Axatilimab-csfr Approved for Chronic Graft-Versus-Host Disease
Expert Perspectives · Lyn Brook · 2024-08-19
The FDA has granted approval to axatilimab-csfr (Niktimvo™, Incyte Corporation), a colony stimulating factor-1 receptor (CSF-1R)–blocking antibody, for chronic graft-versus-host disease (cGVHD) after failure of at least two prior lines of systemic therapy in adult and pediatric patients weighing at least 40 kg.
Context and background: a challenging disease to treat, despite recent progress: “Chronic graft-versus-host disease is a significant and often debilitating complication following bone marrow transplantation. While the actual transplant procedure itself is complex and potentially a fraught endeavor, the long-term management of cGVHD presents unique challenges due to its diverse range of symptoms, the delicate balance between suppressing the graft while also avoiding infectious complications, and the potential for severe, organ-specific complications,” said Tristan Knight, MD, FRCPC, an Oncology Data Advisor Editorial Board Member and Clinical Assistant Professor at Seattle Children’s Hospital.
“Corticosteroids are the current first-line therapy for patients with cGVHD, but most will require additional therapies to be implemented. Belumosudil, ibrutinib, and ruxolitinib have all been approved by the FDA for use in this patient population,” Dr Knight continued. “Despite this expanding armamentarium, treatment failure remains a major obstacle and a major cause of patient morbidity and mortality. In the AGAVE-201 clinical trial, patients had received a median of four prior lines of therapy prior to initiating treatment with axatilimab—including belumosudil (23%), ibrutinib (31%), and ruxolitinib (74%).”
What they studied: Efficacy was measured in the phase 2, open-label trial in which patients with recurrent or refractory cGVHD who had received at least two lines of systemic therapy and required additional treatment were randomized 1:1:1 to receive axatilimab-csfr at a dosage of either 0.3 mg/kg every two weeks, 1.0 mg/kg every two weeks, or 3.0 mg/kg every four weeks.
The primary efficacy outcome measured was overall response rate through Day 1 of Cycle 7. Overall response rate included complete responses and partial responses according to the 2014 National Institutes of Health (NIH) Consensus Development Project on Response Criteria.
What they found: In the 79 patients receiving the recommended dosage, the overall response rate was 75%. The median time to first response was 1.5 months and the median duration of response was 1.9 months, which was calculated based on first response to progression, death, or new systemic therapies for cGVHD. For patients who achieved a response, no death or new systemic therapy initiation was 60% for at least 12 months since response.
Adverse events: The most common adverse events experienced in ≥15% of patients receiving axatilimab-csfr, including laboratory abnormalities, were increased aspartate aminotransferase (AST), infection (pathogen unspecified), increased alanine aminotransferase (ALT), decreased phosphate, decreased hemoglobin, viral infection, increased gamma glutamyl transferase (GGT), musculoskeletal pain, increased lipase, fatigue, increased amylase, increased calcium, increased creatine phosphokinase (CPK), increased alkaline phosphatase (ALP), nausea, headache, diarrhea, cough, bacterial infection, pyrexia, and dyspnea.
Why it matters: “Axatilimab is a rationally designed, highly targeted therapy which directly exploits our understanding of cGVHD pathophysiology. Colony-stimulating factor 1 receptor–driven signaling in the monocyte-macrophage axis sustains the inflammation, tissue injury, and subsequent maladaptive repair and fibrosis which characterizes cGVHD,” said Dr. Knight. “Axatilimab targets and blocks CSF-1R’s ligand-binding domain, and thereby prevents activation of this receptor. This is a novel approach to the treatment of cGVHD, and the impressive results of the AGAVE-201 clinical trial underscore the validity of this strategy.”
“While clearly not a panacea,” he continued, “axatilimab shows both an excellent overall response rate in a heavily pretreated, likely somewhat refractory population of patients, as well as a tolerable safety profile – particularly given the extreme morbidity and mortality which may be associated with cGVHD of this severity.”
Instructions: The recommended dosage of axatilimab-csfr in patients who weigh at least 40 kg is 0.3 mg/kg, up to a maximum dose of 35 mg, as an intravenous infusion over 30 minutes every two weeks, until disease progression or unacceptable toxicity.