Post-hoc Analysis of Pharmacodynamics and Single-Agent Activity of CD3xCD123 Bispecific Antibody APVO436 in Relapsed/Refractory AML and MDS Resistant to HMA or Venetoclax Plus HMA

Justin Watts; Tara L Lin; Alice Mims; Prapti Patel; Cynthia Lee; Anoush Shahidzadeh; Paul Shami; Elizabeth Cull; Christopher R Cogle; Eunice Wang; Fatih M Uckun

doi:10.3389/fonc.2021.806243

Post-hoc Analysis of Pharmacodynamics and Single-Agent Activity of CD3xCD123 Bispecific Antibody APVO436 in Relapsed/Refractory AML and MDS Resistant to HMA or Venetoclax Plus HMA

Front Oncol. 2022 Jan 13:11:806243. doi: 10.3389/fonc.2021.806243. eCollection 2021.

Authors

Justin Watts¹, Tara L Lin², Alice Mims³, Prapti Patel⁴, Cynthia Lee⁵, Anoush Shahidzadeh⁵, Paul Shami⁶, Elizabeth Cull⁷, Christopher R Cogle⁸, Eunice Wang⁹, Fatih M Uckun^{5

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Affiliations

¹ Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, United States.
² Cancer Center and Medical Pavillon, University of Kansas, Westwood, KS, United States.
³ Wexner Medical Center/James Cancer Hospital, The Ohio State University, Columbus, OH, United States.
⁴ Harold C. Simmons Comprehensive Cancer Center, Department of Internal Medicine, Division of Hematology-Oncology, University of Texas Southwestern Medical Center, Dallas, TX, United States.
⁵ Department of Regulatory Affairs and Clinical Research, Aptevo Therapeutics, Seattle, WA, United States.
⁶ Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, United States.
⁷ Greenville Health System, Institute for Translational Oncology Research, Greenville, SC, United States.
⁸ Department of Medicine, Division of Hematology & Oncology, University of Florida, Gainesville, FL, United States.
⁹ Roswell Park Comprehensive Cancer Center, Department of Medicine, Buffalo, NY, United States.
¹⁰ Immuno-Oncology Program, Ares Pharmaceuticals, St. Paul, MN, United States.

Abstract

APVO436 is a recombinant bispecific antibody designed to direct host cytotoxic T-cells to CD123-expressing blast cells in patients with hematologic malignancies. APVO436 showed promising tolerability and single-agent activity in relapsed or refractory (R/R) acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). The primary purpose of this post-hoc analysis was to evaluate the therapeutic and pharmacodynamic effects of APVO436 in 14 R/R AML/MDS patients who had failed treatment with hypomethylating agents (HMA) or venetoclax plus HMA prior to being enrolled in the APVO436 Phase 1 dose-escalation study that was recently completed. Eight of these 14 patients had R/R AML and had failed treatment with HMA (N=2) or venetoclax plus HMA (N=6). The remaining 6 patients had R/R MDS and had also failed treatment with HMA (N=5) or venetoclax plus HMA (N=1). They were treated with APVO436 at submicrogram dose levels >0.08 mcg/kg that were active in preclinical NOD/SCID mouse xenograft models of AML. APVO436 activated patients' T-cells as evidenced by reduced numbers of circulating CD123⁺CD34⁺ and CD33⁺CD34⁺ peripheral blasts. Single-agent activity was observed at dose levels ranging from 0.1 mcg/kg to 0.7 mcg/kg in 4 R/R AML patients (50%), including 3 patients with prolonged stable disease (SD) and one patient with complete remission (CR). Likewise, 3 MDS patients had SD (50%) and 3 additional MDS patients (50%) had a marrow CR at dose levels ranging from 0.1 mcg/kg to 0.8 mcg/kg. The median survival for the combined group of 14 R/R AML/MDS patients was 282 days. This early evidence of single-agent activity of APVO436 in R/R AML/MDS patients who failed HMA with or without venetoclax provides proof of concept supporting its in vivo immunomodulatory and anti-leukemic activity and warrants further investigation of its clinical impact potential.

Keywords: AML – acute myeloid leukaemia; CD123 expression; bispecific antibody (bsAb); myelodysplastic and myeloproliferative syndromes; venetoclax (BCL2 inhibitor).