Abstract
Introduction: Chronic graft-versus-host disease (cGVHD) is a major cause of morbidity and non-relapse mortality among patients who undergo allogeneic hematopoietic stem cell transplantation. In patients with cGVHD, colony-stimulating factor 1 receptor (CSF-1R)–dependent monocytes and macrophages potentiate inflammation and fibrosis, which contribute to multi-organ damage. Treatment with axatilimab (AXA), a high-affinity monoclonal antibody targeting CSF-1R, depletes CSF-1R–dependent monocytes and macrophages. AXA 0.3 mg/kg every 2 weeks (Q2W) was approved by the US Food and Drug Administration (FDA) for the treatment of cGVHD after failure of ≥2 prior lines of therapy based on findings from the pivotal, phase 2 AGAVE-201 study (NCT04710576). In AGAVE-201, an overall response (95% CI) occurred in 74% (63%–83%) of patients receiving AXA 0.3 mg/kg Q2W in the first 6 treatment cycles, and AXA was generally well tolerated, with 6% of patients receiving AXA 0.3 mg/kg Q2W experiencing adverse events (AEs) leading to treatment discontinuation.
Aims: To report long-term treatment duration and safety among patients enrolled in AGAVE-201.
Methods: Patients aged ≥2 years with refractory or recurrent cGVHD after ≥2 prior lines of systemic therapy were randomized 1:1:1 to intravenous AXA 0.3 mg/kg Q2W, 1 mg/kg Q2W, or 3 mg/kg every 4 weeks (Q4W). Treatment with AXA could continue if the patient was deriving clinical benefit per investigator assessment and if the patient reported clinically meaningful symptomatic improvement. The safety follow-up period was 90 days after the last dose of AXA, and survival data were collected for 5 years after the safety follow-up. Long-term overall survival (OS), safety, and duration of treatment were assessed in this analysis, with a focus on the AXA 0.3 mg/kg Q2W cohort (FDA-approved dose).
Results: Of 241 patients enrolled in AGAVE-201, 239 received AXA (0.3 mg/kg Q2W, n=79; 1 mg/kg Q2W, n=81; 3 mg/kg Q4W, n=79). As of March 30, 2025, 205 patients discontinued treatment, 33 patients were still on treatment, and 1 patient completed treatment. The most common reasons for treatment discontinuation were progressive disease (24.9%), adverse event (22.8%), and withdrawal of consent (13.7%). The 46-month OS rate (95% CI) was 77.6% (57.8%–89.0%) among the 0.3 mg/kg Q2W cohort and 74.1% (64.8%–81.3%) across all doses, with median (range) follow-up times of 31.7 (0–46.5) and 31.2 (0–46.5) months, respectively. No new safety signals have emerged during long-term follow-up. Treatment-emergent AEs (TEAEs) occurring in ≥25% of patients during the full study were fatigue (30.4%) in the 0.3 mg/kg Q2W cohort and increased lab parameters (creatine phosphokinase [CPK; 38.9%], aspartate aminotransferase [AST; 38.1%], lipase [29.7%], alanine aminotransferase [26.8%], lactate dehydrogenase [26.4%]) and fatigue (26.8%) across all doses. In the 0.3 mg/kg Q2W cohort and for all doses, 15 patients (19.0%) and 85 patients (35.6%), respectively, had ≥1 treatment-related grade ≥3 TEAE.
Of the 33 patients who remained on treatment (0.3 mg/kg Q2W, n=15; 1 mg/kg Q2W, n=11; 3 mg/kg Q4W, n=7), the median (range) treatment duration was 33.1 (31–41) months for the 0.3 mg/kg Q2W group and 34.0 (31–41) months across all doses. TEAEs occurring in ≥35% of patients still on treatment were upper respiratory tract infection (53.3%), COVID-19 (40.0%), and headache (40.0%) in the 0.3 mg/kg Q2W cohort and headache (45.5%), CPK increased (42.4%), upper respiratory tract infection (42.4%), and AST increased (36.4%) for all doses. In the 0.3 mg/kg Q2W cohort and for all doses, 4 patients (26.7%) and 12 patients (36.4%), respectively, had ≥1 treatment-related grade ≥3 TEAE.Conclusion: Initial data from the AGAVE-201 study showed a promising overall response rate and safety profile for AXA in patients with cGVHD. Long-term safety follow-up showed a continued tolerable safety profile with a prolonged duration of exposure. Of 239 patients who received AXA, 33 (14%) have continued on treatment with a median duration of therapy of 2.8 years, suggesting long-term safety and clinical benefit from treatment. In AGAVE-201, early objective and symptom response may be due to the anti-inflammatory activity of AXA. In patients with long-standing fibrotic disease, prolonged therapy with AXA can be considered to optimize clinical outcomes.
