World’s First Nectin-4-Targeting ADC Enters Phase III Trial in Triple-Negative Breast Cancer

Mabwell announced that it has initiated a randomized Phase III clinical trial of 9MW2821, its proprietary Nectin-4-targeting antibody-drug conjugate, in patients with locally advanced or metastatic triple-negative breast cancer. The study marks another step in the expansion of ADC strategies beyond established targets in this aggressive breast cancer subtype.

The open-label, controlled, multicenter study will compare 9MW2821 with investigator’s choice of chemotherapy. Eligible patients include those with locally advanced or metastatic TNBC who have previously received taxane-based chemotherapy, with or without immunotherapy, and an ADC carrying a topoisomerase inhibitor payload. This design places the trial in a clinically important post-ADC setting, where treatment options remain limited and outcomes are often poor.

Triple-negative breast cancer lacks estrogen receptor, progesterone receptor, and HER2 expression, making endocrine therapy and HER2-directed approaches ineffective. It accounts for approximately 15% to 20% of breast cancer cases globally and is generally considered one of the most aggressive breast cancer subtypes. TNBC is more frequently diagnosed in younger and premenopausal women.

The rationale for 9MW2821 is based on targeting Nectin-4, a tumor-associated antigen being explored as an ADC target across multiple cancers.

According to Mabwell, 9MW2821 is also the first Nectin-4-targeting ADC to report efficacy data in TNBC and has received FDA Fast Track Designation for locally advanced or metastatic Nectin-4-positive TNBC.

The new TNBC study is the fourth pivotal trial initiated for 9MW2821. TNBC is now the third tumor type in which the drug has entered Phase III testing, following urothelial carcinoma and cervical cancer. Mabwell has also started a U.S. clinical study of 9MW2821 in ADC-treated TNBC, with the first patient dosed in August 2025.

The trial comes as topoisomerase inhibitor-based ADCs have become important treatment options in advanced TNBC. However, after progression on these agents, many patients still return to conventional chemotherapy. If successful, 9MW2821 could help define a new ADC sequence for patients whose disease has already been exposed to taxane therapy and prior TOPi-ADC treatment.