Axatilimab Meets ORR End Point in Chronic GVHD After 2 or More Prior Lines of Therapy

Michael A. Metzger

The anti–CSF-R1 antibody axatilimab (SNDX-6352) generated responses in adult and pediatric patients with chronic graft-vs-host disease (GVHD) who received 2 or more prior lines of therapy, meeting the primary end point in all cohorts of patients in the phase 2 AGAVE-201 trial (NCT04710576).¹

Topline data showed that among patients treated with axatilimab at 0.3 mg/kg every 2 weeks, 1.0 mg/kg every 2 weeks, and 3.0 mg/kg every 4 weeks, the overall response rates (ORRs) were 74% (95% CI, 63%-83%), 67% (95% CI, 55%-77%), and 50% (95% CI, 39%-61%), respectively. Notably, responses were observed across key subgroups, including patients who had prior exposure to ruxolitinib (Jakafi), belumosudil (Rezurock), and/or ibrutinib (Imbruvica).

Based on these data, Syndax and Incyte plan to submit a biologics license application to the FDA seeking the approval of axatilimab by the end of 2023.

“Today marks an important day not only for Syndax and Incyte, but, more importantly, for patients suffering from chronic GVHD,” Michael A. Metzger, chief executive officer of Syndax, stated in a news release. “Axatilimab is the first investigational chronic GVHD treatment to target inflammation and fibrosis through the inhibition of disease associated macrophages, and the AGAVE-201 data demonstrates the potentially pronounced impact this mechanism, alone or in combination with standard of care therapies already available for the management of this disease, may have on patients suffering from chronic GVHD.

“These results underscore our belief that axatilimab could provide a valuable and highly differentiated therapeutic option for this devastating disease. We look forward to working with our partners at Incyte as we move axatilimab towards regulatory filing. On behalf of the entire Syndax team, I would like to thank the patients, their caregivers, and the investigators who made this trial possible.”

The open-label, randomized, multicenter AGAVE-201 trial enrolled patients at least 2 years of age with active chronic GVHD that required systemic immune suppression following an allogeneic hematopoietic stem cell transplant.Patients needed to have recurrent or refractory, active chronic GVHD after at least 2 prior lines of systemic therapy that led to disease progression, intolerability, or unacceptable toxicity.²

Other inclusion criteria were a Karnofsky performance status of at least 60, and adequate organ and bone marrow function during the 14 days prior to randomization.

Key exclusion criteria included acute GVHD without manifestations of chronic GVHD, any evidence of relapse of the underlying cancer or post-transplant lymphoproliferative disease at screening, a history of acute or chronic pancreatitis, a history of myositis, or a history or other evidence of severe illness, uncontrolled infection, or any other conditions that would make patients unsuitable for the trial in the opinion of the investigator.

Patients were randomly assigned to receive axatilimab at 0.3 mg/kg every 2 weeks, 1.0 mg/kg every 2 weeks, and 3.0 mg/kg every 4 weeks in 28-day cycles for up to 2 years.

ORR in the first 6 cycles of treatment served as the trial’s primary end point. Secondary end points included duration of response (DOR), percent reduction in daily steroids dose, organ-specific response rates, and validated quality-of-life assessments using the Modified Lee Symptom Scale.¹

A total of 241 patients were enrolled across the 3 cohorts. Patients received a median of 4 prior systemic therapies, with previous treatments including ruxolitinib (74%), belumosudil (23%), and ibrutinib (31%). Additionally, 54% of patients had at least 4 organs involved at baseline, and 45% had lung involvement.

Additionally, among responders treated with 0.3 mg/kg of axatilimab (n = 79), 60% of patients maintained a response at 12 months. The median DOR was not reached in this group. Fifty-five percent of patients treated at 0.3 mg/kg experienced a clinically meaningful improvement in symptoms.

Regarding safety, adverse effects (AEs) were consistent with the on-target toxicities associated with CSF-1R inhibition and with previously reported data for axatilimab. The most common AEs reported in more than 20% of the overall evaluable population (n = 239) included increased aspartate aminotransferase, blood creatine phosphokinase, lipase, blood lactate dehydrogenase, alanine aminotransferase, and fatigue. Additionally, 42.3% of patients experienced serious AEs, and 15.5% of patients discontinued treatment due to AEs.

In the 0.3 mg/kg dose group, fatigue was the only serious AE reported in more than 20% of patients. Thirty-eight percent of patients in the 0.3 mg/kg group experienced serious AEs, and 6.3% of patients in this group discontinued treatment due to AEs.

References

1. Syndax and Incyte announce positive topline results from the pivotal AGAVE-201 trial of axatilimab in chronic graft-versus-host disease. News release. Syndax. July 24, 2023. Accessed July 24, 2023. https://ir.syndax.com/news-releases/news-release-details/syndax-and-incyte-announce-positive-topline-results-pivotal
2. A study of axatilimab at 3 different doses in participants with chronic graft versus host disease (cGVHD) (AGAVE-201). ClinicalTrials.gov. Updated June 18, 2023. Accessed July 24, 2023. https://classic.clinicaltrials.gov/ct2/show/NCT04710576