P536: a first-in-human phase 1 study of io-202 (anti-lilrb4 mab) in acute myeloid leukemia (aml) with monocytic differentiation and chronic myelomonocytic leukemia (cmml) patients

Background: Monocytic AML represents approximately 10-20% of AML and is often associated with extramedullary disease, hyperleukocytosis, and venetoclax-resistance. LILRB4 (also known as ILT3, CD85K, and LIR5) is an immune inhibitory receptor whose expression in patients with AML with monocytic differentiation negatively correlates with overall survival. IO-202 is a humanized IgG1 monoclonal antibody with high affinity and specificity towards LILRB4, and blocks LILRB4 binding to its known ligands apolipoprotein E and fibronectin. IO-202 has three mechanisms of action (MOA) in hematologic malignancies, including activation of T cell cytotoxicity, ADCC or ADCP activities, and reduction of leukemia tissue infiltration in nonclinical models. FDA has granted Fast Track designation for IO-202 for the treatment of relapsed or refractory (R/R) AML. Aims: The presentation will report clinical trial data of IO-202 from the dose escalation (Part 1) stage of the first-in-human phase 1 study in AML and CMML patients (IO-202-CL-001; NCT04372433). Methods: In Part 1 of the study, R/R AML with monocytic differentiation, or R/R CMML patients were enrolled in escalating dose levels (0.03 to 60 mg/kg) as monotherapy and in combination with azacitidine (AZA). IO-202 is administered on day 1 and day 15 of each 28-day cycle, and AZA is administered 75 mg/m2 IV or SC on days 1-7 of each 28-day cycle in patients treated in the combination cohorts. The first 28-day cycle is defined as the dose-limiting toxicity (DLT) period. Safety, tolerability, pharmacokinetics, immunogenicity, clinical activity and pharmacodynamic (PD) biomarkers were assessed. Results: As of February 2023, 46 patients (AML n=36, CMML n=10) were treated in Part 1 with IO-202 monotherapy (9 cohorts; n=31) or in combination with AZA (4 cohorts; n=15). Treatment related AEs in 2 or more subjects were vomiting (4), nausea (3), and abdominal pain, chills, fatigue, infusion related reaction and headache (2 subjects each) in monotherapy and none in combination therapy. No study deaths have been assessed as related to IO-202 administration. No DLTs were observed, and the maximum tolerated dose was not reached. In monotherapy, 1 CMML patient demonstrated Clinical Benefit for more than 1 year, and 1 AML patient achieved PR. In combination therapy, 1 AML patient with high LILRB4 expression who was refractory to azacitidine and venetoclax based combination therapy achieved CR, ongoing at 7+ months. Three CMML patients achieved PR, Optimal Marrow Response, or Clinical Benefit. Based on the available central flow cytometry data, 9 out of 13 patients in monotherapy and 9 out of 11 in combination demonstrated LILRB4-positive blast reduction at 4.5 mg/kg or higher doses of IO-202. These data in conjunction with other PD biomarker data, including T cell activation in the majority of enrolled patients and the potential contribution of ADCC or ADCP in patients with high LILRB4 expression, are consistent with the MOA derived from nonclinical studies. Achieving serum LILRB4 saturation and blast reduction in Part 1 indicates that the preliminary RP2D can be selected for dose expansion cohorts (Part 2 of the Study) from within the tested dose range. Summary/Conclusion: IO-202 is safe and well tolerated as monotherapy and in combination with AZA. Encouraging responses, including monotherapy activity, ongoing CR in an AML patient with high LILRB4 expression, and PR and Optimal Marrow Response in CMML patients, were observed. PD biomarker data supported proposed MOA. Based on Part 1 clinical data, a strategy to select AML patients will be employed in Part 2 expansion cohorts. Keywords: Chronic myelomonocytic leukemia, AML, CMML, Immunotherapy