At the 65^th Annual American Hematology Society (ASH) Meeting in San Diego, California, Daniel Wolff, MD, University Hospital Regensburg, Regensburg, Germany, discussed results from the pivotal, phase 2, open-label, randomized AGAVE-201 trial.

Wolff and coauthors found that axatilimab treatment among heavily pretreated patients with relapsed/refractory (R/R) chronic graft versus host disease (GVHD) resulted in robust clinical activity and durable responses within 3 separate dose cohorts.

Transcript:

The AGAVE-201 trial focused on a patient population [who] developed chronic graft-versus-host disease after allogeneic transplantation [and] is cured from the underlying malignancy, but developed a nasty disease called chronic graft-versus-host disease, which affects multiple organs. Once it fails first-line treatment—steroids—patients frequently require multiple lines of treatment with decreasing efficiency, and those patients are impaired by a bad quality of life for a long time.

The AGAVE-201 trial explored an antibody which targets the CSF-1 receptor, which is a target which has not been treated yet based on animal work published by Kelli MacDonald. The CSF-1 receptor pathway was identified in monocytes and macrophages as one of the key player[s] in inflammation and fibrosis in chronic graft-versus-host disease. Axatilimab is targeting that pathway by targeting the receptor and has been shown in a prior phase 1/2 trial to be efficient in heavily pretreated patients with chronic graft-versus-host disease.

The AGAVE-201 trial compared 3 different doses at 2 schedules, 2 doses derived from the prior trial. The 3rd dose, which was a pretty low dose, was added to explore the lowest efficient dose.

Patients enrolled in the trial were heavily pretreated, had received a median of 4 treatment lines, had multi-organ disease, and failed in [the] vast majority of the last treatment line and prior treatment lines, which included in the majority of the patients FDA-approved agents, including belumosudil.

I have to add the AGAVE-201 trial was a trial done across the globe and had hardly any exclusion criteria except patients who would be harmed, so the AGAVE-201 trial represented the 2 patient populations as we are in clinical routine.

The results were kind of surprising to the community. Not only that the vast maturity of patients took benefit, [but] the surprising result was that the lowest dose we thought would be not sufficient to treat the disease was the most effective one, and was in fact associated with the least toxicity. That came [as] a surprise. [In] 76% of the patients in the low-dose--0.3 mg/kg dose--given every second week, responded to the treatment. An additional 15 patients were stable on treatment.

The response was seen fairly rapid[ly], within less than 2 months and was durable in more than half of the patients. Taking into account that those advanced patients usually [and] frequently require treatment changes and have a low response rate, [it] came as a big surprise that we had durable response in the vast majority of the patients. Symptom burden relief was also pretty quick and just followed the trajectory of those clinical responses.

Something else we observed was we saw responses across all organs. There was no organ not taking any benefit, and we saw responses in manifestations which were sclerotic fibrotic, which were regarded by the vast majority of the physicians as non-reversible. It appears to be that hitting the right target in the right patient is crucial.

The toxicity was pretty manageable, especially in the low-dose arm. [In] the low-dose arm, only 6% had to switch treatment because of side effects, which in this patient population [is] considerably low. Only 1 patient in the low-dose cohort died of adverse effects. In fact, this patient was extremely ill before inclusion into [the] trial and died of a preexisting infection. One specific side effect which puzzles their care provider is that it's an on-target effect on depletion of Kupffer cells in the liver, which impairs the removal of circulating enzymes from the blood. Those enzymes accumulate, you'll get higher counts, but that's not damage. It's just [a] lack of clearance of those enzymes.

Taken together, axatilimab seems to be highly efficient in advanced chronic graft-versus-host disease, including fibrotic manifestations. It has come along with a pretty low toxicity profile. Responses are relatively rapid in this patient population and [with] symptom relief as well. Side effects increase with increasing doses without increasing proficiency.

The last message is this trial [taught] us a lesson insofar that we need sufficiently powered clinical trials for dose finding to identify the optimal dose because the findings of the AGAVE-201 trial would never been identified in a small patient cohort.

Source:

Wolff D, Cutler C, Lee S, et al. Safety and efficacy of axatilimab at 3 different doses in patients with chronic graft-versus-host disease (AGAVE-201). Presented at the 2023 ASH Annual Meeting: December 9-12, 2023. San Diego, CA. Abstract 1