Activity of eftozanermin alfa plus venetoclax in preclinical models and patients with acute myeloid leukemia

Stephen K. Tahir, Emiliano Calvo, Benedito A. Carneiro, Junichiro Yuda, Aditya Shreenivas, Mojca Jongen-Lavrencic, Eelke Gort, Kenichi Ishizawa, Daniel Morillo, Carla Biesdorf, Morey Smith, Dong Cheng, Monica Motwani, David Sharon, Tamar Uziel, Dimple A. Modi, Fritz G. Buchanan, Susan Morgan-Lappe, Bruno C. Medeiros, Darren C. Phillips*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

4 Citations (Scopus)

Abstract

Activation of apoptosis in malignant cells is an established strategy for controlling cancer and is potentially curative. To assess the impact of concurrently inducing the extrinsic and intrinsic apoptosis-signaling pathways in acute myeloid leukemia (AML), we evaluated activity of the TRAIL receptor agonistic fusion protein eftozanermin alfa (eftoza; ABBV-621) in combination with the B-cell lymphoma protein-2 selective inhibitor venetoclax in preclinical models and human patients. Simultaneously stimulating intrinsic and extrinsic apoptosis-signaling pathways with venetoclax and eftoza, respectively, enhanced their activities in AML cell lines and patient-derived ex vivo/in vivo models. Eftoza activity alone or plus venetoclax required death receptor 4/5 (DR4/DR5) expression on the plasma membrane but was independent of TP53 or FLT3-ITD status. The safety/tolerability of eftoza as monotherapy and in combination with venetoclax was demonstrated in patients with relapsed/refractory AML in a phase 1 clinical trial. Treatment-related adverse events were reported in 2 of 4 (50%) patients treated with eftoza monotherapy and 18 of 23 (78%) treated with eftoza plus venetoclax. An overall response rate of 30% (7/23; 4 complete responses [CRs], 2 CRs with incomplete hematologic recovery, and 1 morphologic leukemia-free state) was reported in patients who received treatment with eftoza plus venetoclax and 67% (4/6) in patients with myoblasts positive for DR4/DR5 expression; no tumor responses were observed with eftoza monotherapy. These data indicate that combination therapy with eftoza plus venetoclax to simultaneously activate the extrinsic and intrinsic apoptosis-signaling pathways may improve clinical benefit compared with venetoclax monotherapy in relapsed/refractory AML with an acceptable toxicity profile. This trial was registered at www.clinicaltrials.gov as #NCT03082209.

Original languageEnglish
Pages (from-to)2114-2126
Number of pages13
JournalBlood
Volume141
Issue number17
DOIs
Publication statusPublished - 27 Apr 2023

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© 2023 The American Society of Hematology

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