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Novel drugs for treating cGvHD: Phase I results of axatilimab for heavily pretreated patients

Jan 15, 2021
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Second line or further lines of therapy represent an unmet need in treating patients with chronic graft-versus-host disease (cGvHD) due to disease progression or the lack of response. Axatilimab is a novel, humanized, immunoglobulin G4 (IgG4) antibody inhibiting colony-stimulating factor 1 receptor (CSF-1R) agent, which is currently under development for the treatment of patients with refractory cGvHD following ≥2 lines of systemic therapy. CSF-1/CSF-1R pathway has been shown to associated with the growth and infiltration of donor-derived macrophages leading to cGvHD.

During the 62nd American Society of Hematology (ASH) Annual Meeting and Exposition, Mukta Arora presented the preliminary phase I results1, and this article summarizes the key points.

Study design

The study population included patients ≥6 years of age, with active cGvHD following ≥ 2 lines of prior therapies, and who had Karnofsky performance score ≥60%. Corticosteroids and calcineurin inhibitors were allowed.

Endpoints were safety, tolerability, overall response rate (ORR), and recommended Phase 2 dose (RP2D). Dose escalation design is depicted in Figure 1.

Figure 1. Study design (adapted from Arora et al., 2020)1

Q2W, every 2 weeks; Q4W, every 4 weeks. 

Baseline characteristics

Total number of patients was 15 with a median age of 60 years (range, 29–73 years). Almost half (47%) of patients underwent myeloablative transplant. Peripheral blood stem cells (PBSCs) were used as graft source in 93% of patients. The median time from cGvHD to Cycle 1 Day 1 (C1D1) was 42 months (range, 9.6–187.2 months). Median number of organs involved was 4 (range, 1–9), and median number of prior treatments was 4 (range, 2–9). Prior therapies included ibrutinib, ruxolitinib, and KD025.

Results

Treatment-emergent adverse events (TEAEs) that were considered related to axatilimab, occurred in all patients among different dose ranges. Grade 3–4 events occurring in ≥ 2 patients comprised elevated creatine kinase levels (n = 3), aspartate aminotransferase increase (n = 2), and pneumonia (n = 2). Infectious events were observed in six patients including pneumonia, conjunctivitis, norovirus gastroenteritis, influenza, lung infection, Pseudomonas infection in the foot, and upper respiratory infection. Reactivation of cytomegalovirus was not observed. The results of safety analysis are shown in Table 1.

Table 1. Safety outcomes2

AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CPK, creatine phosphokinase; LDH, lactate dehydrogenase; Q2W, every 2 weeks, Q4W, every 4 weeks; TEAE, treatment-emergent AE.

*0.15 mg/kg Q2W.

0.5 mg/kg Q2W.

All grades regardless of causality.

Outcome, n (%)

< 1 mg/kg Q2W

n = 2

1 mg/kg Q2W

n = 3

3 mg/kg Q2W

n = 6

3 mg/kg Q4W

n = 4

Grade 3–4 TEAE

2 (100)

2 (67)

4 (67)

2 (50)

Related Grade 3–4 TEAE

1 (50)*

1 (33)

3 (50)

2 (50)

Treatment discontinuation

Progression

AE

Physician decision

Death

Other

2 (100)

1 (100)*

0

1 (100)

0

0

2 (67)

1 (33)

0

0

1 (33)

0

3 (50)

0

1 (17)

1 (17)

0

1 (17)

1 (25)

0

0

1 (25)

0

0

TEAEs occurring ≥ 5 patients

Elevated AST

Elevated CPK

Elevated LDH

Elevated amylase

Fatigue

Elevated lipase

Elevated ALT

Elevated creatinine

Nausea

Pyrexia

 

 

1 (50)*

0

1 (50)

1 (50)*

1 (50)

0

1 (50)*

0

2 (100)

0

 

 

1 (33)

1 (33)

2 (67)

1 (33)

0

1 (33)

0

1 (33)

0

1 (33)

 

 

4 (67)

5 (83)

4 (67)

4 (67)

3 (50)

3 (50)

3 (50)

2 (33)

3 (50)

4 (67)

 

 

3 (75)

3 (75)

2 (50)

0

2 (50)

2 (50)

1 (25)

2 (50)

0

0

Efficacy

Responses were achieved at all dose levels with deep and durable responses observed in different organ systems:

  • CR in esophagus, and lower gastrointestinal tract (100%)
  • CR in mouth (56%)
  • PR in joints and fascia (55%), lungs (40%), and skin (40%)
  • CR and PR in eyes (33%)

The median time to response was 1.9 months (range 1–11 months), and ORR was 57%. Lee symptom scores were also improved in most patients.

Conclusion

This patient population represents a heavily pretreated, recurrent/refractory active cGvHD cohort. In this study, axatilimab has shown good tolerability with low infection rates, and clinical activity was shown with responses in different organ systems, and following treatment with ibrutinib, ruxolitinib, and KD025; however, the limitation of small sample size was acknowledged. A phase II study (AGAVE-201) is planned to further investigate the efficacy and safety of axatilimab with three different doses.

  1. Arora M, Jagasia M, Di Stasi A, et al. 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. Oral Abstract #358. 62nd ASH Annual Meeting and Exposition; Dec 6, 2020; Virtual.

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