Notable Clinical Benefit and Safety Data with IO-202 Plus Azacitidine in CMML

For patients with HMA–naive chronic myelomonocytic leukemia, an IO-202 combo demonstrated durable responses, a phase 1b study found.

Data shared during a presentation at the 2024 American Society of Hematology Annual Meeting & Exposition (ASH) on a phase 1b study (NCT04372433) reflected statistically significant response rates and safety data stemming from therapy of IO-202 with azacitidine (Vidaza) in patients with hypomethylating agent (HMA)–naive chronic myelomonocytic leukemia (CMML).¹

In efficacy evaluable patients (n = 18), the regimen elicited a complete remission (CR) rate of 50.0% and an overall response rate (ORR) of 66.7%. Moreover, 38.9% of patients subsequently proceeded to an allogeneic stem cell transplant (ASCT). A total of 3 patients withdrew because of disease progression or lack of response by cycle 6. Notably, efficacy favored those with high LILRB4 expression (n = 6). In this subset of patients, the doublet induced a CR rate of 83.3% and the ORR was 100%.

“Responses occurred early, with a median time to first response of 1 cycle, and a median time to best response of 2.5 cycles, further supporting the hypothesis that these responses are not just due to azacitidine alone but are due to the addition of IO-202,” Gabriel N. Mannis, MD, an associate professor of medicine in the Division of Hematology at Stanford University School of Medicine and medical director of the Inpatient Leukemia Service, in California, stated in a presentation of the data. “These responses have been durable, with patient number 1 continuing on study at the time of data cut, 16 months after initiation of therapy, and no patient thus far having progressive disease after achieving an initial response.”

CMML is a rare but lethal hematologic malignancy with approximately 1100 cases diagnosed annually in the United States. “Despite being dubbed a chronic leukemia, median survival is short, with very few patients being able to proceed to potentially curative ASCT,” Mannis noted. The current standard for these patients is a HMA, typically azacitidine. “Understanding the baseline response rates [with] azacitidine alone have been hampered both by the heterogeneity of patients studied and the variety of different response assessment systems,” he added. CRs with azacitidine are estimated to range from 10% to 20% in HMA-naïve patients with CMML.

IO-202 is a first-in-class IgG1 antibody targeted to LILRB4, a cell surface receptor that is overexpressed in CMML cells. The agent binds with high specificity and affinity to LILRB4, leading to antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis. In vitro, this depletion depends on LILRB4 copy number. The agent has received fast track and orphan drug status² from the FDA for patients with CMML, according to Mannis.

For the phase 1b study, investigators enrolled patients with newly diagnosed CMML who had not previously received a HMA to the expansion cohort. Patients were enrolled irrespective of LILRB4 expression levels.¹

Upon enrollment, patients received a single loading dose of IO-202 at 60 mg/kg intravenously on day 1, followed by every-2-week dosing at 30 mg/kg. Azacitidine was given at a standard dose and schedule of 75 mg/m² intravenously or subcutaneously on days 1 to 7 of each 28-day cycle. “Patients were treated until progression or toxicity with a protocol specification that patients who had not responded after 6 cycles of therapy were required to come off study,” Mannis noted.

By the data cutoff date of October 28, 2024, a total of 21 patients had received treatment; all 21 patients comprised the safety-evaluable set and 18 comprised the efficacy-evaluable set. Efficacy was assessed according to the 2023 International Working Group criteria.

In the total patient population, the median age was 71 years (range, 54-82), and 66.7% of patients were male. Most patients were White (61.9%), more than half had proliferative disease (57.1%), and 19% had CMML-2 disease. Just under half of patients (47.6%) had blasts above 5%, and 38.1% were transfusion dependent at baseline. “As might be expected, symptom burden in this cohort was high, with nearly half of patients having symptom scores of greater than 15, as per the MPN Symptom Assessment Form,” Mannis said.

He added that based on data from healthy donors, high LILRB4 expression was defined as greater than 50% positivity of the marker on cells and greater than 4500 copies/cell; 31.6% of patients had high LILRB4 expression. Forty-five percent of patients were high risk per the CPSS molecular scoring system. Abnormal cytogenetics were observed in 19.1% of patients, and the most frequent gene mutations included ASXL1 (71.4%), TET2 (47.6%), RUNX1 (23.8%), and SRSF2 (23.8%). “Importantly, nearly half of patients had RAS pathway mutations,” he added.

Responses were observed across all subgroups, including those with proliferative disease (66.7%), elevated blast counts (41.7%), unfavorable mutations (75%), and high-risk CPSS molecular scores (50%). All patients achieved or maintained a bone marrow blast percentage under 5%. Additionally, 83% of patients achieved monocyte counts in peripheral blood of 0.5 x 10⁹/L or below, 93% achieved white blood cell counts in peripheral blood of no higher than 10 x 10⁹ cells/L, and 54% achieved hemoglobin levels of at least 10 g/dL without red blood cell transfusion.

“This improvement in hemoglobin translated to two-thirds of transfusion-dependent patients achieving transfusion independence,” Mannis said. “One of the most immediate and striking findings in this cohort was that patients experienced rapid and dramatic symptom improvement, with 100% of patients with a baseline symptom score greater than 15 demonstrating a greater than 50% reduction in their MPN SAF total symptom score.”

He added that, although pre- and post-treatment data are limited, all 3 patients who had RAS pathway mutations at baseline and available data ultimately cleared those mutations while on treatment.

Regarding safety, all patients experienced treatment-emergent adverse effects (TEAEs), 66.7% of which were grade 3 or higher. TEAEs led to dose reduction for 9.5% of patients and discontinuation for 9.5% of patients. Serious TEAEs were experienced by 33.3% of patients and led to discontinuation for 9.5% of patients. Treatment-related AEs (TRAEs) occurred in 90.5% of patients and they were grade 3 or higher for 52.4% of patients. They led to dose reduction or discontinuation for 9.5% and 4.8% of patients, respectively. Serious TRAEs were reported in 28.6% of patients and they led to discontinuation in 4.8% of patients.

“Although nearly all patients had TRAEs, overall, the combination was extremely well tolerated,” Mannis said. “The majority of grade 3 and above AEs were hematologic in nature, with the only serious AEs attributed to IO-202 being infusion-related reactions [IRRs] in 3 patients in addition to an episode of pyrexia in 1 patient. Two of the 3 IRRs were grade 2, with one being grade 3, and all occurred with the initial dose of therapy without subsequent recurrence.”

Mannis concluded that the data support a future pivotal study of the doublet in this population.

Disclosures: Dr Mannis received research funding from ImmuneOnc, Glycomimetics, Jazz, Gilead, Astex, BMS/Celgene, Forty Seven, Syndax Pharmaceuticals, Inc., and Aptose. He has membership on an entity’s board of directors or advisory committees for Stemline, Astellas, Servier, Orbital Therapeutics, Genentech, Immunogen, Wugen, Rigel, Agios, AbbVie, BMS/Celgene, and Forty Seven. He has a consultancy role with Stemline, Servier, Agios, AbbVie, Macrogenics, and Pfizer.

References

1. Mannis GN, Aribi A, Dunavin N, et al. IO-202, a novel anti-LILRB4 antibody, with azacitidine for hypomethylating agent-naive chronic myelomonocytic leukemia: phase 1b expansion cohort results. Blood. 2024;144(suppl 1):1008. doi:10.1182/blood-2024-206538
2. Immune-Onc Therapeutics announces orphan drug designation granted by US FDA for IO-202 (anti-LILRB4) for the treatment of chronic myelomonocytic leukemia (CMML). News release. Immune-Onc Therapeutics, Inc. February 21, 2024. Accessed December 10, 2024. https://www.immune-onc.com/pr-posts/immune-onc-therapeutics-announces-orphan-drug-designation-granted-by-usfda-for-io-202-anti-lilrb4-for-the-treatment-of-chronic-myelomonocytic-leukemia-cmml