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.

Mannis:Stemline: Consultancy, Membership on an entity's Board of Directors or advisory committees; ImmuneOnc: Research Funding; Glycomimetics: Research Funding; Astellas: Membership on an entity's Board of Directors or advisory committees; Jazz: Research Funding; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Research Funding; Astex: Research Funding; Orbital Therapeutics: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; Immunogen: Membership on an entity's Board of Directors or advisory committees; Wugen: Membership on an entity's Board of Directors or advisory committees; Rigel: Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Forty Seven: Membership on an entity's Board of Directors or advisory committees, Research Funding; Syndax Pharmaceuticals, Inc.: Research Funding; Aptose: Research Funding; Macrogenics: Consultancy; Pfizer: Consultancy. Aribi:Kite, a Gilead Company: Consultancy; Seagen: Consultancy. Carraway:BMS: Membership on an entity's Board of Directors or advisory committees; Daiichi: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Stemline: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding. Saultz:Ikena: Research Funding; Rigel: Consultancy; Sanofi: Consultancy. Roboz:Novartis, Pfizer, Roche, GlaxoSmithKline, BMS, Syndax, Rigel: Consultancy; Janssen: Research Funding; OncoPrecision: Current holder of stock options in a privately-held company, Honoraria; AbbVie, Amgen, Astrazeneca, Caribou Biosciences, Celgene, Daiichi Sankyo, Ellipses pharma, Geron, GSK, Glycomimetics, Janssen, Jasper Pharmaceuticals, Jazz Pharmaceuticals, Molecular Partners, Oncoverity: Consultancy. Jonas:Rigel: Consultancy, Other: Travel; Amgen: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech/Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; GlycoMimetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kymera: Consultancy, Membership on an entity's Board of Directors or advisory committees; AROG: Research Funding; Aptose: Research Funding; Celgene: Research Funding; F. Hoffman-La Roche: Research Funding; Forma Therapeutics: Research Funding; Forty-Seven: Research Funding; Hanmi: Research Funding; Immune-Onc: Research Funding; Incyte: Research Funding; Jazz: Research Funding; Loxo Oncology: Research Funding; Pharmacyclics: Research Funding; Sigma Tau: Research Funding; Treadwell: Research Funding; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Madanat:Blueprint Medicines, MD Education, and Morphosys: Other: travel; OncLive, MD Education, Sierra Oncology, Stemline, MorphoSys: Consultancy; Taiho Oncology, Rigel Pharmaceuticals, Novartis: Consultancy; Sierra Oncology, Stemline Therapeutics, Blueprint Medicines, Morphosys, Taiho Oncology, SOBI, Rigel Pharmaceuticals, Geron, Cogent Biosciences and Novartis: Other: Advisory Board; BMS, Kura Oncology, BluePrint Medicines, Geron: Consultancy. Garcia-Manero:Genentech: Research Funding; Bristol Myers Squibb: Other: Personal fees, Research Funding; Forty Seven: Research Funding; AbbVie: Research Funding; Onconova: Research Funding; Astex: Other: Personal fees; H3 Biomedicine: Research Funding; Merck: Research Funding; Aprea: Research Funding; Janssen: Research Funding; Curis: Research Funding; Astex: Research Funding; Novartis: Research Funding; Helsinn: Research Funding; Helsinn: Other: Personal fees; Amphivena: Research Funding; Genentech: Other: Personal fees. Jeyakumar:Pfizer: Research Funding; Jazz Pharma: Research Funding. Pollyea:Abbvie: Honoraria, Research Funding; Medivir: Honoraria; Daiichi Sankyo: Honoraria; Rigel: Honoraria; Novartis: Honoraria; Sumitomo: Honoraria; Adicet: Honoraria; Syros: Honoraria; Qihan: Honoraria; Seres: Honoraria; Gilead: Honoraria; Oncoverity: Honoraria; Aptevo: Honoraria; Bristol Myers Squibb: Honoraria, Research Funding; Boehringer Ingelheim: Honoraria; Sanofi: Honoraria; Karyopharm: Honoraria, Research Funding; MEI: Honoraria; Syndax: Honoraria; Beigene: Honoraria; Hibercell: Honoraria; LINK: Honoraria; Ryvu: Honoraria. Odenike:AbbVie (Inst); Agios (Inst); Aprea AB (Inst); Astex Pharmaceuticals (Inst); AstraZeneca (Inst); Bristol-Myers Squibb (Inst); Celgene (Inst); CTI BioPharma Corp (Inst); Daiichi Sankyo (Inst); Incyte (Inst); Janssen Oncology (Inst); Kartos Therapeutics (Ins: Research Funding; AbbVie; Blueprint Medicines; BMS; Bristol-Myers Squibb/Celgene (Inst); Celgene; CTI; Impact Biomedicines; Kymera; Novartis; SERVIER; Taiho Pharmaceutical; Treadwell Therapeutics: Honoraria. Tabata:Immune-Onc: Ended employment in the past 24 months. Valencia:Immune-Onc: Current Employment. Huang:Immune-Onc: Current Employment. Lin:Immune-Onc: Current Employment. Xiang:Immune-Onc: Current Employment. Liao:Immune-Onc: Current Employment. DiNardo:Servier: Consultancy, Honoraria, Other: meetingsupport, Research Funding; Immunogen: Honoraria; Schrodinger: Consultancy, Honoraria; Notable Labs: Honoraria; GSK: Consultancy, Honoraria; Genetech: Honoraria; Riegel: Honoraria; BMS: Consultancy, Honoraria, Research Funding; GenMab: Consultancy, Honoraria, Other: data safety board; Astex: Research Funding; ImmuneOnc: Research Funding; Cleave: Research Funding; Foghorn: Research Funding; Loxo: Research Funding; Rigel: Research Funding; Amgen: Consultancy; Astellas: Consultancy, Honoraria; Gilead: Consultancy; Jazz: Consultancy, Honoraria; AstraZeneca: Honoraria; Abbvie: Consultancy, Honoraria, Research Funding; Stemline: Consultancy.