Recent Advances in the Development of Antibody-Drug Conjugates in Urothelial Cancer

Abstract

Antibody-drug conjugates (ADCs) have joined the armamentarium against urothelial cancer (UC) as an effective therapy option. Since 2019, the US Food and Drug Administration has approved 2 ADCs for advanced previously treated UC: enfortumab vedotin, which targets nectin-4 and sacituzumab govitecan, which targets trophoblast cell-surface antigen 2. These ADCs are now being tested in earlier disease settings and in previously untreated patients. Furthermore, novel ADCs (e.g., anti–HER-2) are being tested in the clinic and show promising clinical benefit. The next frontier is to understand the mechanisms of resistance and response, gaining experience with ADC-related adverse events and learning the best strategy to sequence and combine these agents with existing therapies. Here, we highlight the recent advances in the development of ADCs for treating localized and metastatic UC.

Metastatic Penile Squamous Cell Carcinoma Responsive to Enfortumab Vedotin

“…The Nectin-4-directed ADC EV was first granted accelerated FDA approval in December 2019 and is approved for use in advanced or metastatic UC after progression on a PD-1 inhibitor and platinum-based chemotherapy [36]. The human IgG1 ADC binds to Nectin-4 on the cell surface and is internalized, allowing for the proteolytic cleavage of the microtubule-disrupting agent monomethyl auristatin E (MMAE) [12,37,38]. In a phase II trial of EV in UC, the ORR exceeded 50%; this ORR was particularly impressive given the significant pre-treatment with both platinum chemotherapies and PD-1/PD-L1 inhibitors [15].…”

“…First granted accelerated FDA approval in December 2019, the Nectin-4-directed antibody-drug conjugate (ADC) Padcev™ (enfortumab vedotin-ejfv) (EV) is approved for use in advanced or metastatic urothelial cancer after progression with a PD-1 inhibitor and platinum-based chemotherapy (if eligible) [12]. The ADC binds to Nectin-4 on the cell surface and is internalized, allowing for the proteolytic cleavage of the microtubuledisrupting agent monomethyl auristatin E (MMAE), leading to cell death.…”

The combination of immune checkpoint inhibitors and antibody-drug conjugates in the treatment of urogenital tumors: a review insights from phase 2 and 3 studies

“…SG is the first approved ADC targeting Trop-2. Originally developed as a second-line treatment for triple-negative breast cancer, SG received FDA approval in April 2021, for the treatment of aUC (receiving platinum-containing chemotherapy) and la/mUC as a second-line treatment [ 83 ].…”