Breaking Ground: The First Nectin-4 Targeted ADC Approved in China – Urothelial Carcinoma

Urothelial Carcinoma

#UrothelialCarcinoma #Nectin4 #ADC

On August 19, the National Medical Products Administration (NMPA) of China officially approved the innovative antibody-drug conjugate (ADC), Enfortumab Vedotin, developed by Astellas and Pfizer. This groundbreaking approval marks the first Nectin-4 targeted ADC to receive approval in China, providing a new treatment option for patients with locally advanced or metastatic urothelial carcinoma who have previously undergone treatment with PD-1/PD-L1 inhibitors and platinum-based chemotherapy.

Nectin-4, a protein found on the surface of cells, is highly expressed in bladder cancer. Enfortumab Vedotin, co-developed by Astellas and Seagen (a Pfizer subsidiary), is a first-in-class ADC that directly targets Nectin-4. By binding to cells expressing this protein, the drug delivers the potent anti-tumor agent monomethyl auristatin E (MMAE) into the cells, halting cell proliferation and inducing programmed cell death.

This ADC had already secured approvals in the United States, Japan, and the European Union for treating urothelial carcinoma. Now, with its approval in China, Enfortumab Vedotin stands as a beacon of hope for Chinese patients battling this challenging form of cancer.

The approval in China was based on data from the EV-203 study (NCT04995419), a phase II, single-arm, open-label, multi-center clinical trial conducted in China. The trial assessed the efficacy, safety, and pharmacokinetics of Enfortumab Vedotin in Chinese patients with locally advanced or metastatic urothelial carcinoma who had been treated with PD-1/PD-L1 inhibitors and platinum-based chemotherapy.

The study enrolled 40 Chinese patients, with the primary endpoint being the independent review committee (IRC) confirmed objective response rate (ORR). Results presented at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting revealed:

– An IRC-confirmed ORR of 37.5%, including one complete response (2.5%) and 14 partial responses (35.0%).

– A disease control rate (DCR) of 82.5% as per investigator assessment and 72.5% as per IRC evaluation.

– Median progression-free survival (PFS) was 4.24 months according to investigators and 4.67 months per IRC assessment.

– Median overall survival (OS) had not been reached at the time of analysis, with a median follow-up of 6.5 months.

The safety profile was manageable, with most treatment-related adverse events (TRAEs) being grade 1-2. These results underscore Enfortumab Vedotin’s meaningful clinical activity and a favorable benefit-risk profile in this patient population.

Astellas is also progressing with a second indication for Enfortumab Vedotin in China. In March 2024, the company submitted an application for its use in combination with the PD-1 inhibitor pembrolizumab as a first-line treatment for adults with locally advanced or metastatic urothelial carcinoma who have not previously received treatment. Insight data predicts that this application could be approved as early as the third quarter of 2025.

Beyond Enfortumab Vedotin, there are over a dozen Nectin-4 targeted ADC projects under development in China. Among them, the most advanced is 9MW2821 from Mabwell, currently in phase III trials for urothelial carcinoma. Other promising candidates include SHR-A2102 from Hengrui, SYS6002 from CSPC, SKB410 from Kelun-Biotech, ADRX-0706 from Dizal/Adcentrx, and BAT8007 from Bio-Thera, all of which have entered clinical stages.