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A phase 1 study evaluating safety and pharmacokinetics of losatuxizumab vedotin (ABBV-221), an anti-EGFR antibody-drug conjugate carrying monomethyl auristatin E, in patients with solid tumors likely to overexpress EGFR

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Summary

Losatuxizumab vedotin (formerly ABBV-221) is a second-generation antibody-drug conjugate targeting epidermal growth factor receptor (EGFR). In this multicenter phase 1 study, eligible patients with EGFR-dependent solid tumors received losatuxizumab vedotin (3 + 3 design) intravenously at starting dose of 0.3 mg/kg over 3 h per 21-day cycle, with alternate dosing schedules utilized (2 weeks on/1 week off or weekly) to mitigate infusion reactions. Forty-five patients received ≥1 doses of losatuxizumab vedotin (13 colon, 6 non-small cell lung cancer, 5 head and neck [HNC], 5 glioblastoma multiforme, 2 breast, 14 other). Tumor samples were evaluated for EGFR protein expression by immunohistochemistry, EGFR and EGFR ligand mRNA expression by RNAseq, and results compared with outcome. Most common adverse events were infusion-related reaction (22/45; 49%) and fatigue (20/45; 44%). While most infusion reactions were grade ≤ 2, four patients experienced grade ≥3 infusion reactions. Several infusion reaction mitigation strategies were explored. Because of the high incidence of infusion reactions, the trial was stopped and the maximum tolerated dose was not reached. The last cleared dose: 6 mg/kg/cycle. Nineteen patients (42%) had stable disease; 4 remained on study >6 months. One HNC patient with increased levels of EGFR and EGFR ligands (amphiregulin, epiregulin) achieved a confirmed partial response. Pharmacokinetic analysis of losatuxizumab vedotin showed exposures appeared to be approximately dose-proportional. The high frequency of infusion reactions necessitated early closure of this trial. The detailed mitigation strategies used in this protocol for infusion-related reactions may provide beneficial information for trial design of agents with high infusion reaction rates.

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Acknowledgments

AbbVie and the authors thank the patients who participated in this clinical trial, the study coordinators, and support staff. This study was funded by AbbVie Inc., North Chicago, IL, USA. Medical writing support was provided by Mary L. Smith, PhD, CMPP, Aptitude Health, Atlanta, GA, USA, funded by AbbVie.

Funding

AbbVie Inc. provided financial support for the study and participated in the design, study conduct, analysis and interpretation of data, as well as the writing, review, and approval of the manuscript.

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Authors and Affiliations

  1. Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA, 02215, USA

    James M. Cleary & Geoffrey I. Shapiro

  2. START Madrid-CIOCC, Madrid, Spain

    Emiliano Calvo

  3. START Madrid-FJD, Hospital Fundación Jiménez Díaz, Madrid, Spain

    Victor Moreno

  4. Massachusetts General Hospital Cancer Center, Boston, MA, USA

    Dejan Juric

  5. AbbVie, Inc., North Chicago, IL, USA

    Carol Ann Vanderwal, Beibei Hu, Maryella Gifford, David Barch, Lisa Roberts-Rapp, Peter J. Ansell, Hao Xiong & Christopher Ocampo

  6. START San Antonio, San Antonio, TX, USA

    Anthony W. Tolcher

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Contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Christopher Ocampo, Beibei Hu, and Hao Xiong. All authors participated in writing the first draft of the manuscript and commented on subsequent versions of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to James M. Cleary.

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Conflict of interest disclosure statements

JM Cleary: Research funding from Merck and Tesaro, consultant to Bristol-Myers Squibb, travel funding from Bristol-Myers Squibb, Agios, and Roche.

E Calvo: Consulting/advisory role with Novartis, GSK, Astellas, Roche/Genentech, Eli Lilly, Nanobiotix, Pfizer; speakers’ bureau for Novartis; research funding from Boehringer Ingelheim, Roche/Genentech, BMS, Novartis, PsiOxus, Janssen, Eisai, AbbVie, OncoMed, PharmaMar, Puma, Spectrum, Sanofi, Eli Lilly, Pfizer, Merck, Nektar, Millennium; travel/accommodations/expenses reimbursed by Eli Lilly, PsiOxus, Novartis.

V Moreno: Consulting fees from Merck, BMS; travel support from Regeneron/Sanofi, BMS; presentations for Nanobiotix, BMS; educational grant from Medscape/Bayer.

D Juric: Consulting/advisory role with Eisai, EMD Serono, Genentech, Ipsen, Novartis; research funding from Eisai, EMD Serono, Genentech, Novartis, Placon, Takeda.

GI Shapiro: Advisory role with Lilly, Pfizer, Merck/EMD Serono, G1 Therapeutics, Roche; research funding from Lilly, Pfizer, and Merck/EMD Serono.

C Vanderwal, B Hu, M Gifford, D Barch, L Roberts-Rapp, PJ Ansell, H Xiong, C Ocampo: Employees of AbbVie and may own stock.

AW Tolcher: Employed by START; consulting/advisory role for Bayer Schering Pharma, Blend Therapeutics, Celator, Janssen, Merus, Nanobiotix, Pierre Fabre, Symphogen, Heron, Asana BioSciences, Akebia Therapeutics, Genmab, Johnson & Johnson, Endocyte, Upsher-Smith, Ascentage, Bicycle Therapeutics, Boehringer Ingelheim, Ignyta, MEDIAN Technologies, OncoMed, Zymeworks, Elekta, Rigontec, New B Innovation (all to institution); leadership role for Symphogen; research funding from AbbVie, ArQule, Asana BioSciences, Astex Pharmaceuticals, Cerulean Pharma, Dicerna, Endocyte, Gilead Sciences, Infinity Pharmaceuticals, MacroGenics, Pfizer, TaiRx, Inc., Bayer, Otsuka, Plexxikon (all to institution).

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These clinical trial data can be requested by any qualified researchers who engage in rigorous, independent scientific research, and will be provided following review and approval of a research proposal and Statistical Analysis Plan (SAP) and execution of a Data Sharing Agreement (DSA). Data requests can be submitted at any time and the data will be accessible for 12 months, with possible extensions considered. For more information on the process, or to submit a request, visit the following link: https://www.abbvie.com/our-science/clinical-trials/clinical-trials-data-and-information-sharing/data-and-information-sharing-with-qualified-researchers.html.

Ethical approval

All patients provided written informed consent, and local ethics committee approval was obtained. This study was conducted in accordance with good clinical practice guidelines and the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

This article does not contain any studies with animals performed by any of the authors.

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Informed consent was obtained from all individual participants included in the study.

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Cleary, J.M., Calvo, E., Moreno, V. et al. A phase 1 study evaluating safety and pharmacokinetics of losatuxizumab vedotin (ABBV-221), an anti-EGFR antibody-drug conjugate carrying monomethyl auristatin E, in patients with solid tumors likely to overexpress EGFR. Invest New Drugs 38, 1483–1494 (2020). https://doi.org/10.1007/s10637-020-00908-3

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