Dr Hamilton on Emi-Le: A Novel Payload ADC in Breast Cancer

Erika Hamilton, MD, director of breast cancer research at the Sarah Cannon Research Institute (SCRI), discusses the mechanism of action of emiltatug ledadotin (Emi-Le; XMT-1660), a B7-H4-directed Dolasynthen antibody-drug conjugate (ADC).

“Emiltatug ledadotin is a B7-H4 antibody-drug conjugate. I think we all understand antibody-drug conjugates at this point, but what is unique about this drug is its novel payload. It is an aristatin payload…it is not an MMAE, it's not an MMAF, it is actually a novel aristatin payload. And then B7-H4 is also a new target for us,” Hamilton explains.

Emi-Le is designed with a proprietary auristatin F-HPA microtubule inhibitor payload with a controlled bystander effect. A phase 1 trial is currently investigating Emi-Le alone for the treatment of adult patients with advanced/metastatic triple-negative breast cancer (TNBC) and hormone receptor-positive/HER2-negative breast cancer, as well as ovarian cancer and endometrial cancer.

In the dose-escalation portion of the study, patients were treated with Emi-Le at doses of 7.2-115 mg/m² per cycle, with all collected data informing the recommended doses for the dose-expansion portion of the trial. Hamilton presented findings from the phase 1 trial at the 2025 American Society of Clinical Oncology (ASCO) 2025 Annual Meeting.

“In the land of ADC resistance, we have seen some resistance of topoisomerase-1 ADCs after another topoisomerase-1 ADC. I think it is important to file this away as both a novel target as well as a novel payload,” Hamilton adds.

In January 2025, the FDA granted a new fast track designation to Emi-Le for the treatment of advanced or metastatic breast cancer, specifically targeting patients with HER2-low or HER2-negative disease, including TNBC. The designation applies to patients who have received a prior topoisomerase-1 inhibitor ADC and, for hormone receptor-positive patients, those who have either received or are ineligible for endocrine therapy. Before that, the FDA had granted fast-track designation to the agent for the treatment of adult patients with advanced or metastatic recurrent TNBC.

REFERENCE:

Hamilton EP, Han HS, Kalinsky K, et al. Initial phase 1 dose escalation data for emiltatug ledadotin (Emi-Le), a novel B7-H4-directed dolasynthen antibody-drug conjugate. J Clin Oncol. 2025;43(suppl_16):3009. doi:10.1200/JCO.2025.43.16_suppl.3009