Initial phase 1 dose escalation data for emiltatug ledadotin (Emi-Le), a novel B7-H4-directed dolasynthen antibody-drug conjugate.

Abstract

3009 Background: B7-H4 is a transmembrane protein over-expressed in breast (BC), ovarian (OC), endometrial (EC), and adenoid cystic carcinoma type 1 (ACC-1) cancers, with limited expression in healthy tissues. Emi-Le (XMT-1660) is a B7-H4-directed Dolasynthen ADC designed with a proprietary auristatin F-HPA microtubule inhibitor payload with controlled bystander effect. Methods: The Phase 1 trial is investigating Emi-Le monotherapy in adult patients (pts) with advanced/metastatic TNBC, HR+/HER2- BC, OC, EC and ACC-1. In dose escalation, eligible pts received Emi-Le at doses of 7.2-115 mg/m2 per cycle, with all collected data informing the recommended doses for the expansion (EXP) portion of the trial. Tumors were evaluated retrospectively for B7-H4 expression by IHC, with the preliminary high cutoff set at TPS≥70. Results: As of December 13, 2024, 130 pts were dosed. Across all tumor types, median age of pts was 55; median 4.5 prior lines of therapy (range 0-15). B7-H4 status was evaluated for 103 pts, with 44% determined to be B7-H4 TPS high. Overall, Emi-Le was generally well tolerated. The most common TRAEs were transient AST increase (38%, G3 14%), proteinuria (31%, G3 9%), nausea (29%, G3 1%) and fatigue (28%, G3 0%). The only G3 TRAEs in ≥5% of pts were AST increase and proteinuria. No G4 or 5 TRAEs were reported. No observed dose-limiting treatment-related neutropenia, neuropathy, ocular toxicity, interstitial lung disease or thrombocytopenia. TRAEs leading to discontinuation were observed in 2.3% of pts. Clinical activity was correlated with both dose and B7-H4 expression. For pts treated with doses ranging from 38.1–67.4 mg/m2 per cycle (intermediate dose range), the confirmed ORR in evaluable pts with high B7-H4 expression was 23% (6/26), including a 23% (3/13) confirmed ORR in evaluable pts with TNBC, with all 13 pts having previously received at least one topoisomerase-1 inhibitor (topo-1) ADC. At doses ≥76.2 mg/m2 per cycle (high dose range), the confirmed ORR in evaluable pts with high B7-H4 expression was 22% (2/9), with 78% (7/9) having ≥30% reduction in target lesions. Of the 8 pts with confirmed responses at doses ≥38.1 mg/m2, 5 had reduction in target lesions > 60%, including 1 CR. All 4 pts with high B7-H4 expression treated at the initial EXP dose of 67.4mg/m2 Q4W had tumor reductions and were on treatment with durations of ≥16 weeks as of data cutoff. Conclusions: Based on the initial reported data, Emi-Le appears to have encouraging clinical activity and tolerability in a heavily pretreated population. Further clinical development is ongoing in the EXP portion of the trial at a dose of 67.4 mg/m2 Q4W in pts with advanced/metastatic TNBC who have received 1-4 prior lines of systemic therapy, including at least one topo-1 ADC. Dose exploration is ongoing to identify a potential second higher EXP dose. Clinical trial information: NCT05377996 .