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
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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

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Figure 6

Efficacy of EnaV monotherapy and combination therapy in an osimertinib-resistant NSCLC PDX model.

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Efficacy of EnaV monotherapy and combination therapy in an osimertinib-r...
(A) Tumor growth curves of the osimertinib-resistant NSCLC PDX model LCx-MR007 upon treatment with EnaV (2 mg/kg or 4 mg/kg) or osimertinib 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 osimertinib treatment indicated with pink arrowheads. (B) Kaplan-Meier survival plot of the osimertinib-resistant PDX model LCx-MR007 treated with EnaV (2 mg/kg or 4 mg/kg), osimertinib, or combinations as indicated. (C and D) Tumor sizes compared on day 7 after randomization. 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.