Mukta Arora, MD, PI and Professor of Medicine, Division of Hematology, Oncology and Transplantation, University of Minnesota speaks about the ASH 2020 abstract – 358 Phase 1 Study of Axatilimab (SNDX-6352), a CSF-1R Humanized Antibody, for Chronic Graft-Versus-Host Disease after 2 or More Lines of Systemic Treatment.
Context:
A significant cause of morbidity and late non-relapse mortality after allogeneic hematopoietic cell transplantation is chronic graft versus host disease (cGVHD) and is usually associated with prolonged immune suppression. There are few appropriate treatment options for patients (pts) with insufficient response to steroids and they reflect an unmet medical need. Severe toxicity, immunosuppression, and increased risk of infections are correlated with available therapies. Preclinical studies show that CSF-1/CSF-1R is a crucial regulatory pathway involved in the expansion and penetration of cGVHD-mediating donor-derived macrophages. Axatilimab (SNDX-6352, axa) is a high-affinity CSF-1R humanized, full-length IgG4 antibody. By binding to CSF-1R and blocking its activation by its two recognized ligands, CSF-1 and IL-34, Axa influences the migration, proliferation, differentiation, and survival of monocytes and macrophages. It provides a novel therapeutic treatment alternative for these pts.
Methodology:
SNDX-6352-0503 is a phase 1/2 dose-escalation and dose-expansion study evaluating protection, tolerability, pharmacokinetics (PK)/pharmacodynamics (PD), and axa efficacy in pts >6 years of age with active symptomatic cGVHD despite approximately 2 previous treatment lines. The Phase 1 endpoints were protection, tolerability, PK, and PD, with the primary objective of determining the appropriate biological dosage, with the overall response rate (CR+PR) of 6 months being the primary endpoint of the Phase 2 analysis. Pts were administered in intervals of 28 days. The deadline for data was 22 July 2020.
Outcomes:
In the Phase 1 study, 12 pts were reported. The median age at registration was 58y (range, 29-73y), 8 male pts. A median of 5 previous lines of care had failed in Pts (range 4-9). 0.15 mg/kg (n=1), 0.5 mg/kg (n=1), 1 mg/kg (n=3), 3 mg/kg (n=6) every 2 weeks (q2w) and 3 mg/kg q4w (n=1) were included in the dose. 5 pts (42 percent) of these are still getting axa. For all pts, the median number of cycles is 5 (range 1-12). 2 of the 3 pts whose starting dose was 3 mg/kg q2w and remaining in the sample were reduced; 1 to 2 mg/kg q4w and 1 to 1 mg/kg q2w, respectively. Seven pts (58%) is discontinued due to adverse events (3 mg/kg q2w, n=2); traumatic fall death (1 mg/kg q2w, n=1); judgment of the investigator (0.5 mg/kg q2w, n=1); incremental cGVHD (1 and 0.15 mg/kg q2w, n=1 each and non-compliance (3 mg/kg q2w, n=1).
Two out of 6 pts (17%) at a dose of 3 mg/kg q2w registered an emergent adverse event that was considered a dose-limiting toxicity (DLT) treatment: 1 with CTCAE Grade 4 creatine kinase increased with myositis symptoms after dose 1 and 2 with amylase/lipase elevation that delayed the third dose for >2 weeks. At 1 mg/kg q2w, the latter pt restarted therapy and stayed on medication after 5 cycles.
Four pts (1 at 0.15 mg/kg and 3 at 3 mg/kg q2w, 33 percent) had an associated treatment-related emerging Grade 3 adverse event: increase in aspartate aminotransferase (n=2); increase in creatine phosphokinase (n=2); and increase in gamma-glutamyl transferase (n=2). Such biochemical elevations may result from the blockade of CSF-1R on Kupffer cells, leading to inhibition of the clearance of these enzymes, consistent with the mechanism of action of the axa, and if the clinical manifestations of hepatitis, pancreatitis, or rhabdomyolysis have not been associated with an asymptomatic impact. 2 pts (almost grade 2) periorbital edema was observed; no additional CSF-1Ri class-effect-related TEAEs were observed.
In 7 pts (58 percent) across all dose levels, clinical responses as specified by the 2014 NIH cGVHD Consensus Criteria were observed; the median response time was 12 weeks. In the esophagus (n=1/1), eyes (n=3/10), joints/fascia (n=5/9), mouth (n=1/7), and skin (n=3/8), organ-specific responses were observed. Prior treatments obtained by the responders included ibrutinib (6 pts), ruxolitinib (5 pts), and KD025 (3 pts); all of these were received by 3 of the responding pts. In the Lee Symptom Score, six pts (50 percent) recorded at least a 7-point improvement. Preliminary PK profiles and pharmacodynamic endpoints, including nonclassical circulating CD14+CD16+ and intermediate monocyte kinetics CD14++CD16+, are consistent with those observed in healthy volunteers, and solid tumor pts are shown in the figure below.
Findings:
These data show that axatilimab is clinically active in heavily pretreated pts with active cGVHD, with an appropriate safety profile and responses observed. In the Phase 1 study at 3 mg/kg q4w and the Phase 2 study at 1 mg/kg q2w, enrollment begins.