First-in-human, dose-escalation, phase (ph) I trial to evaluate safety of anti-Axl antibody-drug conjugate (ADC) enapotamab vedotin (EnaV) in solid tumors.

Abstract

2525 Background: Axl, a transmembrane receptor tyrosine kinase, is aberrantly overexpressed in various human cancers and associated with poor prognosis and treatment resistance. EnaV, a novel ADC of anti-Axl human IgG1 and monomethyl auristatin E, demonstrated potent anti-tumor activity in xenograft models. Methods: In a ph1 trial (NCT02988817), patients (pts) with relapsed/refractory cancer received single agent EnaV, 0.3–2.8 mg/kg once every 3 wks (1Q3W) or 0.45–1.4 mg/kg 3 times over 4 wks (3Q4W). Endpoints included dose-limiting toxicities (DLTs), adverse events (AEs) and pharmacokinetics (PK). DLTs were classed as hematological (e.g. Grade [G] 3/4 febrile neutropenia; G4 neutropenia or anemia) or non-hematological (e.g. severe skin toxicities; G3/4 neuropathy or infusion reactions; ≥G3 treatment-related AEs in first treatment cycle). Upon determining maximum tolerated dose (MTD) per arm and recommended ph2 dose (RP2D), ph2a (dose expansion) will enroll ≤297 pre-treated pts with advanced/metastatic cancer in 7 cohorts. Results: 47 pts with NSCLC (n=8), melanoma (n=9), ovarian (n=22), cervical (n=3) and endometrial (n=5) cancer enrolled in ph1 (1Q3W n=32; 3Q4W n=15). Most pts were female (87%), White (94%) and aged <65 y (66%). MTD was 2.2 mg/kg in 1Q3W arm and 1.0 mg/kg in 3Q4W arm; RP2D was 2.2 mg/kg 1Q3W. EnaV median elimination half-life: 0.9–2.2 d across doses/schedules. In 47 enrolled pts, there were 6 DLTs (Table). Most common AEs (any G; ≥40% pts) were fatigue (64%), nausea (57%), constipation (57%), diarrhea (47%), vomiting (45%) and decreased appetite (43%). 3 pts (1Q3W arm) had partial response (1 NSCLC [2.2 mg/kg dose]; 2 ovarian [1.5 and 2.4 mg/kg dose levels]). Conclusions: The RP2D of single agent EnaV in pre-treated pts with solid tumors was 2.2 mg/kg 1Q3W. EnaV had encouraging preliminary anti-tumor activity and will be evaluated in 7 ph2a expansion cohorts to further assess safety, tolerability, PK, anti-tumor activity and Axl expression. Funding: Genmab A/S. Clinical trial information: NCT02988817. [Table: see text]