FDA Grants Breakthrough Therapy Designation to Emiltatug Ledadotin for Adenoid Cystic Carcinoma
Key Insights
The FDA has granted breakthrough therapy designation to emiltatug ledadotin (Emi-Le), a B7-H4 (search)-directed antibody-drug conjugate, for treating locally advanced, recurrent or metastatic adenoid cystic carcinoma (search) with solid histology or high-grade transformation.
Phase 1 trial data demonstrated a manageable safety profile with 83.0% any-grade treatment-related adverse events and achieved a 55.6% overall response rate in evaluable patients with ACC type 1.
Adenoid cystic carcinoma (search) affects more than 200,000 people globally with no currently approved systemic therapies for advanced or metastatic disease, representing a significant unmet medical need.
The FDA has granted breakthrough therapy designation to emiltatug ledadotin (Emi-Le; XMT-1660), an investigational B7-H4 (search)-directed antibody-drug conjugate (ADC), for the treatment of patients with locally advanced, recurrent or metastatic adenoid cystic carcinoma (search) (ACC) with solid histology or high-grade transformation. This designation represents a significant milestone for patients with this rare cancer, which currently has no approved systemic therapies for advanced or metastatic disease.
Clinical Trial Results Drive FDA Decision
The breakthrough therapy designation is supported by data from an ongoing phase 1 trial (NCT05377996) investigating the safety, tolerability, and antitumor activity of Emi-Le in patients with solid tumors, including aggressive ACC, endometrial cancer (search), ovarian cancer (search), and breast cancer (search).
Initial data from the dose-escalation portion of the trial demonstrated that Emi-Le was associated with a manageable safety profile and generated confirmed objective responses across several tumor types. 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.
TRAEs led to treatment discontinuation in 3.5% of patients, dose reduction in 16.3%, and dose delay in 23.4%. Notably, 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%).
Promising Efficacy in Adenoid Cystic Carcinoma
Among evaluable patients with ACC type 1 (ACC-1) treated across all doses and regardless of B7-H4 (search) 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 was not reached (95% CI, 4.3 weeks-NR).
Study Design and Patient Population
The dose-escalation and backfill cohorts enrolled patients at least 18 years of age with advanced or metastatic ACC-1, triple-negative breast cancer (search) (TNBC), hormone receptor (HR)-positive/HER2-negative breast cancer (search), ovarian cancer (search), and endometrial cancer (search). Patients needed to have an ECOG performance status of 0 or 1 and disease progression after receiving available standard-of-care therapy. B7-H4 (search) expression was evaluated retrospectively using fresh or archived tissue.
Patients received Emi-Le at varying dose ranges: subtherapeutic doses of 7.2 mg/m² to 28.7 mg/m² (n = 16), intermediate doses of 38.1 mg/m² to 67.4 mg/m² (n = 83), or high doses of 76.2 mg/m² to 115.0 mg/m² (n = 42). The primary endpoints were the determination of the maximum tolerated dose, as well as safety and tolerability. Secondary endpoints included ORR, duration of response, disease control rate, pharmacokinetics, and anti-drug antibodies.
Addressing Significant Unmet Medical Need
Adenoid cystic carcinoma (search) occurs in the secretory glands, typically in the head and neck, but also in other areas of the body. Globally, more than 200,000 people have ACC. It is diagnosed in roughly four per one million people annually, and does not discriminate by ethnicity or lifestyle factors. Currently, there are no approved or preferred systemic therapies to treat advanced or metastatic ACC; most people are treated with surgery or radiation, but the disease recurs in 50 percent of cases, often becoming more aggressive with metastases in distant areas of the body.
Regulatory History and Company Commitment
Emi-Le has previously earned FDA fast track designations for the treatment of patients with other aggressive cancers. In September 2022, the FDA granted fast track designation to Emi-Le for the treatment of adult patients with advanced or metastatic TNBC. 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 (search), including TNBC and certain HR-positive breast cancers, following treatment with a topoisomerase 1-directed ADC.
"At Servier, we are committed to pursuing first-in-class medicines for rare diseases in oncology," stated Peter Adamson, global head of Oncology Clinical Development at Servier. "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."
Emi-Le is a B7-H4 (search)-directed Dolasynthen ADC with a precise, target-optimized drug-to-antibody ratio (DAR 6) and a proprietary auristatin-F HPA payload with controlled bystander effect. The compound represents a potentially innovative and differentiated approach to targeting B7-H4, a well-characterized target in certain cancers including ACC.