Emiltatug ledadotin (Emi-Le)

No systemic therapy is approved for recurrent or metastatic ACC, so no approved comparator exists. Emiltatug ledadotin is the only B7-H4-directed ADC identified with an FDA Breakthrough Therapy designation in ACC and a sponsor-led phase 2 trial in ACC (EMBLEM-1). In the ASCO 2026 abstract, the objective response rate was 40% (10 of 25 evaluable participants with ACC); the oral presentation reported 35.6% in 45 evaluable participants with ACC and 46.9% in 32 evaluable participants with aggressive ACC. A patient foundation described historical response rates in ACC trials as rarely above 15%. Other B7-H4-directed ADCs use topoisomerase I inhibitor payloads and have been developed mainly in gynecologic and breast cancers. Puxitatug samrotecan (AZD8205) produced 90% complete responses in two ACC-I patient-derived xenograft models and is in an investigator-sponsored phase 2 trial in ACC; in its first-in-human study (46 participants, no ACC cohort), grade 3 or higher neutropenia occurred in 37.0%. Mocertatug rezetecan (GSK5733584) is entering phase 3 trials in ovarian and endometrial cancers, and its grade 3 or higher adverse events were described as predominantly hematologic. Felmetatug vedotin (SGN-B7H4V), whose phase 1 trial listed ACC among its conditions, was terminated. In ACC, the reported safety profile of emiltatug ledadotin is dominated by proteinuria and transient AST increase, with neutropenia in 2.2% of all participants. Non-ADC investigational agents in ACC include the oral MYB mRNA degrader REM-422 (3 partial responses in 7 biomarker-positive participants at the recommended phase 2 dose), the MDM2 inhibitor alrizomadlin, and the gamma-secretase inhibitor AL101. No head-to-head or indirect comparisons were identified.