Durable responses seen with axatilimab in recurrent/refractory GVHD

The anti–CSF-R1 antibody axatilimab offers rapid and durable responses in patients with recurrent/refractory chronic graft-versus-host disease (GVHD) in the pivotal phase II AGAVE-201 trial.

The highest overall response rate (ORR) was seen with the lowest dose (0.3 mg/kg) at 74 percent (95 percent confidence interval [CI], 63–83) within the first 6 months. Sixty percent of the patients were still responding at 1 year.

As for those treated with axatilimab 1 mg/kg, the ORR was 67 percent (95 percent CI, 55–77). Patients treated with the highest dose of 3 mg/kg had an ORR of 50 percent (95 percent CI, 39–61).

When asked to elucidate on the inverse dose response to axatilimab, Dr Danielle Wolff, senior physician and head of the GvHD Competence Center at Regensburg University Hospital in Regensburg, Germany, said the high dose leads to a prolonged depletion of monocytes and macrophages, which increases, in turn, the CSF-1 level in the circulation. “Once those monocytes reappear, they're kind of stimulated by this huge excess of CSF-1, which is not present in the lower doses. It is the most likely explanation, but may not be the only one.”

New therapeutic strategy

“Axatilimab, with its unique mechanism of action, may represent a new therapeutic strategy in chronic GVDH,” Wolff pointed out during his presentation at ASH 2023. “The highest ORR and the least toxicity observed with the lowest dose underlines the crucial importance of sufficiently powered studies in this vulnerable patient population.”

AGAVE-201 evaluated three different doses of intravenous axatilimab (0.3 mg/kg Q2W, 1 mg/kg Q2W, or 3 mg/kg Q4W) in allogeneic hematopoietic cell transplant (alloHCT) patients (n=241) with recurrent or refractory chronic GVHD. [ASH 2023, abstract 1]

Randomization was stratified by severity of chronic GVHD. Patients were allowed in the study if they were using corticosteroids, calcineurin inhibitors, or mTOR inhibitors. No additional systemic chronic GVHD therapy was allowed. Median age of the patients was 53; 65 percent were male. Eighty percent had severe disease.

“These patients were heavily treated – having received a median of four prior systemic treatments,” said Wolff. “Fifty-four percent had ≥4 organs involved; 55 percent had failed GVHD therapy.”

Axatilimab was continued for as long as there was clinical benefit to the therapy (assessed by the investigator). The primary efficacy endpoint was ORR in the first 6 cycles (24 weeks) as defined by the National Institutes of Health 2014 consensus criteria.

The key secondary endpoint was the proportion of patients reporting a clinically significant reduction of symptoms, as measured by the modified Lee Symptom Scale (mLSS) score, with a threshold of ≥7 points.

Organ-specific responses were particularly notable in fibrosis-dominated organs, including the oesophagus (78 percent), joints and fascia (76 percent), lung (47 percent), and skin (27 percent).

The median failure-free survival in the 0.3 mg/kg group was 17.3 months, with 55 percent of the patients reporting a clinically meaningful change of at least 7 points in their symptom burden.

Periorbital oedema was a notable side effect of axatilimab at higher doses, occurring in >20 percent of the higher dose groups vs 2.5 percent in the 0.3 mg/kg group. Axatilimab was generally well tolerated. The most common AEs were consistent with on-target effects and prior trials.

New therapies needed

Chronic GVHD is an immune-mediated complication following alloHCT, affecting multiple organs. In GVHD, the donated stem cells see the recipient’s body cells as foreign cells and attack them.

Despite recent approvals of treatment options in chronic GVHD, Wolff said there is an unmet need to develop new, well tolerated, and rapidly working agents that provide durable responses to improve patients’ quality of life. Axatilimab may just fit the role.