Work

Kinetics and Management of Hepatic Laboratory Elevations Associated with Axatilimab in the Agave-201 Study

Year: 2025

Type: article

Abstract: Introduction Axatilimab (AXA), a monoclonal antibody that binds to colony-stimulating factor 1 receptor (CSF-1R), modulates monocytes and macrophages mediating chronic graft-versus-host disease (cGVHD). In the pivotal AGAVE-201 study, AXA 0.3 mg/kg every 2 wk (Q2W; FDA-approved regimen) yielded high response rates and was generally well tolerated in patients with cGVHD. As an on-target effect of CSF-1R inhibition, AXA may induce clearance of Kupffer cells in the liver, leading to increased persistence of circulating enzymes, including alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Objectives To describe dynamics and dose changes for treatment-emergent adverse events (TEAEs) related to hepatic laboratory values in AGAVE-201 (NCT04710576). Methods Patients were randomized 1:1:1 to intravenous AXA (0.3 mg/kg Q2W, 1 mg/kg Q2W, 3 mg/kg Q4W); treatment continued based on investigator assessment of clinical benefit. Eligible patients had baseline ALT/AST ≤2.5 × upper limit of normal (ULN; ≤5 × ULN with liver cGVHD) and total bilirubin ≤1.5 × ULN. Safety laboratory assessments were performed during screening, Days (D)1, 8, 15, and 22 of Cycle (C)1; D1 and 15 of C2 to C6; D1 or 15 of C7+, and safety follow-up. Results Among 241 randomized patients in AGAVE-201 ( Table 1 ), 239 received AXA, including 79 who received 0.3 mg/kg Q2W. Median (range) cumulative exposure was 387.8 (22.5–1935.0) mg, 944.0 (77.0–4647.0) mg, and 994.9 (164.1–3968.5) mg in the 0.3 mg/kg Q2W, 1 mg/kg Q2W, and 3 mg/kg Q4W groups, respectively. Various baseline laboratory values were generally within normal ranges, with mild elevations in ≤25.8% of patients, although a majority (52.3%) had mild lactate dehydrogenase elevations ( Table 1 ). Median ALT levels on study are shown in the Figure . AST and ALT elevations were reported in 44 (55.7%) and 39 (49.4%) patients, respectively, with 0.3 mg/kg, and 185 (77.4%) and 136 (56.9%) patients, respectively, with all doses. Laboratory-based TEAEs (any grade or grade ≥3) were less frequent with 0.3 mg/kg relative to all doses ( Table 2 ). Across all doses, no grade ≥3 bilirubin increases and no discontinuations due to laboratory-based TEAEs occurred. Dose modifications due to these TEAEs were not required for grade ≤2 events per protocol; of patients with dose modifications ( Table 2 ), all but 1 (with concurrent grade 1 ALT/AST increases; 1 mg/kg group) experienced resolution. AST/ALT elevations (consistent with AXA mechanism of action) appeared to be mostly isolated laboratory findings unaccompanied by clinical symptoms. Conclusion In AGAVE-201, elevations in hepatic laboratory values occurred with no accumulation. Laboratory-based TEAEs during AXA treatment were mostly transient, grade 1/2, required few dose changes, and did not result in treatment discontinuation. Altogether, these results indicate that the effects of AXA on liver function were minimal.

Source: Transplantation and Cellular Therapy

DOI: 10.1016/j.jtct.2025.01.444