Enapotamab vedotin, an AXL-specific antibody-drug conjugate, shows preclinical antitumor activity in non-small cell lung cancer
Louise A. Koopman, Mikkel G. Terp, Gijs G. Zom, Maarten L. Janmaat, Kirstine Jacobsen, Elke Gresnigt-van den Heuvel, Marcel Brandhorst, Ulf Forssmann, Freddy de Bree, Nora Pencheva, Andreas Lingnau, Maria A. Zipeto, Paul W.H.I Parren, Esther C.W. Breij, Henrik J. Ditzel
Louise A. Koopman, Mikkel G. Terp, Gijs G. Zom, Maarten L. Janmaat, Kirstine Jacobsen, Elke Gresnigt-van den Heuvel, Marcel Brandhorst, Ulf Forssmann, Freddy de Bree, Nora Pencheva, Andreas Lingnau, Maria A. Zipeto, Paul W.H.I Parren, Esther C.W. Breij, Henrik J. Ditzel
View: Text | PDF
Research Article Oncology Therapeutics

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

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.

Authors

Louise A. Koopman, Mikkel G. Terp, Gijs G. Zom, Maarten L. Janmaat, Kirstine Jacobsen, Elke Gresnigt-van den Heuvel, Marcel Brandhorst, Ulf Forssmann, Freddy de Bree, Nora Pencheva, Andreas Lingnau, Maria A. Zipeto, Paul W.H.I Parren, Esther C.W. Breij, Henrik J. Ditzel

×

Figure 5

EnaV treatment overcomes resistance to EGFR inhibitors in vivo.

Options: View larger image (or click on image) Download as PowerPoint
EnaV treatment overcomes resistance to EGFR inhibitors in vivo. (A) Tumo...
(A) Tumor growth curves of the EGFR-mutant NSCLC PDX model LU1868 upon treatment with EnaV (2 mg/kg or 4 mg/kg) or erlotinib or combinations as indicated. Mean tumor sizes are displayed for each group (n = 8 per group) up to the day the first mouse of a group was sacrificed. Days of EnaV or isotype-ADC treatment indicated with red arrowheads; days of erlotinib treatment indicated with orange arrowheads. (B) Same as A for EGFR-mutant NSCLC PDX model LU0858. (C–F) Statistical analysis (Mann-Whitney U test + Bonferroni’s post hoc test; P values: *P < 0.05, **P ≤ 0.01, and ***P ≤ 0.001) was performed on the last day that both groups were intact, but no later than day 25 after randomization, because PK studies indicated all administered drug was cleared by day 25 (data not shown), to identify significant differences in tumor sizes between groups. (C and D) Tumor sizes in the PDX model LU1868, compared on day 21 after randomization. (E and F) Tumor sizes in PDX model LU0858, compared on day 11 after randomization. (G and H) Combination therapy in EGFR-mutant, erlotinib-resistant NSCLC PDX models in vivo. Kaplan-Meier plots of NSCLC PDX model LU1868 (G) and LU0858 (H) after treatment with EnaV only (2 mg/kg or 4 mg/kg), erlotinib only, or combinations as indicated. Mice were considered tumor progression–free until a cutoff tumor size of 750 mm3 was reached. Statistically significant differences determined by Mantel-Cox analysis, *P < 0.05.