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The biology and rationale of targeting nectin-4 in urothelial carcinoma

Nature Reviews Urology volume 18, pages 93–103 (2021)Cite this article

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Abstract

Bladder cancer is the tenth most common cancer type worldwide. Urothelial carcinoma is the most common type of bladder cancer and accounts for 90% of bladder cancer cases in the USA and Europe. Novel approaches are needed to improve patient outcomes. Nectin-4 is a tumour-associated antigen found on the surface of most urothelial carcinoma cells. In the antibody–drug conjugate enfortumab vedotin, human anti-nectin-4 antibody is linked to the cytotoxic microtubule-disrupting agent monomethyl auristatin E. In ongoing phase I, II and III clinical trials, enfortumab vedotin has been evaluated as a monotherapy and in combination with a checkpoint inhibitor and/or chemotherapy in locally advanced and metastatic urothelial carcinoma. Encouraging data from the phase II study resulted in the FDA granting accelerated approval for enfortumab vedotin in December 2019 for patients with locally advanced or metastatic urothelial carcinoma who were previously treated with platinum and a checkpoint inhibitor therapy. Moreover, data from a phase I study led to the FDA granting breakthrough therapy designation to enfortumab vedotin combined with pembrolizumab as a first-line treatment in February 2020 for cisplatin-ineligible patients with locally advanced or metastatic urothelial carcinoma. Results of ongoing and future combination studies of enfortumab vedotin with immunotherapy and other novel agents are eagerly awaited.

Key points

  • The majority of patients with locally advanced or metastatic urothelial carcinoma treated with an anti-PDL1 checkpoint inhibitor immunotherapy given in the post-platinum or cisplatin-ineligible setting will fail to achieve complete remission; novel treatment approaches are needed to improve clinical outcomes for these patients.

  • An emerging target for systemic treatment of locally advanced or metastatic urothelial carcinoma is the tumour-associated antigen nectin-4, which is overexpressed in various cancer types, including 97% of urothelial carcinomas.

  • In the nectin-4 targeting antibody–drug conjugate enfortumab vedotin, human anti-nectin-4 antibody is linked to the cytotoxic microtubule-disrupting agent monomethyl auristatin E, and its preclinical activity has been successfully demonstrated in several solid tumours, including bladder cancer.

  • Enfortumab vedotin is being evaluated in ongoing phase I, II and III clinical trials either as a monotherapy or in combination with the checkpoint inhibitor pembrolizumab and/or chemotherapy in patients with locally advanced or metastatic urothelial carcinoma.

  • On the basis of data from the phase II EV-201 study, the FDA granted accelerated approval to enfortumab vedotin in December 2019 for patients with locally advanced or metastatic urothelial carcinoma whose disease has progressed on platinum and checkpoint inhibitor therapy.

  • Data from the phase Ib/II EV-103 study led to the FDA granting breakthrough therapy designation to enfortumab vedotin combined with pembrolizumab in February 2020 as a first-line treatment for cisplatin-ineligible patients with locally advanced or metastatic urothelial carcinoma.

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Fig. 1: Mechanism of action of enfortumab vedotin.
Fig. 2: Nectin-4 is a therapeutic target for urothelial carcinoma.

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  1. Karmanos Cancer Institute, Department of Oncology, Wayne State University School of Medicine, Detroit, MI, USA

    Elisabeth I. Heath

  2. Genitourinary Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Jonathan E. Rosenberg

  3. Weill Cornell Medical College, New York, NY, USA

    Jonathan E. Rosenberg

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E.I.H. researched data for the article, made a substantial contribution to discussion of content, wrote and reviewed/edited the manuscript before submission. J.E.R. wrote and reviewed/edited the manuscript before submission.

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E.I.H. and J.E.R. have received honoraria from Astellas Pharma Global Development and Seagen.

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Heath, E.I., Rosenberg, J.E. The biology and rationale of targeting nectin-4 in urothelial carcinoma. Nat Rev Urol 18, 93–103 (2021). https://doi.org/10.1038/s41585-020-00394-5

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