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Pharmacokinetics and immunogenicity of eftozanermin alfa in subjects with previously-treated solid tumors or hematologic malignancies: results from a phase 1 first-in-human study

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Abstract

Purpose

Eftozanermin alfa is a second-generation tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor agonist that enhances death receptor 4/5 clustering on tumor cells to induce apoptosis. We report the pharmacokinetics and immunogenicity of eftozanermin alfa administered intravenously to 153 adults with previously-treated solid tumors or hematologic malignancies from the first-in-human, open-label, dose-escalation and dose-optimization study.

Methods

Dose escalation evaluated eftozanermin alfa monotherapy 2.5–15 mg/kg on Day 1 or Days 1/8 of a 21-day cycle. Dose optimization evaluated eftozanermin alfa monotherapy or combination therapy with either oral venetoclax 400–800 mg daily (eftozanermin alfa 1.25–7.5 mg/kg Days 1/8/15 of a 21-day cycle) or chemotherapy (eftozanermin alfa 3.75 or 7.5 mg/kg Days 1/8/15/22 of a 28-day cycle and FOLFIRI regimen [leucovorin, 5-fluorouracil, and irinotecan] with/without bevacizumab on Days 1/15 of a 28-day cycle).

Results

Systemic exposures (maximum observed concentration [Cmax] and area under the concentration–time curve [AUC]) of eftozanermin alfa were approximately dose-proportional across the entire dose escalation range with minimal to no accumulation in Cycle 3 versus Cycle 1 exposures. Comparable exposures and harmonic mean half-lives (35.1 h [solid tumors], 31.3 h [hematologic malignancies]) were observed between malignancy types. Exposures (dose-normalized Cmax and AUC) in Japanese subjects were similar to non-Japanese subjects. Furthermore, eftozanermin alfa/venetoclax combination therapy did not have an impact on the exposures of either agent. Treatment-emergent anti-drug antibodies were observed in 9.4% (13/138) of subjects.

Conclusions

The study results, including a pharmacokinetic profile consistent with weekly dosing and low incidence of immunogenicity, support further investigation of eftozanermin alfa.

Trial registration ID: NCT03082209.

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Data availability

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Acknowledgements

AbbVie and authors thank all the study investigators and patients who participated in this clinical trial. Writing and editorial assistance was provided by AbbVie employee Wesley Wayman, PhD and Lorraine R. Baer, PharmD (Baer PharMed Consulting, Ltd.), with funding provided by AbbVie.

Disclosures

All authors had access to relevant data and participated in the drafting, review, and approval of this manuscript. No honoraria or payments were made for authorship.

Funding

AbbVie funded and participated in the study design, research, analysis, data collection, interpretation of data, reviewing, and approval of the manuscript.

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Authors and Affiliations

  1. Clinical Pharmacology, AbbVie Inc., 1 North Waukegan Road, Bldg. AP31-3, North Chicago, IL, 60064, USA

    Carla Biesdorf, Satya R. Siddani, David Hoffman & Rajeev M. Menon

  2. AbbVie Biotherapeutics Inc., South San Francisco, CA, USA

    Xiaowen Guan, Bruno C. Medeiros & Akshanth R. Polepally

  3. AbbVie Inc., Ludwigshafen, Germany

    Nils Boehm

  4. National Cancer Center Hospital East, Kashiwa, Chiba, Japan

    Toshihiko Doi

  5. Erasmus Medisch Centrum, Rotterdam, The Netherlands

    Maja de Jonge

  6. South Texas Accelerated Research Therapeutics (START), San Antonio, TX, USA

    Drew Rasco

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  1. Carla Biesdorf
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Correspondence to Carla Biesdorf.

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Conflict of interest

Carla Biesdorf, Satya R. Siddani, David Hoffman, Nils Boehm, Bruno C. Medeiros, Rajeev M. Menon, and Akshanth R. Polepally are current employees of AbbVie Inc. and may own stock. Xiaowen Guan was an employee of AbbVie Inc. at the time of study conduct and may own stock. Toshihiko Doi is an employee of National Cancer Center Hospital East and has received research funding from Abbvie, Inc., Maja de Jonge is an employee of Erasmus Medisch Centrum and has received research funding from Abbvie, Inc., Drew Rasco is an employee of South Texas Accelerated Research Therapeutics (START) and has received research funding from Abbvie, Inc.

Ethics approval

The study protocol and all other study-related documents were reviewed and approved by an ethics committee/independent institutional review board (IRB) at each participating site. All subjects provided written, informed consent prior to the start of any screening or study-specific procedures. The study was conducted in accordance with the protocol, International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines, applicable regulations, and guidelines governing clinical study conduct and ethical principles that have their origin in the Declaration of Helsinki.

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AbbVie was the affiliation for Xiaowen Guan, PhD, at the time of study conduct.

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Biesdorf, C., Guan, X., Siddani, S.R. et al. Pharmacokinetics and immunogenicity of eftozanermin alfa in subjects with previously-treated solid tumors or hematologic malignancies: results from a phase 1 first-in-human study. Cancer Chemother Pharmacol 93, 329–339 (2024). https://doi.org/10.1007/s00280-023-04613-9

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