IO-202, a Novel Anti-LILRB4 Antibody, with Azacitidine for Hypomethylating Agent-Naive Chronic Myelomonocytic Leukemia: Phase 1b Expansion Cohort Results

Introduction Chronic myelomonocytic leukemia (CMML) is a rare and lethal hematological malignancy. Hypomethylating agents (HMAs), including azacitidine (AZA), are the only approved treatment for CMML, yet they offer complete remission (CR) rate of only 10%-20%, highlighting the unmet medical need. IO-202 is a humanized IgG1 monoclonal antibody with high affinity and specificity for leukocyte immunoglobulin-like receptor B4 (LILRB4, also known as ILT3), which is predominantly expressed in monocytes and monocytic blasts. IO-202 induces antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) in vitro and in leukemia patients. We hereby present the interim analysis of the Phase 1b dose expansion study of IO-202 combined with AZA for the treatment of HMA-naïve patients with CMML (NCT04372433). Methods Eligible HMA-naïve CMML patients across the US were enrolled. IO-202 was administered at 30 mg/kg IV on Day 1 and Day 15 of each 28-day cycle following a loading dose of 60 mg/kg on Cycle 1 Day 1. AZA was administered 75 mg/m2 IV or SC on Days 1-7 of each 28-day cycle. Adverse events (AEs) were graded according to the NCI CTCAE, Version 5.0. Efficacy was evaluated based on the IWG 2023 response criteria for higher-risk myelodysplastic syndromes. LILRB4 expression was assessed using multiparameter flow cytometry. Results As of July 8, 2024, 21 patients, 14 male and 7 female, were enrolled. The median age was 71 years (range 54 - 82). There were 18 CMML-1 (<10% blasts in bone marrow [BM] and <5% blasts in peripheral blood [PB]) and 3 CMML-2 (10%-19% blasts in BM and 5%-19% blasts in PB), with 11 classified as dysplastic and 10 as proliferative. The most common gene mutations were ASXL1 (62%), TET2 (38%) and CBL (24%), with RUNX1 and SRSF2 at 19% each. Five patients had prior therapies including 4 with hydroxyurea and 1 with fedratinib. Of the 21 patients, 16 experienced treatment-emergent adverse events (TEAEs) and 11 of these had treatment-related adverse events (TRAEs). Grade 3-4 TRAEs were reported in 3 patients. The most common TRAEs were infusion-related reaction (IRR, n=6), as well as anemia, platelet count decreased, pruritus, and pyrexia (n=2 each). Three patients each had 1 serious adverse event related to IO-202 as determined by investigators. All of them were Grade 2 and resolved without treatment delay, interruption, or dosage change in IO-202. No study deaths or dose limiting toxicities were reported As of April 2024, 16 of 21 patients have received at least one dose of IO-202 + AZA treatment. The remaining 5 patients were enrolled in May 2024 or later whose data are limited now but will be updated at the Annual Meeting. Of the 16, 14 were efficacy-evaluable, as 2 patients withdrew from the study without post treatment BM data. Among 13 patients with LILRB4 expression data in BM at baseline, 8 had >50% LILRB4 positive blasts. Key efficacy data are as following: The CR rate, including both CR (4) and CR equivalent (CRe, a CR classification for patients with <5% BM blasts at baseline) (4), was 57.1% (8/14).The objective response rate (ORR) was 78.6% (11/14). Three non-responders (assessed by C2D1 BM) included 2 who dropped out within 2 cycles of treatment due to an unrelated AE or hematopietic stem cell transplant (HCT), respectively, and 1 who has yet to show a response.Rapid response correlated with baseline LILRB4 expression. Seven of 8 patients with >50% LILRB4 positive blasts were responders after the first cycle (1 CR, 5 CR with limited count recovery, and 1 hematologic improvement of platelets).Response to IO-202 + AZA occurred in patients with a variety of dysplastic or proliferative status and gene mutations.Among the 14 efficacy-evaluable patients, 6 (43%) proceeded to HCT, 1 withdrew due to AEs unrelated to IO-202, and 7 remain on study (Cycles 4-12), of which 6 have achieved CR or CRe so far. Conclusions IO-202 + AZA is well tolerated, with a CR rate of 57.1% and ORR of 78.6%. Nearly half of evaluable patients (6/14) have been bridged to HCT thus far. Preliminary efficacy outcomes appear superior to AZA alone, with rapid, sustained responses to IO-202 + AZA. Translational data suggest LILRB4 expression as a biomarker for response to therapy, supporting the mechanism of action for IO-202. In light of the paucity of effective therapies for CMML, these data support a future pivotal study of IO-202 + AZA in HMA-naïve CMML.