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Lookup NU author(s): Professor Ruth PlummerORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
©2025 The Authors; Published by the American Association for Cancer Research. PURPOSE: AXL, a receptor tyrosine kinase related to oncogenic processes, is aberrantly expressed in various cancers and associated with treatment resistance. Enapotamab vedotin (EnaV), a novel anti-AXL human IgG1 and monomethyl auristatin E antibody-drug conjugate, demonstrated antitumor activity in preclinical models, including non-small cell lung cancer (NSCLC). This phase 1/2 study assessed the safety and preliminary efficacy of EnaV in solid tumors. PATIENTS AND METHODS: This study comprised dose-escalation and dose-expansion phases; both phases investigated EnaV once every 3 weeks (Q3W) and EnaV on days 1, 8, and 15 of a 28-day cycle (3Q4W). Primary objectives determined the maximum tolerated dose (dose escalation) and safety (dose expansion). Pharmacokinetic profile, antitumor activity, and AXL expression were also assessed. RESULTS: During dose escalation, 32 patients received EnaV Q3W; 15 received EnaV 3Q4W. The maximum tolerated dose and recommended phase 2 dose were 2.2 mg/kg in Q3W and 1.0 mg/kg in 3Q4W schedules. In dose expansion, 189 patients received EnaV Q3W; 70 received EnaV 3Q4W. Common adverse events in dose expansion included fatigue, constipation, nausea, decreased appetite, and diarrhea. Overall response rates ranged from 4.5% to 12.5% with Q3W dose schedule and from 9.1% to 11.5% with 3Q4W dose schedule. Disease control rates for NSCLC cohorts were 40.9% to 50.0%. NSCLC subset analysis demonstrated correlation between radiomics signature and disease control. The relationship between clinical activity and AXL expression was not apparent. CONCLUSIONS: EnaV had an acceptable safety profile; however, because the evaluation of antitumor activity did not show clinically meaningful responses, clinical development of EnaV was discontinued. SIGNIFICANCE: EnaV, an anti-AXL human IgG1 and monomethyl auristatin E antibody-drug conjugate, showed single-agent antitumor activity in preclinical models. This phase 1/2 study of EnaV demonstrated a manageable safety profile and antitumor activity in selected tumor types. Further studies exploring alternative targeting modalities, patient selection, and/or combinations are needed.
Author(s): Rohrberg KS, Lopez JS, Milhem MM, Blank CU, Reijers I, Thistlethwaite F, Plummer R, Piha-Paul SA, Janne PA, Shum E, Shaw HM, Debruyne PR, Lao C, Baurain J-F, Choe JH, Gort E, Zhao Y, Jerusalem G, Schoffski P, Chen AW, Cohen EA, Mankowski WC, Roshkovan L, Katz SI, Kontos D, Brady LK, Qutaish M, Castro PG, Pencheva N, Bajaj G, Fu Y, Windfeld K, Reiter P, Jure-Kunkel M, Higgs BW, Amiri KI, Ahmadi T, Forssmann U, Ramalingam SS, Vergote I
Publication type: Article
Publication status: Published
Journal: Cancer Research Communications
Year: 2025
Volume: 5
Issue: 11
Pages: 2066-2078
Online publication date: 26/11/2025
Acceptance date: 30/10/2025
Date deposited: 10/12/2025
ISSN (electronic): 2767-9764
Publisher: American Association for Cancer Research
URL: https://doi.org/10.1158/2767-9764.CRC-25-0359
DOI: 10.1158/2767-9764.CRC-25-0359
Data Access Statement: Clinical trial data can be requested by qualified researchers for use in rigorous, independent scientific research as long as the trials are not part of an ongoing or planned regulatory submission. Sharing of data is subject to protection of patient privacy and respect for the patient’s informed consent. The data will be provided following review and approval of a research proposal and Statistical Analysis Plan and execution of a Data Sharing Agreement Data. For approved requests, the data will be accessible for 12 months, with possible extensions considered. For more information on the process or to submit a request, contact clinicaltrials@genmab.com.
PubMed id: 41166388
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