Emiltatug Ledadotin Shows Early Clinical Activity and Safety in Advanced/Metastatic TNBC

Advanced/Metastatic TNBC | Image
Credit: © Sebastian Kaulitzki
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Treatment with emiltatug Ledadotin (Emi-Le; XMT-1660) at intermediate doses demonstrated preliminary clinical activity and tolerability in heavily pretreated patients with locally advanced/metastatic triple-negative breast cancer (TNBC) who were previously treated with a topoisomerase-1 antibody-drug conjugate (ADC), according to preliminary data from the dose escalation and backfill cohorts of an ongoing phase 1 trial (NCT05377996) presented at the 2025 ESMO Breast Congress.1

Among evaluable patients with B7-H4–high TNBC (n = 13), the confirmed objective response rate (ORR) with Emi-Le at this dose level was 23% (95% CI, 5%-54%). Evaluable patients were heavily pretreated, and all had previously received at least 1 topoisomerase-1 ADC. Notably, patients who received 4 or fewer prior lines in the locally advanced or metastatic setting (n = 7) achieved an ORR of 29%. However, there were no observed responses in patients with B7-H4–low TNBC.

The median progression-free survival (PFS) with Emi-Le was 16 weeks (95% CI, 6.1-not reached [NR]) for patients with B7-H4–high TNBC who received 4 or fewer prior lines of treatment vs 6.7 weeks (95% CI, 1.6-NR) in those who received more than 4 prior treatments. Patients with B7-H4–low disease who received 4 or fewer lines of therapy achieved a median PFS of 6.4 weeks (95% CI, 4.1-12.4.

Similar trends in overall survival (OS) were observed. The median OS with Emi-Le was not reached (95% CI, 11-NR) among patients with B7-H4–high disease treated with 4 or fewer prior lines of treatment vs 10.2 months (95% CI, 3.4-NR) in patients treated with more than 4 prior lines of therapy. Patients with B7-H4–low TNBC who received 4 or fewer lines of therapy achieved a median OS of 5.7 months (95% CI, 3.2-NR).

“There's a high unmet medical need for patients with metastatic TNBC following treatment with a topoisomerase-1 ADC,” Erika P. Hamilton, MD, a medical oncologist and director of the breast and gynecologic research program at Sarah Cannon Research Institute in Nashville, Tennessee, stated in a presentation of the data. “The preliminary data [with] Emi-Le shows quite encouraging clinical activity and tolerability among patients who have already received a topoisomerase-1 ADC, with a 23% ORR among patients with B7-H4–high disease and a 29% ORR if we select for patients with 4 or fewer therapies.”

Trial Design and Patient Characteristics

Emi-Le is a homogeneous DAR 6 dolasynthen ADC, with site-specific bioconjugation and a proprietary auristatin payload.2

The phase 1 dose escalation and expansion study included patients 18 years of age or older with advanced or metastatic TNBC, hormone receptor–positive/HER2-negative breast cancer, endometrial cancer, ovarian cancer, or adenoid cystic carcinoma type 1.1 Patients were required to have experienced disease progression following standard-of-care treatment for their respective tumor types, and have an ECOG performance status of 0 or 1.

Notably, B7-H4 expression in tumors was evaluated retrospectively. Along with the dose escalation study, backfill cohorts are enrolling more patients at various dose levels of Emi-Le. Data from the dose escalation portion of the study and backfill cohorts will be assessed to determine the recommended phase 2 dose.

Three dose ranges were evaluated in the study: the subtherapeutic dose, which ranged from 7.2 mg/m2 to 28.7 mg/m2 (n = 16); the intermediate dose range of 38.1 mg/m2 to 67.4 mg/m2 (n = 83); and the high dose range of 76.2 mg/m2 to 115.0 mg/m2 (n = 42).

The study’s primary end points were identification of the maximum tolerated dose and safety. Secondary end points include ORR, duration of response, disease control rate, pharmacokinetics, and antidrug antibodies.

The median age of patients with TNBC who were treated at an intermediate dose was 49.5 years. Patients received a median of 4 (range, 1-9) prior lines of therapy in the locally advanced/metastatic setting. The majority of patients (93.2%) were previously treated with either fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) or sacituzumab govitecan (Trodelvy); this included 31.8%, 86.4%, and 25.0% of patients who received prior T-DXd, sacituzumab govitecan, or both, respectively. Tumor proportion score (TPS) was known for 81.8% of patients, including those with high (TPS ≥ 70; 38.9%) and low (TPS < 70; 61.1%) expression.

Additional Safety Data and Future Directions

At the data cutoff of March 8, 2025, 2 patients had experienced treatment-related adverse effects (TRAEs) that led to treatment discontinuation, which included nephrotic syndrome in a patient with concurrent gout flare (n = 1) and pain in the extremity (n = 1).

Of note, no dose-limiting treatment-related neuropathy, neutropenia, ocular toxicity, thrombocytopenia, or interstitial lung disease were observed.

Among all patients with TNBC in the intermediate dose range (n = 44), 77.3% experienced any-grade TRAEs, with grade 3 TRAEs in 36.4%. Treatment-related serious AEs (SAEs) were observed in 6.8% of patients. Additionally, TRAEs leading to treatment discontinuation, dose reduction, dose delay, and death were reported in 4.5%, 9.1%, 6.8%, and 0% of patients, respectively.

“Further clinical development of Emi-Le is ongoing at the dose expansion. These are specifically patients who have received 1 to 4 prior [lines of treatment]. We’re looking across 2 dose cohorts: 67.4 mg/m2 every 4 weeks, as well as a 44.5 mg/m2 dose on days 1 and 8, followed by 80 mg/m2 every 4 weeks [beginning] at cycle 2,” Hamilton explained in the presentation.

In the dose expansion phase of the study, patients are required to have advanced or metastatic TNBC with prior exposure to 1 to 4 lines of treatment for locally advanced or metastatic disease, including at least 1 prior topoisomerase-1 ADC. Notably, patients are stratified based on B7-H4 expression. The primary end points are safety and preliminary antitumor activity, with secondary end points including PK and ADA.

Disclosures: Dr Hamilton serves on an advisory board (institutional only) for Accutar Biotechnology, Arvinas, AstraZeneca, BeiGene, Circle Pharma, Daiichi Sankyo, Entos, Gilead Sciences, Halda Therapeutics, Incyclix Bio, IQVIA, Janssen, Jazz Pharmaceuticals, Jefferies LLC, Johnson and Johnson, Lilly, Medical Pharma Services, Mersana, Novartis, Pfizer, Pyxis Oncology, Roche/Genentech, Samsung Bioepis, Shoria Pharma, Stemline Therapeutics, Tempus Labs, and Zentalis Pharmaceuticals. Contracted research/grants (institutional only) have been supplied by Abbvie, Acerta Pharma, Accutar Biotechnology, ADC Therapeutics, AKESOBIO Australia, Amgen, Aravive, ArQuale, Artios, Arvinas, AstraZeneca, AtlasMedx, BeiGene, Black Dimond, Bliss BioPharmaceuticals, Boehringer Ingelheim, Bristol-Myers Squibb, Cascadian Therapeutics, Clovis, Compugen, Contest Therapeutics, Cullinan, Curis, CytomX, Daiichi Sankyo, Dana Farber Cancer Institute, Dantari, Deciphera, Duality Biologics, eFFECTOR Therapeutics, Eisai, Ellipses Pharma, Elucide Oncology, EMD Serono, Fochon Pharmaceuticals, FujiFilm, G1 Therapeutics, Gilead Schieces, H3 Biomedicine, Harpoon, Huchinson MediPharma, Immunogen, Immunomedics, Incyte, Infinity Pharmaceuticals, Inspirna, InventisBio, Jacobio, Karyopharm, K-Group Beta, Kind Pharmaceuticals, Leap Therapeutics, Lilly, Loxo Oncology, Lycera, Mabspace Biosciences, Macrogenics, MedImmune, Mersana, Merus, Millennium, Molecular Templates, Myriad Genetic Laboratories, Novartis, Nucana, Olema, OncoMed, Oncothyreon, ORIC Pharmaceuticals, Orinove, Orum Therapeutics, Pfizer, PharmaMar, Pieris Pharmaceuticals, Pionyr Immunotherapeutics, Plexxikon, Prelude Therapeutics, Profound Bio, Radius Health, Renegeron, Relay Therapeutics, Repertoire Immune Medicine, Rgenix, Roche/Genentech, SeaGen, Sermonix Pharmaceuticals, Shattuck Labs, Silverback Therapeutics, StemCentRx, Stemline Therapeutics, Sutro, Syndax, Syros, Taiho, TapImmune, Tesaro, Tolmar, Torque Therapeutics, Treadwell Therapeutics, Verastem, Zenith Epigenetics, and Zymeworks.

References

1. Hamilton E, Han H, Abuhadra N, et al. Clinical activity of emiltatug ledadotin (Emi-Le), a B7-H4-directed ADC, in patients with TNBC who received at least one prior topoisomerase-1 inhibitor (Topo-1) ADC. Presented at: 2025 ESMO Breast Congress; May 14-17, 2025; Munich, Germany. Abstract 298MO.
2. Corporate presentation. Mersana Therapeutics, Inc. January 10, 2025. Accessed May 15, 2025. https://ir.mersana.com/static-files/a6b76e0c-b081-4f62-bdfc-b21f8f15bff0