Engaging Innate Immunity By AFM28, an Innate Cell Engager (ICE®) Targeting CD123-Positive Leukemic Cells in Patients with Relapsed/Refractory Acute Myeloid Leukemia: Safety and Efficacy Results of a First-in-Human Phase 1 Study
Authors: Montesinos Pau , Arnan Montserrat , De Botton Stephane , Calbacho Maria , Rodriguez Veiga Rebeca , Bories Pierre , Ansoleaga Belén , Hueso Thomas , Daver Naval , Wunderle Lydia , Harstrick Andreas , Pietzko Kerstin , Hajela Pallavi , Vasile Alexandra , Witte Tania , Saenger Elmarie , Récher Christian 
Published: December 2024

Background
AFM28 is a high-affinity bispecific CD123/CD16A ICE®, developed for treatment of CD123-expressing hematological malignancies, e.g. acute myeloid leukemia (AML). Its primary mechanism of action is the induction of antibody-dependent cellular cytotoxicity by CD16A-expressing innate effector cells, primarily natural killer (NK) cells, towards CD123-expressing leukemic cells. Herein, we report the results of AFM28-101, a phase 1 multiple ascending dose escalation study (NCT05817058), investigating the safety and early efficacy signs of AFM28 in patients with relapsed/refractory (R/R) CD123-positive AML.
Patients and Methods
AFM28-101 is a first-in human phase 1, multicenter, open-label, non-randomized, multiple ascending dose escalation study evaluating the safety, tolerability, pharmacokinetics (PK), immunogenicity, pharmacodynamics (PD), and antileukemic activity of AFM28 monotherapy in adult patients with CD123-positive R/R AML, who experienced up to 3 relapses or were at least primary refractory and received at most 3 regimes of previous standard anti-leukemia therapy. 24 patients were enrolled in the dose escalation of the study consisting of 6 dose levels (25 mg to 300 mg) and received i.v. AFM28 once weekly for 28-day cycles until disease progression, intolerable toxicity, patient withdrawal, or termination at the investigator's discretion. The dose escalation was guided by a Bayesian logistic regression model. The primary endpoint was assessed by the incidence of dose limiting toxicities considering the totality of treatment-emergent adverse events (TEAEs). Secondary endpoints included the incidence, severity and seriousness of TEAEs, efficacy, immunogenicity and characterizing PK. Exploratory endpoints included PD biomarkers. Responses were determined using 2017 European Leukemia Network (ELN) classification criteria.
Results
As of 11 July 2024, 24 patients with R/R AML were enrolled in the study. The median age at enrollment was 72 (28-82) years, and ECOG was 0 (50%) or 1 (50%). Median bone marrow blast count at screening was 36.5% (5-83%) and the majority of patients (83%) were classified with adverse risk according to ELN 2022 classification. Patients received a median of 2 prior lines (1-3) of antileukemic therapy with 5 patients (21%) with previous hematopoietic stem cell transplantation, 16 patients (67%) previously treated with venetoclax combinations, and 10 patients (42%) treated with intensive chemotherapy. Patients received a median of 2 AFM28 cycles (1-11) with a median treatment duration of 7.4 weeks. TEAEs were reported in 24 patients (100%) with grade ≥ 3 TEAEs in 3 patients (13%). The most common TEAE were infusion-related reactions (IRR) in 10 patients (42%), no Grade 3 or higher IRR events across all dose levels were observed. Two cases of cytokine release syndrome (CRS) were reported: one Grade 1 at dose level 300 mg after first infusion in cycle 1 and one Grade 3 at dose level 50 mg in cycle 2. All CRS and IRR events were fast resolving under standard of care treatment without the use of tocilizumab. One dose limiting toxicity (at 200 mg) was observed in a patient with possibly related fatal pneumonitis. No other pneumonitis events or unexpected safety signals were observed during the trial, demonstrating AFM28 is well tolerated up to 300 mg flat dose infusion once weekly.
To date, in the two highest dose levels, i.e., 250 mg and 300 mg, 4 out of 12 patients achieved complete remission (CR) or complete remission with incomplete hematological recovery (CRi) resulting in a Composite Complete Remission rate (CRcR, defined as CR+CRi) of 33.3%. One patient treated with 250 mg with complete remission continues benefiting from the treatment over 6 cycles. At the highest dose level (300 mg), 3 out of 6 patients achieved CR or CRi, respectively, as best response. CR/CRi were observed upon completion of 1-3 cycles of treatment.
The final safety and efficacy data including preliminary PK and PD results will be presented at the conference.
Conclusions
AFM28 monotherapy demonstrated early signs of clinical efficacy and a well-managed safety profile up to a weekly dose of 300mg in patients with R/R AML. These results support further development of AFM28 in combination with e.g., allogenic off-the-shelf NK cells in AML.