IO-202 Plus Azacitidine Could Bring Long-Awaited Change in HMA-Naive CMML

Early efficacy and safety data for the combination of the azacitidine and IO-202, a humanized IgG1 monoclonal antibody targeting LILRB4, point to the potential for this regimen to improve upon the long-stagnant standard of care for patients with hypomethylating agent (HMA)–naive patients with chronic myelomonocytic leukemia (CMML), according to Gabriel Mannis, MD.

Findings from an interim analysis of a phase 1b dose-expansion study (NCT04372433) presented at the 2024 ASH Annual Meeting showed that efficacy-evaluable patients treated with IO-202 plus azacitidine (n = 18) achieved a complete remission (CR) rate of 50% and an overall response rate (ORR) of 66.7%. Seven patients (38.9%) were successfully bridged to hematopoietic stem cell transplant.

In the safety population (n = 21), no dose-limiting toxicities were observed. The rates of any-grade treatment-emergent adverse effects (TEAEs) and treatment-related AEs (TRAEs) were 100% and 90.5%, respectively. The respective rates of grade 3 or higher TEAES and TRAEs were 66.7% and 52.4%. TEAEs led to treatment discontinuation and dose reduction in 9.5% of patients each. These respective rates were 4.8% and 9.5% for TRAEs. Notably, all dose reductions were limited to azacitidine.

“Taken all together, [these data are] an exciting new development in a disease that for many, many years has not had much to be excited about,” Mannis said in an interview with OncLive®.

In the interview, Mannis provided background on IO-202 and the rationale for combining the agent with azacitidine in the management of CMML; detailed key findings from the study; and explained the potential for this combination to bring change to the standard of care for CMML.

Mannis is an associate professor of medicine in the Division of Hematology at Stanford University School of Medicine and medical director of Stanford’s Inpatient Leukemia Service in Palo Alto.

OncLive: What was the rationale for investigating the addition of IO-202 to azacitidine for the treatment of patients with CMML who were naive to an HMA?

Mannis: CMML is a rare disease. It is not typically something that is well studied. My focus is acute myeloid leukemia, but CMML affects probably approximately 1000 people in the United States per year, so [it is] relatively rare. However, it's a very serious disease. Despite being called a chronic leukemia, the median survival is [typically] less than 3 years; therefore, we desperately need newer treatments.

The standard treatment at the moment is a single-agent HMA like azacytidine. Response rates in terms of complete remissions tend to be quite low, on the order of approximately 10% to 20%. The rationale for this study [was this] huge unmet need. The current standard of care doesn't work very well, and we have this new drug [in IO-202] that we think could be very active in this patient population.

IO-202 is a naked monoclonal antibody that targets the protein, which is expressed almost exclusively on monocytes. In fact, it's a protein that has higher expression on leukemic monocytes in CMML vs healthy donors or even on monocytes in patients with myelodysplastic syndrome.

This is a good target for [developing treatments for] patients with CMML. [IO-202] is a monoclonal antibody, so we don't think that there are going to be a lot of off-target [adverse] effects. The rationale was to combine standard-of-care azacitidine with this antibody that specifically targets the abnormal cells in CMML.

What methods were utilized in the study, and what specific patient population was enrolled?

This study was limited to patients with CMML who had not received prior treatment with an HMA. Aside from that, we didn't restrict [enrollment] based on age. We did not require any specific level of expression of LILRB4. Therefore, it was a pretty broad population. In the end, we enrolled 21 patients as part of this phase 1b expansion cohort. Since CMML is a disease mostly [seen in] older men, that was reflected in our patient population. The median age was 71 years, and two-thirds of patients were male.

What were the key findings from the phase 1b trial presented at the 2024 ASH Annual Meeting?

We presented the data for the first 21 patients treated on this study. Azacitidine was given at the standard 7-day dosing in combination with IO-202 given every 2 weeks.

The key finding of this study, first and foremost, was that there was no significant safety signal. The addition of IO-202 didn't seem to contribute to any hematologic toxicity, such as lower blood counts, [and we] didn't [see] any significant gastrointestinal toxicity. We saw a couple infusion-related reactions that were mild and likely due to this antibody—[infusion-related reactions] are a known AE of essentially all antibodies. However, from a safety perspective, we didn't see any concerning signals, which is important in these early-phase trials.

Excitingly, beyond not seeing any safety issues In this patient population, 50% went into CR remission, and [the ORR was 66.7%]. Historically, the CR rate is approximately. 10% to 20% [for standard treatment in CMML]. [IO-202] seems to enhance the activity of azacitidine; these drugs work together to improve upon the standard of care.

Additionally, [38.9%] of patients [proceeded to] hematopoietic stem cell transplant, which is the only potential curative therapy for these patients. The first patient on study, who was ongoing at the time of the data cutoff, has been on the study now more than 16 months.

The responses happened quickly, [and] they seemed to be durable. They seemed to improve over time, and again, without any additional toxicity, which is always a concern when you're adding another drug to standard therapy.

What are the next steps for researching this combination?

This is a small study, and we're looking forward to working with the FDA to develop a pivotal study that hopefully would lead to the approval of IO-202 in combination with azacitidine.

For years and years, we have had no advancements in the treatment of [CMML]. The next step would be a larger study to enroll and treat more patients, potentially randomly assigning them between azacitidine plus IO-202 vs azacitidine alone. Some of those specifics will depend on conversations with regulatory agencies, but ideally, we will see this drug continue to move forward and potentially become available to more patients in the future.

CMML is a disease that warrants more study. Like many rare diseases, because there aren't many patients, there's less money and interest in terms of finding new and better treatments. One takeaway is that this is a disease that desperately needs new treatments.

The second important takeaway is that we have a drug now that looks promising in terms of its safety and mechanistically, and it should be effective in this patient population. Now early data suggest that [IO-202] does seem to improve responses in this difficult-to-treat patient population.

Reference

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-206538