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.

person Malaka Ameratunga The Alfred Hospital, Melbourne, Australia info_outline Malaka Ameratunga, R Donald Harvey, Morten Mau-Sørensen, Fiona Thistlethwaite, Ulf Forssmann, Manish Gupta, Hrefna Johannsdottir, Terrie Ramirez-Andersen, Mika Linette Bohlbro, Nedjad Losic, Annette L. Ervin-Haynes, Juanita Suzanne Lopez, Ignace Vergote

Authors person Malaka Ameratunga The Alfred Hospital, Melbourne, Australia info_outline Malaka Ameratunga, R Donald Harvey, Morten Mau-Sørensen, Fiona Thistlethwaite, Ulf Forssmann, Manish Gupta, Hrefna Johannsdottir, Terrie Ramirez-Andersen, Mika Linette Bohlbro, Nedjad Losic, Annette L. Ervin-Haynes, Juanita Suzanne Lopez, Ignace Vergote Organizations The Alfred Hospital, Melbourne, Australia, Emory University School of Medicine, Atlanta, GA, Rigshospitalet, Copenhagen, Denmark, The Christie NHS Foundation Trust and University of Manchester, Manchester, United Kingdom, Genmab A/S, Copenhagen, Denmark, Genmab A/S, Princeton, NJ, Genmab, Princeton, NJ, The Royal Marsden Hospital, London, United Kingdom, University Hospital Leuven, Leuven Cancer Institute, Leuven, Belgium Abstract Disclosures Research Funding Pharmaceutical/Biotech Company 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 DLT Dose, mg/kg (n) 1Q3W Constipation 2.0 (1); 2.2 (1) Vomiting 2.2 (1) γ-glutamyltransferase increase 2.4 (1) 3Q4W Febrile neutropenia 1.2 (1) Diarrhea 1.2 (1)