The FDA has granted breakthrough therapy designation to the investigational B7-H4–directed antibody-drug conjugate (ADC) emiltatug ledadotin (Emi-Le; XMT-1660) for the treatment of patients with locally advanced, recurrent or metastatic adenoid cystic carcinoma (ACC) with solid histology or high-grade transformation.1
The safety, tolerability, and antitumor activity of Emi-Le are under investigation in a phase 1 trial (NCT05377996) in patients with solid tumors, including aggressive ACC, endometrial cancer, ovarian cancer, and breast cancer.
Initial data reported from the dose-escalation portion of the trial showed that Emi-Le was associated with a manageable safety profile and generated confirmed objective responses in several tumor types. Data presented at the 2025 ASCO Annual Meeting showed that among patients in the dose-escalation and backfill cohorts (n = 141), including those with ACC (n = 13), the rates of any-grade and grade 3 treatment-related adverse effects (TRAEs) were 83.0% and 36.9%, respectively.2 TRAEs led to treatment discontinuation (3.5%), dose reduction (16.3%), and dose delay (23.4%). No TRAEs led to death. The most common grade 3 TRAEs included increased aspartate aminotransferase levels (17%), proteinuria (14%), anemia (6%), nausea (1%), increased alanine aminotransferase levels (1%), decreased platelet counts (1%), and pyrexia (1%).
Among evaluable patients with ACC type 1 (ACC-1) treated across all doses and regardless of B7-H4 expression (n = 9), the overall response rate (ORR) was 55.6%, including 4 confirmed partial responses (PRs) and 1 unconfirmed PR. Six patients were in ongoing treatment at a data cutoff of March 8, 2025. The median progression-free survival (PFS) was not reached (NR; 95% CI, 4.3 weeks-NR).
“At Servier, we are committed to pursuing first‑in‑class medicines for rare diseases in oncology,” Peter Adamson, global head of Oncology Clinical Development at Servier, stated in a news release.1 “This breakthrough therapy designation for Emi‑Le will help accelerate development and may provide an important new treatment option for patients with few effective choices today. Following the acquisition of Day One Biopharmaceuticals, this designation reinforces our confidence in Day One’s portfolio and our commitment to advancing innovative treatments for patients facing difficult‑to‑treat cancers.”
What is the design of the phase 1 study of Emi-Le in patients with solid tumors?
The dose-escalation and backfill cohorts enrolled patients at least 18 years of age with advanced or metastatic ACC-1, triple-negative breast cancer (TNBC), hormone receptor (HR)–positive/HER2-negarive breast cancer, ovarian cancer, and endometrial cancer. Patients needed to have an ECOG performance status of 0 or 1 and disease progression after receiving available standard-of-care therapy. B7-H4 expression was evaluated retrospectively using fresh or archived tissue.
Emi-Le FDA Breakthrough Therapy Designation for ACC
- The FDA granted breakthrough therapy designation to Emi-Le for the treatment of patients with locally advanced, recurrent, or metastatic ACC featuring solid histology or high-grade transformation.
- Phase 1 clinical trial data demonstrated that Emi-Le has a manageable safety profile and achieved a 55.6% ORR in evaluable patients with ACC-1.
- Emi-Le has previously earned FDA fast track designations for the treatment of patients with other aggressive cancers, specifically advanced or metastatic triple-negative and HER2-low or -negative breast cancers.
Patients in the dose-escalation and backfill cohorts received Emi-Le at a subtherapeutic dose range of 7.2 mg/m2 to 28.7 mg/m2 (n = 16), an intermediate dose range of 38.1 mg/m2 to 67.4 mg/m2 (n = 83), or a high dose range of 76.2 mg/m2 to 115.0 mg/m2 (n = 42). The primary end points were the determination of the maximum tolerated dose, as well as safety and tolerability. Secondary end points included ORR, duration of response, disease control rate, pharmacokinetics, and anti-drug antibodies.
What is the regulatory history of Emi-Le?
In September 2022, the FDA granted fast track designation to Emi-Le for the treatment of adult patients with advanced or metastatic TNBC.3 Additionally, in January 2025, the FDA granted the same designation to the agent for the treatment of adult patients with advanced or metastatic HER2-low or -negative breast cancer, including TNBC and certain HR-positive breast cancers, following treatment with a topoisomerase 1–directed ADC.4
References
- Emiltatug ledadotin (Emi-Le) granted breakthrough therapy designation by the U.S. FDA for adenoid cystic carcinoma (ACC). News release. Servier. May 12, 2026. Accessed May 12, 2026. https://servier.mediaroom.com/2026-05-12-Emiltatug-Ledadotin-Emi-Le-Granted-Breakthrough-Therapy-Designation-by-the-U-S-FDA-for-Adenoid-Cystic-Carcinoma-ACC
- 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
- Mersana Therapeutics announces FDA fast track designation granted to XMT-1660 for the treatment of triple-negative breast cancerXMT-1660 currently being studied in a phase 1 trial enrolling patients with breast, endometrial and ovarian cancers. News release. Mersana Therapeutics, Inc. September 12, 2022. Accessed May 12, 2026. https://www.biospace.com/mersana-therapeutics-announces-fda-fast-track-designation-granted-to-xmt-1660-for-the-treatment-of-triple-negative-breast-cancerxmt-1660-currently-being-studied-in-a-phase-1-trial-enrolling-patients-with-breast-endometrial-and-ovarian-cancers
- Mersana Therapeutics announces additional FDA fast track designation granted to emiltatug ledadotin (XMT-1660). News release. Mersana Therapeutics, Inc. January 10, 2025. Accessed May 12, 2026. https://www.biospace.com/press-releases/mersana-therapeutics-announces-additional-fda-fast-track-designation-granted-to-emiltatug-ledadotin-xmt-1660
