1. Academic Validation
  2. Enapotamab vedotin, an AXL-specific antibody-drug conjugate, shows preclinical antitumor activity in non-small cell lung cancer

Enapotamab vedotin, an AXL-specific antibody-drug conjugate, shows preclinical antitumor activity in non-small cell lung cancer

  • JCI Insight. 2019 Nov 1;4(21):e128199. doi: 10.1172/jci.insight.128199.
Louise A Koopman 1 Mikkel G Terp 2 Gijs G Zom 1 Maarten L Janmaat 1 Kirstine Jacobsen 2 Elke Gresnigt-van den Heuvel 1 Marcel Brandhorst 1 Ulf Forssmann 1 Freddy de Bree 1 Nora Pencheva 1 Andreas Lingnau 1 Maria A Zipeto 3 Paul Whi Parren 1 2 4 Esther Cw Breij 1 Henrik J Ditzel 2 5
Affiliations

Affiliations

  • 1 Genmab, Utrecht, Netherlands.
  • 2 Department of Cancer and Inflammation Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark.
  • 3 Crown Bioscience San Diego, San Diego, California, USA.
  • 4 Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, Netherlands.
  • 5 Department of Oncology, Odense University Hospital, Odense, Denmark.
Abstract

Targeted therapies and immunotherapy have shown promise in patients with non-small cell lung Cancer (NSCLC). However, the majority of patients fail or become resistant to treatment, emphasizing the need for novel treatments. In this study, we confirm the prognostic value of levels of Axl, a member of the TAM Receptor tyrosine kinase family, in NSCLC and demonstrate potent antitumor activity of the AXL-targeting antibody-drug conjugate enapotamab vedotin across different NSCLC subtypes in a mouse clinical trial of human NSCLC. Tumor regression or stasis was observed in 17/61 (28%) of the patient-derived xenograft (PDX) models and was associated with AXL mRNA expression levels. Significant single-agent activity of enapotamab vedotin was validated in vivo in 9 of 10 AXL-expressing NSCLC xenograft models. In a panel of EGFR-mutant NSCLC cell lines rendered resistant to EGFR inhibitors in vitro, we observed de novo or increased Axl protein expression concomitant with enapotamab vedotin-mediated cytotoxicity. Enapotamab vedotin also showed antitumor activity in vivo in 3 EGFR-mutant, EGFR inhibitor-resistant PDX models, including an osimertinib-resistant NSCLC PDX model. In summary, enapotamab vedotin has promising therapeutic potential in NSCLC. The safety and preliminary efficacy of enapotamab vedotin are currently being evaluated in the clinic across multiple solid tumor types, including NSCLC.

Keywords

Cancer; Drug therapy; Lung cancer; Oncology; Therapeutics.

Figures
Products