Emiltatug ledadotin (Emi-Le), a B7-H4–directed antibody-drug conjugate (ADC), in patients with aggressive adenoid cystic carcinoma (ACC): Phase 1 interim analysis.

Abstract

6010 Background: ACC is a rare cancer that typically arises in the salivary glands but can affect various organs. About 40% of patients (pts) have an aggressive form of ACC (referred to as ACC-I; Ferrarotto et al., Clin Cancer Res 2021) characterized by solid/basaloid or high-grade transformation histology and poor prognosis with median progression-free survival (PFS) of 2–3 months and median overall survival (OS) of approximately 3 years. There are no approved systemic therapies for recurrent or metastatic ACC. B7-H4 is an immune checkpoint protein with elevated expression in ACC and other cancers. Emi-Le (XMT-1660) is a B7-H4-directed ADC with an auristatin F-HPA microtubule inhibitor payload. Here we report antitumor activity results from the Phase 1 ACC-specific dose escalation/backfill cohort, along with safety data for all enrolled pts (NCT05377996). Methods: Adult pts with select advanced or metastatic solid tumors, including aggressive ACC, were enrolled. Eligibility criteria for ACC pts required features consistent with aggressive disease that included 1 of the following: 1) clinically aggressive phenotype, defined as < 3 years to recurrence/progression or de novo metastatic disease with atypical metastatic sites and solid tumor morphology, and/or 2) molecular features consistent with poor prognosis (activating NOTCH1–4 mutations or c-Myc positive or p63 negative/low per IHC). Across dose escalation and backfill, eligible pts received Emi-Le at doses of 7.2–115 mg/m 2 IV per Q3W or Q4W cycle. Pts with ACC received Emi-Le at doses of 57.4–89 mg/m 2 IV per Q3W or Q4W cycle. Primary objectives included safety and preliminary antitumor activity. Results: As of October 1, 2025, 221 pts were dosed. Of these, 35 pts had ACC, with a median of 1 prior line of therapy (range 0–3), median age 58 years, and 57% were female. For the safety set of 221 pts, Emi-Le was well tolerated with no new safety signals identified. The most common treatment-related adverse events (TRAEs) were proteinuria (49.8%), transient AST increase (49.3%), and fatigue (41.2%). The only Grade 3 TRAEs in ≥10% of pts were transient AST increase (17.6%) and proteinuria (17.6%). TRAEs leading to treatment discontinuation occurred in 3.6% of pts. No treatment-related deaths were reported. Among 25 evaluable (≥1 post-baseline scan) pts with ACC, objective response rate was 40% (9/25 confirmed, 1/25 unconfirmed ongoing and on treatment) and disease control rate was 76% (19/25). At data cut-off, median PFS (95% CI: 13.0 weeks, not reached [NR]) and OS (95% CI: 26.6 weeks, NR) have not been reached. Conclusions: Based on these data, Emi-Le appears to demonstrate favorable tolerability and promising antitumor activity in pts with aggressive ACC who have no available treatments and a poor prognosis. Further clinical development is ongoing. Clinical trial information: NCT05377996 .