Eftozanermin alfa (ABBV-621) monotherapy in patients with previously treated solid tumors: findings of a phase 1, first-in-human study
LoRusso, Patricia; Ratain, Mark J; Doi, Toshihiko; Rasco, Drew W; de Jonge, Maja J A; Moreno, Victor; Carneiro, Benedito A; Devriese, Lot A; Petrich, Adam; Modi, Dimple; Morgan-Lappe, Susan; Nuthalapati, Silpa; Motwani, Monica; Dunbar, Martin; Glasgow, Jaimee; Medeiros, Bruno C; Calvo, Emiliano
(2022) Investigational New Drugs, volume 40, issue 4, pp. 762 - 772
(Article)
Abstract
Eftozanermin alfa (eftoza), a second-generation tumor necrosis factor-related apoptosis-inducing ligand receptor (TRAIL-R) agonist, induces apoptosis in tumor cells by activation of death receptors 4/5. This phase 1 dose-escalation/dose-optimization study evaluated the safety, pharmacokinetics, pharmacodynamics, and preliminary activity of eftoza in patients with advanced solid tumors. Patients received eftoza 2.5-15 mg/kg
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intravenously on day 1 or day 1/day 8 every 21 days in the dose-escalation phase, and 1.25-7.5 mg/kg once-weekly (QW) in the dose-optimization phase. Dose-limiting toxicities (DLTs) were evaluated during the first treatment cycle to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). Pharmacodynamic effects were evaluated in circulation and tumor tissue. A total of 105 patients were enrolled in the study (dose-escalation cohort, n = 57; dose-optimization cohort, n = 48 patients [n = 24, colorectal cancer (CRC); n = 24, pancreatic cancer (PaCA)]). In the dose-escalation cohort, seven patients experienced DLTs. MTD and RP2D were not determined. Most common treatment-related adverse events were increased alanine aminotransferase and aspartate aminotransferase levels, nausea, and fatigue. The one treatment-related death occurred due to respiratory failure. In the dose-optimization cohort, three patients (CRC, n = 2; PaCA, n = 1) had a partial response. Target engagement with regard to receptor saturation, and downstream apoptotic pathway activation in circulation and tumor were observed. Eftoza had acceptable safety, evidence of pharmacodynamic effects, and preliminary anticancer activity. The 7.5-mg/kg QW regimen was selected for future studies on the basis of safety findings, pharmacodynamic effects, and biomarker modulations. (Trial registration number: NCT03082209 (registered: March 17, 2017)).
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Keywords: Apoptosis, Dose-escalation, Dose-optimization, Phase 1, Solid tumor, TRAIL-R agonist, Pharmacology (medical), Oncology, Pharmacology, Journal Article
ISSN: 0167-6997
Publisher: Kluwer Academic Publishers
Note: Funding Information: Patricia LoRusso: Consulting/advisory role for Agios, AbbVie, Pfizer, Genmab, Halozyme, Roche‑Genentech, CytomX, Five Prime, Takeda, SOTIO, Cybrexa, Agenus, AstraZeneca, Boehringer Ingelheim, NCI, Shattuck, Breakthrough Cancer, and I-Mab. Mark J. Ratain: Grants or contracts to institution from Alliance Foundation, Bristol-Myers Squibb, AbbVie, Xencor, Incyte, and Boston Biomedical; royalties related to UGT1A1 genotyping from Mayo Medical Laboratories (institution and self); consulting fees for Apotex, Aptevo, Arvinas Operations, Ayala Pharma, bluebird bio, EMD Serono, EQRX, Sandoz, Actavis, Aurobindo, Dr. Reddy’s Laboratories, Mylan, Hetero Labs, Breckenridge Pharmaceutical, Teva, Shilpa, Accord, MSN, Natco, Pneuma Respiratory, Genentech, Celltrion, Eagle Pharmaceuticals; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Virology Education V.V.; payment for expert testimony from Apotex; patents planned, issued or pending for low dose tocilizumab for COVID-19 (pending); participation on a Data Safety Monitoring Board (DSMB) or Advisory Board for Credit Suisse (Scientific Advisory Board), Mereo and T3 Pharmaceuticals (DSMBs); leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid for Optimal Cancer Care Alliance (Director and Treasurer); other financial or non-financial interests from Emerson Lake Safety (honorarium for judging Sternfels Prize). Toshihiko Doi: Grants or contracts to institution from Lilly, MSD, Daiichi Sankyo, Amgen, Sumitomo Dainippon, Taiho Pharmaceutical, Novartis, Merck Serono, Janssen Pharma, Boehringer Ingelheim, Pfizer, BMS, AbbVie, IQVIA, Eisai; consulting for Chugai Pharma, Takeda, AbbVie, Bayer, Rakuten Medical, Otuska Pharma, Sumitomo Dainippon, and Taiho Pharmaceutical; payment or honoraria from BMS, Rakuten Medical, Ono Pharma, Oncolys BioPharma, Taiho Pharmaceutical; participation on a Data Safety Monitoring Board or Advisory Board for MSD, Daiichi Sankyo, Amgen, Novartis, Boehringer Ingelheim, Janssen Pharma, AbbVie, Bayer, Astellas Pharma. Drew W. Rasco: Research funding to institution from AbbVie, Arcus, Ascentage, Astex, Seven and Eight Biopharma, Bolt, Boehringer Ingelheim, BMS, Cullinan Oncology, Compugen, Constellation, GSK, Kronos, TD2, PureTech Health, Merck, Molecular Templates, Takeda. Maja J.A. de Jonge: Advisor for Faron Pharmaceuticals Ltd. Victor Moreno: Consulting/advisory role for Roche, BMS, Janssen, and Basilea. Benedito A. Carneiro: Institutional research support from AbbVie, Bayer, AstraZeneca, MedImmune, Astellas, Actuate Therapeutics, Pfizer, Dragonfly Therapeutics. Advisory role for Foundation Medicine, Tempus, G1 Therapeutics, Seattle Genetics. Lot A. Devriese: Advisory role for MSD, BMS, Merck. Martin Dunbar, Bruno C. Medeiros, Jaimee Glasgow, Susan Morgan-Lappe, Dimple Modi: Employed by AbbVie and may own stock. Adam Petrich, Silpa Nuthalapati, Monica Motwani: Former employees of AbbVie and may own stock. Emiliano Calvo: Honoraria or consultation fees: Astellas, Novartis, Nanobiotix, Pfizer, Janssen-Cilag, GLG Pharma, PsiOxus Therapeutics, Merck, Medscape, Bristol-Myers Squibb, Gilead Sciences, Seattle Genetics, Pierre Fabre, Boehringer Ingelheim, Cerulean Pharma, EUSA Pharma, Gehrmann Consulting, AstraZeneca, Roche, Guidepoint, Servier, Celgene, AbbVie, amcure, OncoDNA, Alkermes. Leadership role: director clinical research, START Madrid; director clinical research, HM Hospitals Group, Madrid; leadership in medical society: founder and president, not-for-profit Foundation INTHEOS (Investigational Therapeutics in Oncological Sciences); Methods in Clinical Cancer Research (MCCR) Workshop, Zeist, Netherlands (joint ECCO-AACR-EORTC-ESMO Workshop on MCCR), co-director. Stocks or ownership: START, Oncoart Associated, International Cancer Consultants. Licensing fees or royalties: None. Direct research funding as project lead: Novartis, AstraZeneca, BeiGene. Institutional financial support from clinical trials: AbbVie, ACEO, amcure, Amgen, AstraZeneca, Bristol-Myers Squibb, CytomX Therapeutics, GlaxoSmithKline, Genentech/Roche, H3 Biomedicine, Incyte, Janssen, Kura, Lilly, Loxo, Nektar Therapeutics, MacroGenics, Menarini, Merck, Merus, Nanobiotix, Novartis, Pfizer, PharmaMar, Principia, PUMA, Sanofi, Taiho, Tesaro, BeiGene, Transgene, Takeda, Incyte, Inovio, MSD, PsiOxus, Seattle Genetics, Mersana, GSK, Daiichi, Nektar, Astellas, ORCA, Boston Therapeutics, Dynavax, Debiopharm, Boehringer Ingelheim, Regeneron, Millennium, Synthon, Spectrum, Rigontec. Non-remunerated activities: scientific board at PsiOxus; memberships for SEOM, EORTC, ESMO, and ASCO. Full/Part-time employment: HM Hospitals Group and START, Program of Early Phase Clinical Drug Development in Oncology, employee: medical oncologist, director clinical research. Publisher Copyright: © 2022, The Author(s).
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