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

Area of Science:

• Oncology
• Pharmacology

Background:

• Bladder cancer is a prevalent malignancy globally, with urothelial carcinoma comprising 90% of cases in the US and Europe.
• Nectin-4, a tumor-associated antigen, is highly expressed on urothelial carcinoma cells, making it a potential therapeutic target.

Purpose of the Study:

• To evaluate the efficacy and safety of enfortumab vedotin, an antibody-drug conjugate targeting Nectin-4, in patients with locally advanced or metastatic urothelial carcinoma.
• To explore the potential of enfortumab vedotin in combination therapies for urothelial carcinoma.

Main Methods:

• Enfortumab vedotin, an antibody-drug conjugate linking an anti-nectin-4 antibody to monomethyl auristatin E, was assessed in phase I, II, and III clinical trials.
• Studies included monotherapy and combination approaches with checkpoint inhibitors and/or chemotherapy.

Main Results:

• Enfortumab vedotin received accelerated FDA approval in December 2019 for previously treated advanced urothelial carcinoma.
• Breakthrough therapy designation was granted in February 2020 for enfortumab vedotin combined with pembrolizumab as a first-line treatment for cisplatin-ineligible patients.

Conclusions:

• Enfortumab vedotin demonstrates significant clinical activity and represents a promising novel therapeutic option for urothelial carcinoma.
• Ongoing and future studies are crucial to further define the role of enfortumab vedotin in combination with other agents for bladder cancer treatment.