Axatilimab, a colony stimulating factor (CSF)-1 receptor inhibitor, has emerged as a promising treatment for chronic graft-versus-host disease (GVHD) in patients who have progressed after at least two prior systemic therapies. The FDA approved axatilimab (Niktimvo; Incyte) in August, marking a significant advancement in the field. This approval was supported by the AGAVE-201 trial, which demonstrated a superior response rate in heavily pretreated patients.
Novel Mechanism of Action
Dr. Daniel Wolff, a professor at University Hospital Regensburg and an investigator on the AGAVE-201 trial, highlighted that axatilimab targets monocytes and macrophages, components of the immune system not typically addressed by traditional GVHD treatments that focus on T cells and B cells. This novel approach offers a new avenue for patients who have exhausted other treatment options. In the AGAVE-201 trial, patients who had failed a median of four prior lines of therapy still experienced response rates above 50%, with the lowest dose showing a 74% benefit that was lasting for most patients.
Adverse Event Profile
While axatilimab offers significant benefits, its unique mechanism of action also presents a distinct side effect profile. A notable effect is the depletion of Kupffer cells, which increases the half-life of circulating liver and pancreatic enzymes. According to Dr. Wolff, this does not indicate organ damage but can complicate the diagnosis of organ damage caused by other factors. Periorbital swelling is another potential side effect, more commonly observed at higher doses not included in the approved label. However, at the approved low dose, axatilimab did not appear to increase the risk of infections compared to what is typically observed in this patient population. Infusion-related side effects are rare, and overall, axatilimab is considered well-tolerated compared to other treatment options like calcineurin inhibitors.
Future Research
Future trials are planned to evaluate axatilimab as a frontline treatment for chronic GVHD. One of the most anticipated trials will assess axatilimab in combination with ruxolitinib as a steroid-free frontline treatment. Steroids have been the standard of care for chronic GVHD for the past 40 years, but their use is associated with numerous side effects. This trial aims to provide a steroid-free alternative. Another trial will compare axatilimab in combination with steroids against steroids alone in the frontline setting. Additionally, a third trial in Europe will repeat the AGAVE-201 trial in advanced chronic GVHD, randomizing patients to the optimal dose of axatilimab versus the best available treatment.
The rationale for moving axatilimab to frontline treatment is to prevent the irreversible organ damage that occurs in advanced GVHD. Furthermore, the mechanism of action of targeting the CSF-1 receptor pathway without significantly increasing infectious risk makes it an attractive option for early treatment, potentially allowing for combination therapies that target multiple effectors in chronic GVHD without excessive immunosuppression. These trials are crucial to determine whether this approach will translate into improved outcomes for patients with chronic GVHD.
