Abstract Background: Breast cancer is the leading cause of cancer death for women worldwide, with triple-negative breast cancer (TNBC) considered one of the most aggressive sub-types and accounting for ∼15-20% of all cases. Unfortunately, there remains an unmet medical need for effective and well-tolerated treatments for advanced/metastatic TNBC, particularly for patients who have received a prior standard-of-care topoisomerase-1 inhibitor (topo-1) ADC. In heavily pretreated patients, standard-of-care single-agent chemotherapy has limited efficacy, with response rates of ∼5%, median PFS ∼7 weeks, median OS ∼6.7 months. Emiltatug ledadotin (Emi-Le; XMT-1660) is a B7-H4-directed Dolasynthen ADC designed with a precise, target-optimized drug-to-antibody ratio (DAR 6) and a proprietary auristatin F-HPA microtubule inhibitor payload with controlled bystander effect. The FDA has granted Emi-Le two Fast Track designations for the treatment of adult patients with certain breast cancers, including patients with advanced or metastatic TNBC and patients with advanced or metastatic HER-2 low / HER-2 negative breast cancer who have previously been treated with topo-1 ADCs. As of March 8, 2025 data cutoff, treatment was generally well tolerated in the dose escalation portion of the ongoing Phase 1 trial. In patients with TNBC dosed with 38.1-67.4 mg/m2 per cycle, the most common TRAEs were transient AST increase (43%, G3 18%), fatigue (32%, G3 0%), typically asymptomatic proteinuria (30%, G3 7%), and nausea (27%, G3 2%). In patients with B7-H4 high TNBC dosed with 38.1-67.4 mg/m2 per cycle dose range, all of whom were heavily pretreated and had received at least one prior topo-1 ADC, interim clinical data demonstrated: 23% (3/13) confirmed response rate overall; 29% (2/7) in patients with ≤4 prior lines in locally advanced/metastatic setting; a preliminary median PFS of 16 weeks (6.1, NR) and a median OS not yet reached in patients with ≤4 prior lines in the locally advanced/metastatic setting. Method: Based on these encouraging clinical activity and tolerability data, the expansion portion (EXP) of the Phase 1 trial has been initiated and is actively enrolling patients with TNBC who have received 1-4 prior lines of systemic therapy in the advanced/metastatic setting, including at least one topo-1 ADC. EXP has a Simon 2-stage design and will evaluate two dosing regimens: 67.4 mg/m2 Q4W or 80 mg/m2 Q4W with a 44.5 mg/m2 loading dose on days 1 and 8 of the first 4-week cycle. Patients are being evaluated for B7-H4 expression by IHC and are stratified into B7-H4 TPS “high” and B7-H4 TPS “low” cohorts. NCT05377996 Citation Format: N. Abuhadra, A. Giordano, K. M. Kalinsky, H. Han, N. P. McAndrew, A. I. Spira, K. C. Kelley, J. A. O'Shaughnessy, D. Starks, N. Chan, R. Parajuli, G. M. Wulf, A. Chaudhry, J. S. Wang, F. Meric-Bernstam, A. Tiersten, A. M. Weise, D. L. Richardson, P. A. Robinson, L. A. Huppert, C. Rogalski, N. Zizlsperger, A. Reske, E. P. Hamilton. Emiltatug Ledadotin (Emi-Le): A B7-H4-Directed Dolasynthen Antibody-Drug Conjugate (ADC) Being Investigated in Phase 1 Dose Expansion in Patients with Triple Negative Breast Cancer who Received at Least One Prior Topoisomarase-1 Inhibitor ADC abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS1-08-23.
Abuhadra et al. (2026) studied this question.