Phase I/II Study of AXL-Specific Antibody-Drug Conjugate Enapotamab Vedotin in Patients with Advanced Solid Tumors.

Receptor Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Axl Receptor Tyrosine Kinase; Immunoconjugates; AXL protein, human; Oligopeptides; Humans; Female; Male; Middle Aged; Aged; Adult; Maximum Tolerated Dose; Aged, 80 and over; Receptor Protein-Tyrosine Kinases/antagonists & inhibitors; Receptor Protein-Tyrosine Kinases/immunology; Proto-Oncogene Proteins/antagonists & inhibitors; Proto-Oncogene Proteins/immunology; Immunoconjugates/administration & dosage; Immunoconjugates/adverse effects; Immunoconjugates/pharmacokinetics; Immunoconjugates/therapeutic use; Neoplasms/drug therapy; Neoplasms/pathology; Neoplasms; Oncology; Cancer Research

Abstract :

[en] [en] 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.

Disciplines :

Oncology

Author, co-author :

Rohrberg, Kristoffer Staal ; Department of Oncology, Copenhagen University Hospital (Rigshospitalet), Copenhagen, Denmark

Lopez, Juanita S ; Drug Development Unit, Royal Marsden Hospital/Institute of Cancer Research, Sutton, United Kingdom

Milhem, Mohammed M ; Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa

Blank, Christian U ; Division of Molecular Oncology and Immunology, Department of Medical Oncology, Netherlands Cancer Institute (NKI), Amsterdam, the Netherlands ; Department of Medical Oncology, Leiden University Medical Center (LUMC), Leiden, the Netherlands ; Department of Hematology and Oncology, University Clinic Regensburg (UKR), Regensburg, Germany

Reijers, Irene ; Division of Molecular Oncology and Immunology, Department of Medical Oncology, Netherlands Cancer Institute (NKI), Amsterdam, the Netherlands

Thistlethwaite, Fiona ; The Christie NHS Foundation Trust and Division of Cancer Sciences, The University of Manchester, Manchester, United Kingdom

Plummer, Ruth ; Newcastle University, Newcastle upon Tyne, United Kingdom

Piha-Paul, Sarina A ; Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas

Jänne, Pasi A ; Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts

Shum, Elaine ; Medical Oncology, Laura and Isaac Perlmutter Cancer Center, NYU Langone Health, New York, New York

More authors (30 more)

Language :

English

Title :

Phase I/II Study of AXL-Specific Antibody-Drug Conjugate Enapotamab Vedotin in Patients with Advanced Solid Tumors.

Publication date :

01 November 2025

Journal title :

Cancer Research Communications

eISSN :

2767-9764

Publisher :

American Association for Cancer Research Inc., United States

Volume :

Issue :

Pages :

2066 - 2078

Peer reviewed :

Peer Reviewed verified by ORBi

Additional URL :

https://aacrjournals.org/cancerrescommun/article-pdf/doi/10.1158/2767-9764.CRC-25-0359/3667740/crc-25-0359.pdf

Funders :

Genmab

Funding text :

RepareX, Roche, GSK, and AbbVie outside the submitted work, as well as honorary for presentations: Amgen, GSK, and MSD and advisory board: CDRlife, Genmab, AbbVie, and MSD. J.S. Lopez reports grants from Astex, MSD, Jannsen, and Verastem, grants and personal fees from Genmab and Roche-Genentech, personal fees from GSK, Novartis, and Servier, and personal fees and nonfinancial support from Basilea outside the submitted work. M.M. Milhem reports other support from Replimmune and Nayva Expert outside the submitted work. C.U. Blank reports other support from advisory role: Bristol Myers Squibb, MSD, Roche, Novartis, GSK, AstraZeneca, Pfizer, Lilly, Genmab, Pierre Fabre, Third Rock Ventures, Senya, and Hexal/Sandoz and grants from research funding: Bristol Myers Squibb, Novartis, Nano-String, 4SC, and Senya Therapeutics outside the submitted work. F. Thistlethwaite reports other support from Genmab and grants from Cancer Research UK and National Institutes for Health Research during the conduct of the study, as well as other support from Achilles, Adaptimmune, Agalimmune, Amgen, Biontech, Bristol Myers Squibb, Chugai Pharmaceutical, Corbus, Crescendo Biologics, GSK, Immunocore, Incyte, Iovance, Janssen, Kymab/Sanofi, Leucid, Moderna, Novalgen, Nucana, Oxford Vac-medix, Roche, RS Oncology, Seagen, Takeda, UCB, Zymeworks, Byondis BV, personal fees and other support from CytomX, Grey Wolf Therapeutics, and T-Knife, and personal fees from Immatics outside the submitted work. R. Plummer reports other support and personal fees from Genmab during the conduct of the study, as well as personal fees from Immunocore, Novartis, Bristol Myers Squibb, Ellipses, Incyte, Astex Therapeutics, Pierre Faber, MSD, Biosceptre, Mythix Therapeutics, Cybrexa, Sanofi Aventis, Bayer, Benevolent AI, and Nerviano outside the submitted work. S.A. Piha-Paul reports other support from ABM Therapeutics, Alkermes, Axcynsis Therapeutics, BioMarin Pharmaceutical, Boehringer Ingelheim, Chugai Pharmaceutical, Cyclacel Pharmaceuticals, Daiichi Sankyo, ENB Therapeutics, Epigenetix, Genmab US, Gilead Sciences, Immunity Bio, Immunome, Immunomedics, Incyte, Innovent Biologics, iTeos Belgium SA, Jazz Pharmaceuticals, Johnson & Johnson, Loxo Oncology, MSD, Mitsubishi Tanabe Pharma America, Nectin Therapeutics, Nested Therapeutics, NRG Oncology, Nurix, OncoNano Medicine, Pfizer Pharmaceuticals, Phanes Therapeutics, Pieris Pharmaceuticals, Puma Biotechnology, Purinomia Biotech, Replimune, Roche/Blueprint, Solve Therapeutics, Strand Therapeutics, Tallac Therapeutics, Theradex Oncology, Toragen Therapeutics, TransThera Bio, ViroMissile, and Xencor and grants from NCI/NIH P30CA016672, Cancer Prevention Research Institute of Texas Precision Oncology Decision Support Core (RP150535), and Clinical and Translational Science Award Grant 1UM1TR0045906 outside the submitted work and has worked as a consultant for Mitsubishi Tanabe Pharma America. P.A. Janne reports grants and personal fees from Revolution Medicines, Eli Lilly, Daiichi Sankyo, Takeda Oncology, and AstraZeneca, personal fees from Boehringer Ingel-heim, Pfizer, Roche/Genentech, SFJ Pharmaceuticals, Voronoi, Biocartis, Novartis, Sanofi, Mirati Therapeutics, Transcenta, Syndax, Nuvalent, Bayer, Eisai, Allorion Therapeutics, Accutar Biotech, AbbVie, Scorpion Therapeutics, Merus, Frontier Medicines, Hongyun Biotechnology, Duality Biologics, Blueprint Medicines, Dizal Pharma, GlaxoSmithKline, Myris Therapeutics, Tolremo, and Bristol Myers Squibb, and grants from PUMA outside the submitted work; in addition, P.A. Ja\u00A8nne has a patent to EGFR mutations issued, licensed, and with royalties paid. E. Shum reports personal fees from AstraZeneca, Genentech, Bristol Myers Squibb, Janssen, Regeneron, and Boehringer Ingelheim outside the submitted work. H.M. Shaw reports other support from National Institutes for Health Research University College London Hospitals Clinical Research Facility during the conduct of the study, as well as personal fees and other support from Bristol Myers Squibb, MSD, Immunocore, Scancell, Regeneron, and Agenus, other support from Ideaya, Iovance, EORTC, and NovalGen, and personal fees from CDR Life, Sanofi Genzyme, Eisai, Pierre Fabre, and Therakos outside the submitted work. P.R. Debruyne reports personal fees and other support from Ipsen, personal fees from MSD and Astellas, and other support from UCB and Mural Oncology outside the submitted work. C. Lao reports other support from Genmab during the conduct of the study and other support from Bristol Myers Squibb outside the submitted work and joined Bristol Myers Squibb as a full-time employee after this work was completed. J.H. Choe reports personal fees from Replimune, Exelixis, MSD, and Eisai and grants and personal fees from Coherus Biosciences, Bicara, Merus, and Summit Therapeutics outside the submitted work. G. Jerusalem reports nonfinancial support and other support from Genmab during the conduct of the study, as well as personal fees and nonfinancial support from Novartis, Roche, Pfizer, Lilly, Amgen, Bristol Myers Squibb, and AstraZeneca and personal fees from Diaccurate, Daiichi Sankyo, and Seagen outside the submitted work. A.W. Chen reports other support from Genmab during the conduct of the study. L. Roshkovan reports grants from Genmab during the conduct of the study. D. Kontos reports grants from Genmab during the conduct of the study and grants from Calico, iCAD, and Hologic outside the submitted work. P.G. Castro reports a patent to US2022273809A1 issued and salaried employment with Genmab that includes relevant stocks and warrants during the conduct of this study and outside the submitted work. N. Pencheva reports grants, nonfinancial support, and other support from Genmab during the conduct of the study and outside the submitted work; in addition, N. Pencheva has a patent to AXL antibody\u2013drug conjugates for use in treating cancer|publication number: 20220273809 pending and a patent to AXL-specific antibodies for cancer treatment|publication number: 20210070869 pending. G. Bajaj reports other support from Genmab US outside the submitted work. K. Windfeld reports personal fees from Genmab during the conduct of the study and other support from Genmab outside the submitted work. M. Jure-Kunkel reports other support from Genmab during the conduct of the study. B.W. Higgs reports other support from Genmab during the conduct of the study. K.I. Amiri reports employment with Genmab and that the work is related to a Genmab-owned asset. T. Ahmadi reports employment with Genmab and grants from Genmab during the conduct of the study and outside the submitted work. S.S. Ramalingam reports grants from Genmab during the conduct of the study and grants from Amgen, Astra Zeneca, Bristol Myers Squibb, Pfizer, and Merck outside the submitted work. I. Vergote reports personal fees from Bristol Myers Squibb, Eisai, Hoffmann-La Roche, Genmab, GSK, ITM, Karyopharm, MSD, Novocure, Oncoinvent, Regeneron, AbbVie, AstraZeneca, Corcept, Daiichi Sankyo, Immunogen, Kronos Bio, Mersana, Novartis, Verastem Oncology, and Zentalis outside the submitted work. No disclosures were reported by the other authors.We acknowledge and thank the patients and their families for their participation in this study. We also acknowledge and thank all the participating study sites, investigators, the data monitoring committee, and other research personnel for their support of this trial. Medical writing and editorial assistance were provided by Amy Zannikos, PharmD, of Peloton Advantage, an OPEN Health company, and funded by Genmab A/S. This study was funded by Genmab.

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