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

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. New and more effective treatments are urgently needed for bladder cancer. This Review discusses the role of nectin-4 as a therapeutic target for enfortumab vedotin (an antibody-drug conjugate) in locally advanced and metastatic urothelial carcinoma and outlines related clinical data.

Automated summary

Bladder cancer is the tenth most common cancer type worldwide, with urothelial carcinoma being the most prevalent subtype. Enfortumab vedotin, a novel antibody-drug conjugate targeting Nectin-4, has shown promising results in clinical trials for locally advanced and metastatic urothelial carcinoma. Further research on the combination of enfortumab vedotin with immunotherapy and other agents is eagerly awaited to provide more effective treatments for bladder cancer.