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

doi:10.3389/fonc.2021.806243

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.

Highlights

AML is a common hematologic malignancy in adults with more than 10 thousand anticipated deaths in the US alone for 2021 (SEER Program, www.seer.cancer.gov)
We used immunophenotyping by multiparameter flow cytometry to examine the effects of APVO436 on tumor burden reflected by CD123+CD34+CD38- target blast cells [19]
In contrast to these 3 AML cases, Table 2 and Figure S1 illustrate that the CD34+CD38-CD123+ cells from the 4th AML patient, UPN05, were not depleted to APVO436 treatments, their expansion was prevented which was associated with stable disease with a time to progression of 238 days

Summary

Introduction

AML is a common hematologic malignancy in adults with more than 10 thousand anticipated deaths in the US alone for 2021 (SEER Program, www.seer.cancer.gov). There is an urgent and unmet need for effective new treatment modalities for elderly patients with newly diagnosed AML [1,2,3,4,5,6]. No effective salvage treatment strategies exist for elderly patients with relapsed AML who often suffer cumulative organ toxicity from previous chemotherapy representing an additional hurdle to identifying effective options for their reinduction therapy [10, 11]. Not surprisingly, these patients have a dismal prognosis and are in urgent need of new strategies for their chemoresistant leukemia

Methods

Results

Conclusion