2. Academic Validation
  3. Activity of eftozanermin alfa plus venetoclax in preclinical models and patients with acute myeloid leukemia

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

  • Blood. 2023 Jan 30;blood.2022017333. doi: 10.1182/blood.2022017333.
Stephen K Tahir 1,  Emiliano Calvo 2,  Benedito A Carnero 3,  Junichiro Yuda 4,  Aditya Shreenivas 5,  Mojca Jongen-Lavrencic 6,  Eelke Gort 7,  Kenichi Ishizawa 8,  Daniel Morillo 9,  Carla Biesdorf 1,  Morey Smith 1,  Dong Cheng 1,  Monica Motwani 10,  David Sharon 1,  Tamar Uziel 1,  Dimple A Modi 11,  Fritz G Buchanan 1,  Susan Morgan-Lappe 1,  Bruno C Medeiros 12,  Darren C Phillips 1
Affiliations

Affiliations

  • 1 AbbVie Inc., North Chicago, Illinois, United States.
  • 2 START Madrid-CIOCC, Centro Integral Oncologico Clara Campal, Madrid, Spain.
  • 3 Legorreta Cancer Center at Brown University, Lifespan Cancer Institute, Providence, Rhode Island, United States.
  • 4 National Cancer Center Hospital East, Kashiwa, Japan.
  • 5 Medical College of Wisconsin, Wauwatosa, Wisconsin, United States.
  • 6 Erasmus Medical Center, Rotterdam, Netherlands.
  • 7 University Medical Center Utrecht, Utrecht, Netherlands.
  • 8 Yamagata University Faculty of Medicine, Yamagata, Japan.
  • 9 Hospital Universitario Fundación Jiménez Díaz, Madrid, Spain.
  • 10 Precision Medicine, AbbVie Inc., United States.
  • 11 Regeneron, Tarrytown, New York, United States.
  • 12 AbbVie Inc., South San Francisco, California, United States.
PMID: 36720090 DOI: 10.1182/blood.2022017333
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 Bcl-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 activity in AML cell lines and patient-derived ex vivo/in vivo models. Eftoza activity alone or plus venetoclax required death receptor (DR)4/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 50% (2/4) of patients treated with eftoza monotherapy and 78% (18/23) treated with eftoza plus venetoclax. An overall response rate of 30% (7/23; 4 complete responses [CR], 2 CR with incomplete hematologic recovery, 1 with morphologic leukemia-free state [MLFS]) 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. Registered at www.clinicaltrials.gov as NCT03082209.

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