Axatilimab effective, safe for chronic graft-versus-host disease
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SALT LAKE CITY — Axatilimab appeared effective for heavily pretreated patients with active chronic graft-versus-host disease, according to phase 1/phase 2 study results.
More than two-thirds of patients treated at two doses selected for further investigation responded to therapy, and more than half of patients reported clinically meaningful improvement in symptoms.
The agent also appeared safe, findings presented at Tandem Meetings | Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR showed.
Background and methodology
An estimated 30% to 50% of allogeneic hematopoietic stem cell transplant recipients develop chronic GVHD, and the condition is a major cause of late morbidity and mortality.
Corticosteroids are administered as standard front-line treatment; however, approximately half of patients who achieve inadequate response or experience disease progression require second-line treatment.
Although three agents are approved in the United States for systemic treatment of chronic GVHD after one or two prior lines of therapy, many patients still fail to respond.
Axatilimab (SNDX-6352, Syndax) is an immunoglobulin G4 monoclonal antibody. The agent targets CSF-1 receptor-expressing monocytes and profibrotic macrophages that are involved in chronic GVHD development, according to study background.
Carrie L. Kitko, MD, associate professor of pediatrics and medical director of the pediatric stem cell transplant program at Vanderbilt-Ingram Cancer Center, and colleagues conducted their trial to evaluate the safety and efficacy of axatilimab for patients aged 6 years or older with active chronic GVHD after two or more lines of prior therapy.
Researchers enrolled 40 patients (median age, 59 years; range, 16-73; 63% male) with median Karnofsky performance score at enrollment of 80 (range, 60-100).
Sixty-five percent had received myeloablative transplant and 45% had related donors.
Patients had received a median four prior lines of therapy (range, 1-11). Twenty-six had received ibrutinib (Imbruvica; Janssen, Pharmacyclics), 21 had received ruxolitinib (Jakafi, Incyte) and eight had received belumosudil (Rezurock, Kadmon).
Study participants had a median four (range, 1-9) involved organs at baseline, and 26 patients (65%) had four or more organs involved.
The phase 1 portion of the study included 17 patients treated at one of five dose levels: 0.15 mg/kg (n = 1), 0.5 mg/kg (n = 1), 1 mg/kg (n = 3) or 3 mg/kg (n = 6) every 2 weeks, or 3 mg/kg every 4 weeks (n = 6).
The phase 2 dose-expansion portion of the study included 23 patients who received axatilimab dosed at 1 mg/kg every 2 weeks (n = 23).
Overall response rate at 6 months served as the primary objective.
Results
Twenty-three patients (58%) had discontinued treatment at data cutoff. The most common reasons for discontinuation included progression (18%; n = 7), physician decision (15%; n = 6) and adverse events (10%; n = 4).
Researchers reported a 68% response rate among 31 evaluable patients treated at the two dose levels — 1 mg/kg every 2 weeks and 3 mg/kg every 4 weeks — advanced to a pivotal trial, with median time to response of 0.9 months (range, 0.9-11) and median time on treatment of 6.7 months (range, 0.9-26.7).
Results showed responses in difficult-to-treat organ systems, including the eyes (4 of 24), esophagus (3 of 6), upper GI tract (4 of 4), lungs (5 of 15), liver (1 of 4), lower GI tract (4 of 4), skin (3 of 28), mouth (9 of 17), joints/fascia (16 of 24) and eyes (4 of 24).
Treatment appeared well-tolerated, Kitko said.
In the overall cohort, the majority of patients (73%) experienced axatilimab-related adverse events, the most common of which were increased aspartate aminotransferase (35%), creatine phosphokinase (33%), alanine aminotransferase (25%), lipase (23%) and amylase (23%).
Eight patients (20%) treated at the two dose levels advanced to the pivotal trial experienced grade 3 or higher treatment-emergent adverse events. These included three cases (8%) of increased creatine phosphokinase, two cases (5%) of increased lipase, and one case each (3%) of hypersensitivity, periorbital edema and septic arthritis.
Serum enzyme elevations likely reflect the on-target effect of axatilimab on Kupffer cells in the liver, Kitko said. Researchers observed no evidence of end-organ damage or myositis/pancreatitis with enzyme elevations.
Infection rates appeared comparable to prior experience in chronic GVHD, Kitko said.
In the overall cohort, nine patients (18%) developed upper respiratory infections and four (10%) developed cellulitis. Researchers reported two cases (5%) each of pneumonia, pseudomonas infection, urinary tract infection and influenza.
Investigators observed no cases of cytomegalovirus reactivation.
Sixteen (53%) of 30 evaluable patients achieved 7-point reduction from baseline in normalized Lee symptom score (median change, –7.8), and 19 (79%) of 24 patients with skin thickening reported improvement in skin score. Researchers observed these improvements regardless of NIH consensus criteria.
“Development of axatilimab is proceeding in a global, open-label, pivotal phase 2 study — AGAVE-201 — evaluating patients with active chronic GVHD after two prior lines of systemic therapy,” Kitko said.
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Kitko CL, et al. Abstract 35. Presented at: Tandem Meetings | Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR; April 23-26, 2022; Salt Lake City.
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