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

Document Type

Conference Proceeding

Publication Date

5-28-2025

Publication Title

J Clin Oncol

Keywords

antibody drug conjugate, DNA topoisomerase inhibitor, emiltatug ledadotin, adenoid cystic carcinoma, adult, bystander effect (cell), bystander suppression, conference abstract, drug dose escalation, drug megadose, drug therapy, endometrium, eye toxicity, fatigue, female, human, human tissue, interstitial lung disease, monotherapy, nausea, neutropenia, phase 1 clinical trial, proteinuria, recommended drug dose, side effect, special situation for pharmacovigilance, systemic therapy, thrombocytopenia, triple negative breast cancer

Abstract

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.

PubMed ID

Not assigned.

Volume

43

Issue

16_suppl

Find It @ Sladen

Share

COinS