Rapid Readouts: Safety, Tolerability, and Efficacy of Axatilimab, a CSF-1R humanized antibody, for Chronic Graft-versus-Host Disease after 2 or more Lines of Systemic Treatment

Background

• Chronic Graft-Versus-Host Disease (cGVHD) affects 30 to 50% of patients who have received allogeneic hematopoietic cell transplantation (HCT). Many patients with cGVHD fail to respond to available therapies or eventually progress. Sclerosis and lung involvement are often difficult to treat and may lead to poor outcomes.
• Blocking CSF-1 / CSF-1R signaling may prevent and treat cGVHD
• Axatilimab is an anti-CSF-1R monoclonal antibody targeting macrophage-driven diseases
• Key clinical features of axatilimab
  • High-affinity humanized IgG4 monoclonal antibody
  • Binds to ligand-binding domain on CSF-1R
  • Blocks the binding of both CSF-1 & IL-34 ligands
  • Administered via 30-minute infusion every 2 to 4 weeks
  • Highly effective in selectively reducing levels of circulating pro-fibrotic/non-classical monocytes
  • Intermittent dosing allows for monocyte recovery prior to subsequent dose

Methods

• Phase 1/2 trial enrolled 40 patients; phase 1 dose escalation and phase 2 dose expansion
• Study population included patients who were 6 years of age or older with active cGVHD after 2 or more prior treatments and a KPS of 60 or higher
  • Phase 1 Dose Escalation
    • 1 patient each in Cohort 1 and 2 (0.15 mg/kg Q2W and 0.5 mg/kg Q2W, respectively)
    • 3 patients in Cohort 3 (1 mg/kg Q2W)
    • 4 patients in Cohort 4 (3 mg/kg Q2W)
    • 6 patients in Cohort 5 (3 mg/kg Q4W)
    • Primary endpoints: Safety, overall response rate (ORR), recommended phase 2 dose (RP2D)
  • Phase 2 Expansion
    • 23 patients to receive 1.0 mg/kg Q2W
    • Primary endpoint: ORR (2014 NIH consensus criteria)

Results

• Baseline Characteristics
  • Heavily pretreated patient population
  • Median age: 59 (16-73); majority were male
  • 65% received myeloablative transplant; 93% received a peripheral blood transplant
  • 65% of patients had at least 4 organs involved
  • Majority had received at least one of the new FDA-approved therapies
• Treatment was well-tolerated with very few discontinuations due to adverse events (AEs)
  • Most common AEs were increases in AST/ALT, CPK, amylase, and lipase without evidence of end organ damage; periorbital edema
  • Infection rates were in line with contemporary experience in cGVHD
  • No CMV or EBV reactivations reported
• Best change in normalized Lee Symptom Score (LSS)
  • Median change (points): -7.8 (range 3.1, -37.6)
  • 16 (53%) of 30 LSS-evaluable patients achieved a 7-point reduction from baseline
  • Improvement seen regardless of response by NIH consensus criteria
• Response
  • Responses seen in all dose levels and across all organ systems
  • Median time to response: 0.9 months
  • Median time on treatment: 6.7 months
  • Best ORR: 68%
• Axatilimab advances to Pivotal Phase 2 Trial – AGAVE-201
  • Inclusion: 2 years and older, recurrent or refractory active cGVHD after 2 or more lines of systemic therapy
  • Stratification factors: Prior therapy (ibrutinib, ruxolitinib, belumosudil)
  • Severity of cGVHD
  • 1:1:1 randomization to 0.3 mg/kg Q2W (N = 70); 1 mg/kg Q2W (N = 70); 3 mg/kg Q4W (N = 70)