corresponding author

Correspondence to Wataru Fukuokaya.

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Funding

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

Conflict of interest

Wataru Fukuokaya, Takahiro Kimura, Takafumi Yanagisawa, Shoji Kimura, Shunsuke Tsuzuki, Yuhei Koike, Yuya Iwamoto, Yuki Enei, Masatoshi Tanaka, Fumihiko Urabe, Hajime Onuma, Mariko Honda, Jun Miki, Yu Oyama, Hirokazu Abe, and Shin Egawa declare that they have no conflicts of interest that might be relevant to the contents of this article.

Ethics approval and consent to participate

This study received the approval by the Ethics Committee of each institutions included in this study.

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All authors have approved the final version submitted.

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Not applicable.

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Author contributions

All authors made substantial contributions to the conception and design of the study, acquisition of data, analysis and interpretation of data, drafting the article, and revising it critically for important intellectual content.

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Fukuokaya, W., Kimura, T., Yanagisawa, T. et al. Impact of Dose-Effect in Smoking on the Effectiveness of Pembrolizumab in Patients with Metastatic Urothelial Carcinoma. Targ Oncol 16, 189–196 (2021). https://doi.org/10.1007/s11523-020-00786-y

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  • DOI: https://doi.org/10.1007/s11523-020-00786-y

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