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Durable Response to Enfortumab Vedotin Compared to Re-challenging Chemotherapy in Metastatic Urothelial Carcinoma After Checkpoint Inhibitors

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Abstract

Background

Enfortumab vedotin (EV), an antibody–drug conjugate targeting Nectin-4, has been used for patients with metastatic urothelial carcinoma (mUC) after progressing on checkpoint inhibitors (CPIs). Re-challenging chemotherapy with platinum agents and continuing CPIs beyond progressive disease (PD) have often been chosen following PD on CPIs, and several studies indicate favorable treatment effects of re-challenging chemotherapy. There is little evidence for comparing EV and re-challenging chemotherapy in real-world clinical practice.

Objective

The aim was to reveal the real-world treatment outcomes of EV, re-challenging chemotherapy, and continuing CPIs beyond PD in mUC patients.

Patients and Methods

A multi-institutional dataset of 350 mUC patients treated with CPIs was utilized. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and duration of response (DOR) were evaluated to compare the treatment arms.

Results

One hundred and nine mUC patients were treated with EV with a median follow-up of 6.4 months. The ORR and disease control rate (DCR) were 48% and 70%, respectively. The OS from PD on pembrolizumab exhibited significant differences among the three groups, with a median OS of 8, 14, and 29 months in continuing pembrolizumab beyond PD, re-challenging chemotherapy, and EV, respectively. When comparing the survival outcomes from the initiation of the treatment, there is neither a difference in OS (p = 0.124), PFS (p = 0.936), nor ORR (p = 0.816) between EV and re-challenging chemotherapy. Notably, the DOR in patients who achieved an objective response was significantly longer in the EV group than the re-challenging chemotherapy group (a median of 11 and 5 months, p = 0.049). For OS, the difference was not statistically significant (27 and 11 months in EV and re-challenging chemotherapy, respectively: p = 0.05).

Conclusions

A superior effect of EV on patient survival compared to re-challenging chemotherapy and continuing pembrolizumab beyond PD was observed in our real-world analysis, which is attributed to the durable DOR in EV treatment despite the similar ORR to re-challenging chemotherapy.

Plain Language Summary

Enfortumab vedotin (EV) is an antibody–drug conjugate targeting Nectin-4 and is now utilized for patients with metastatic urothelial carcinoma following treatment with checkpoint inhibitors (CPIs). Until recently, repeating chemotherapy using platinum drugs or continuing CPIs were often the treatments used for these patients. In the present study, we reported real-world treatment outcomes, mainly focusing on EV and repeating chemotherapy. Although the objective responses to the treatments were comparable, the duration of response for patients responding to the treatment was significantly longer in patients treated with EV than in those repeating chemotherapy, resulting in extended survival time with EV treatment.

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Author notes

  1. Taizo Uchimoto and Shuya Tsuchida contributed equally to this work.

Authors and Affiliations

  1. Department of Urology, Osaka Medical and Pharmaceutical University, 2-7 Daigaku-machi, Takatsuki, Osaka, 569-8686, Japan

    Taizo Uchimoto, Shuya Tsuchida, Kazumasa Komura, Takuya Higashio, Takuya Matsuda, Kazuki Nishimura, Takuya Tsujino, Ko Nakamura, Tatsuo Fukushima, Kyosuke Nishio, Teruo Inamoto & Haruhito Azuma

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

    Wataru Fukuokaya, Shutaro Yamamoto, Kosuke Iwatani, Fumihiko Urabe, Keiichiro Mori, Takafumi Yanagisawa, Shunsuke Tsuduki, Jun Miki & Takahiro Kimura

  3. Department of Urology, Tokyo Medical University, 6-7-1 Nishi-shinjuku, Shinjuku-ku, Tokyo, 160-0023, Japan

    Takahiro Adachi, Yosuke Hirasawa, Takeshi Hashimoto & Yoshio Ohno

  4. Department of Urology, Fujita-Health University School of Medicine, 1-98 Dengakugakubo Kutsukake-cho, Toyoake, Aichi, 470-1192, Japan

    Atsuhiko Yoshizawa, Masanobu Saruta, Kiyoshi Takahara & Ryoichi Shiroki

  5. Department of Urology, Kindai University Faculty of Medicine, 377-2, Oono-higashi, Osakasayama, Osaka, 589-8511, Japan

    Mamoru Hashimoto, Kazutoshi Fujita & Hirotsugu Uemura

Authors
  1. Taizo Uchimoto
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Corresponding authors

Correspondence to Kazumasa Komura or Takahiro Kimura.

Ethics declarations

Funding

Kazumasa Komura was partially supported by Grant-in-Aid No. 21H03070 (Japan Society for the Promotion of Science: JSPS), the Kenzo Suzuki Memorial Foundation, the SGH Foundation, the Naito Memorial Foundation, and the Cancer Translational Research Foundation of Japanese Urological Association (JUA).

Conflict of Interest

Taizo Uchimoto, Shuya Tsuchida, Kazumasa Komura, Wataru Fukuokaya, Takahiro Adachi, Yosuke Hirasawa, Takeshi Hashimoto, Atsuhiko Yoshizawa, Masanobu Saruta, Mamoru Hashimoto, Takuya Higashio, Takuya Matsuda, Kazuki Nishimura, Takuya Tsujino, Ko Nakamura, Tatsuo Fukushima, Kyosuke Nishio, Shutaro Yamamoto, Kosuke Iwatani, Fumihiko Urabe, Keiichiro Mori, Takafumi Yanagisawa, Shunsuke Tsuduki, Kiyoshi Takahara, Teruo Inamoto, Jun Miki, Kazutoshi Fujita, Takahiro Kimura, Yoshio Ohno, Ryoichi Shiroki, Hirotsugu Uemura, and Haruhito Azuma declare that they have no conflicts of interest that might be relevant to the contents of this manuscript.

Ethics Approval

This study was approved by the Institutional Review Board (IRB) from Osaka Medical and Pharmaceutical University (approval number: RIN-750-2571, approved on 24th January 2020). This observational study adhered to ethical principles aligned with the Declaration of Helsinki, the International Conference on Harmonisation’s Good Clinical Practice guidelines, Good Pharmacoepidemiology Practices, and relevant laws for noninterventional and observational studies.

Consent to Participate

Not applicable.

Consent to Publish

Not applicable.

Data Availability

The data from this study can be accessed by academic and commercial partners upon a reasonable request, subject to IRB approval and a data use agreement. For further details or to reanalyze the study’s data, contact the Lead Contact at kazumasa.komura@ompu.ac.jp.

Code Availability

Not applicable.

Author Contributions

T. Uchimoto: conceptualization, data curation, analysis, investigation, methodology, software, visualization, writing original draft, supervision. S. Tsuchida: data curation, analysis, investigation, methodology, software, visualization. K. Komura: data curation, investigation, investigation, writing the original draft, supervision. W. Fukuokaya: investigation, data curation, validation. A. Adachi: validation, methodology. Y. Hirasawa: methodology, validation. T. Hashimoto: methodology, validation. A. Yoshizawa: data curation. M. Saruta: data curation. M. Hashimoto: analysis. T. Higashio: data curation, analysis. T. Matsuda: investigation. K. Nishimura: data curation. T. Tsujino: methodology, data curation. K. Nakamura: investigation. T. Fukushima: data curation, analysis. K. Nishio: validation. S. Yamamoto: data curation. K. Iwatani: investigation, supervision. F. Urabe: investigation, validation, supervision. K. Mori: methodology, data analysis. T. Yanagisawa: investigation. S. Tsuduki: writing original draft, review. K, Takahara: editing, supervision. T. Inamoto: data curation. J. Miki: data curation, analysis. K. Fujita: review and editing, supervision. T. Kimura: investigation, validation, supervision. Y. Ohno: supervision. R. Shiroki: supervision. H. Uemura: supervision. H. Azuma: supervision.

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Uchimoto, T., Tsuchida, S., Komura, K. et al. Durable Response to Enfortumab Vedotin Compared to Re-challenging Chemotherapy in Metastatic Urothelial Carcinoma After Checkpoint Inhibitors. Targ Oncol (2024). https://doi.org/10.1007/s11523-024-01047-y

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