IO-202 Monotherapy and Combination Demonstrates Efficacy in AML and CMML

Data from a phase 1 (NCT04372433) clinical trial reveal that IO-202, alone and in combination with azacitidine (Vidaza) and venetoclax (Venclexta), show promising efficacy in patients with relapsed/refractory monocytic leukemias (M4 and M5 acute myeloid leukemia [AML]) and high-risk relapsed/refractory chronic myelomonocytic leukemia (CMML).¹

Results from the trial have led to enrollment in an expansion cohort with IO-202 in combination with azacitidine specific to this rare disease.

Phase 1a of the trial examined dose escalation of IO-202 as a monotherapy and in combination with azacitidine. Phase 1b of the trial studied dose expansion data of IO-202 in combination with azacitidine for the treatment of patients with hypomethylating agent (HMA)-naive CMML.

“This is the first-in-human clinical trial that investigated IO-202, a humanized immunoglobulin G1 antibody with high affinity and specificity toward LILRB4, in patients with CMML and AML,” stated Aribi et al in the study.¹ “Rapid and significant depletion of LILRB4-positive blasts have been observed, indicating strong target engagement and antibody effector function. IO-202 is, to our knowledge, the first anti-LILRB4 antibody under clinical development for HMA-naive CMML, with potential applicability in other hematologic malignancies such as AML.”

Patients with relapsed/refractory monocytic AML expressing high LILRB4 on leukemia blasts demonstrated clinical activity, including a complete response (CR) in dose escalation with IO-202 plus azacitidine. Patients with HMA-naive CMML demonstrated a 27.8% CR rate and a 66.7% overall response rate (ORR) when treated with IO-202 plus azacitidine. In a subset of 6 patients with the highest LILRB4 expression, the CR rate was 33.3% and the ORR was 100%.¹

All 18 efficacy-evaluable patients with HMA-naive CMML reached some form of investigator-assessed clinical benefit, which included symptomatic improvement, a decrease in transfusions, reduced blasts and/or monocytes, and resolution of thrombocytopenia. Out of these patients, 38.9% proceeded to allogeneic hematopoietic cell transplantation (HCT).

Phase 1a consisted of 46 total patients, with 31 receiving IO-202 monotherapy (n = 26, relapsed/refractory AML) (n = 5, relapsed/refractory CMML). The remainder 15 patients received a combination of IO-202 plus azacitidine (n = 10, relapsed/refractory AML) (n = 5, relapsed/refractory CMML).¹

Only 2 patients were enrolled in the dose expansion of IO-202 plus azacitidine for patients with LILRB4 relapsed/refractory AML.

IO-202 was found to be well-tolerated as a monotherapy and in combination with azacitidine. The maximum administered dose was 60 mg every 2 weeks intravenously. Treatment emergent adverse events (AEs) were reported in 100% of patients, and treatment-related AEs were reported in 47.9% of patients. In ≥10% of patients, treatment-related AEs included nausea, fatigue, and vomiting.

In patients who received IO-202 monotherapy, 3 experienced grade ≥3 treatment-related AEs, and 4 had serious AEs leading to withdrawal from the study. These symptoms included hallucination, acute respiratory distress syndrome, and chest pain. In patients who received combination treatment, all grade ≥3 treatment-related AEs and serious AEs were attributed to azacitidine alone or to both drugs, per investigator’s assessments.

In patients with HMA-naive CMML, the overall rates of treatment emergent and treatment-related AEs were 100% and 90.5%, respectively. There were only 3 grade 3 treatment related AEs attributed to IO-202, which included diarrhea, somnolence, and infusion-related reactions. There were 4 cases of serious AEs related to IO-202, 3 infusion-related reactions, and 1 case of pyrexia.

Of the 18 efficacy-evaluable patients, 7 (38.9%) proceeded to allogeneic HCT. Patients had a median age of 70 (range, 61-74). They received a median of 5 treatment cycles (range, 3.5-12) of IO-202 plus azacitidine before allogeneic HCT.¹

Several clinically meaningful improvements were found during treatment. All the efficacy-evaluable patients achieved or sustained a BM blast percentage <5%, and peripheral blood markers improved notably, with 88% of patients achieving monocyte counts ≤1 × 10⁹/L and 93% having white blood cell counts ≤10 × 10⁹/L.

The data reported support a future pivotal study of IO-202 plus azacitidine in patients with HMA-naive CMML.

REFERENCE:

1. Aribi A, Mannis G, Madanat Y et al. A phase 1 study of IO-202, an anti-LILRB4 antibody, in chronic myelomonocytic leukemia and acute myeloid leukemia. Blood Neoplasia (2025) 2 (4): 100126. doi.org/10.1016/j.bneo.2025.100126