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1008 IO-202, a Novel Anti-LILRB4 Antibody, with Azacitidine for Hypomethylating Agent-Naive Chronic Myelomonocytic Leukemia: Phase 1b Expansion Cohort ResultsClinically Relevant Abstract

Program: Oral and Poster Abstracts
Type: Oral
Session: 637. Myelodysplastic Syndromes: Clinical and Epidemiological: Defining and Treating Chronic Myelomonocytic Leukemia
Hematology Disease Topics & Pathways:
Research, Clinical trials, Clinical Research
Monday, December 9, 2024: 5:45 PM

Gabriel N Mannis, MD1, Ahmed Aribi, MD2*, Neil Dunavin, MD, MS3*, Hetty E. Carraway, MD, MBA4, Jennifer N. Saultz, DO5, Gail J. Roboz, MD6, Brian A. Jonas, MD, PhD7, Yazan F Madanat, MD8, Guillermo Garcia-Manero, MD9, Deepa Jeyakumar, MD10, Daniel A Pollyea, MD11, Olatoyosi Odenike, MD12, William Blum, MD13, Gary J. Schiller, MD14, Yasuhiro Tabata, MD, PhD15, Donna Valencia16*, Tao Huang16*, Wen Hong Lin16*, Hong Xiang16*, Charlene Liao, PhD16* and Courtney D. DiNardo, MD, MSc17

1Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA
2Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA
3University of California San Francisco, San Francisco, CA
4Department of Hematology and Medical Oncology, Cleveland Clinic Taussig Cancer Institute, Cleveland, OH
5Knight Cancer Institute, Oregon Health & Science University, Portland, OR
6Weill Cornell Medicine and The New York Presbyterian Hospital in New York City, New York, NY
7UC Davis Comprehensive Cancer Center, Davis, CA
8Division of Hematology/Oncology, Department of Internal Medicine, University of Texas Southwestern, Dallas, TX
9Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
10Department of Medicine, Division of Hematology Oncology, Chao Family Comprehensive Cancer Center, University of California Irvine Health, University of California Irvine, Orange, CA
11Division of Hematology, University of Colorado, Denver, CO
12Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL
13Emory University, Winship Cancer Institute, Atlanta, GA
14Division of Hematology and Oncology, University of California, Los Angeles, Los Angeles, CA
15Lexington, MA
16Immune-Onc, Palo Alto
17Department of Leukemia, UT MD Anderson Cancer Center, Houston, TX

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.

Disclosures: 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: Aptose: Research Funding; F. Hoffman-La Roche: Research Funding; Celgene: Research Funding; Forma Therapeutics: Research Funding; Forty-Seven: Research Funding; Hanmi: Research Funding; Immune-Onc: Research Funding; Loxo Oncology: Research Funding; Jazz: Research Funding; Incyte: Research Funding; AROG: Research Funding; Amgen: Research Funding; Rigel: Consultancy, Other: Travel; 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; Kymera: Consultancy, Membership on an entity's Board of Directors or advisory committees; GlycoMimetics: 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; Pfizer: 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; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, 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; Pharmacyclics: Research Funding; Sigma Tau: Research Funding; Treadwell: 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.

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