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SAN DIEGO -- Axatilimab achieved rapid and durable responses in patients with recurrent/refractory chronic graft-versus-host disease (cGVHD), according to the phase II AGAVE-201 trial.

The highest overall response rate (ORR) was observed in patients treated with the lowest dose of axatilimab at 0.3 mg/kg every 2 weeks, with an ORR of 74% (95% CI 63-83) within the first 6 months, reported Daniel Wolff, MD, PhD, of the University Hospital of Regensburg in Germany.

In addition, the response to therapy was rapid (a median of 1.7 months), with that response maintained for 12 months or longer in 60% of patients, he stated in a presentation at the American Society of Hematology annual meeting.

The ORR among patients treated at a dose of 1.0 mg/kg every 2 weeks was 67% (95% CI 55-77), while the ORR for those treated at the highest dose -- 3.0 mg/kg every 4 weeks -- was 50% (95% CI 39-61).

"Axatilimab, with its unique mechanism of action, may represent a new therapeutic strategy in chronic graft-versus-host disease," Wolff said. "The highest overall response rate and the least toxicity was observed with the lowest dose, and that underlines the crucial importance of sufficiently powered studies in this vulnerable patient population."

Chronic GVHD is a major cause of late morbidity in as many as 50% of patients. It's a multi-organ, inflammatory disease that requires multiple lines of treatment that decrease in efficacy. Wolff noted that "despite recent approvals of treatment options in chronic graft-versus-host disease, there is an unmet need to develop new, well tolerated, rapidly working agents that provide durable responses to improve the quality of life of patients."

He explained that colony-stimulating factor-1 receptor (CSF-1R)-dependent monocytes and macrophages play a key role in cGVHD inflammation and fibrosis. Axatilimab is an investigational, high-affinity anti-CSF-1R monoclonal antibody that targets monocytes and macrophages, and was shown to have biological and clinical activity in heavily pre-treated patients with cGVHD in a . The agent was granted by the FDA in for the treatment of patients with cGVHD and idiopathic pulmonary fibrosis.

included patients, ages ≥2 years, who had been treated with at least three prior lines of therapy, and had active cGVHD. Patients were allowed in the study if they were using corticosteroids, calcineurin inhibitors, or mTOR inhibitors, while no additional systemic chronic GVHD therapy was allowed.

Among the 241 patients randomized to receive one of three dose levels, the median age was 53, and 63% were male. The time from cGVHD diagnosis to randomization was a median of 4 years, and 80% of patients had severe disease, with 54% having four or more organs involved.

In addition, these patients were heavily pretreated, having received a median of four prior systemic treatments, with more than half (55%) having failed their prior cGVHD therapy.

Wolff explained that organ-specific responses were seen across all involved organs, and were particularly notable in fibrosis-dominated organs, including the esophagus (78%), joints and fascia (76%), lung (47%), and skin (27%).

The median failure-free survival in the 0.3 mg/kg group was 17.3 months (95% CI 14.2-not evaluable).

More than half (55%) of the patients in the 0.3 mg/kg group reported a clinically meaningful change of at least a 7-point improvement in symptom burden as measured by the Modified Lee Symptom Scale.

In the low-dose cohort, 6.3% of patients had an adverse event (AE) leading to treatment discontinuation, compared with 22.2% in the 1.0 mg/kg cohort and 17.7% in the 3.0 mg/kg group. One patient in the low-dose group had a fatal AE (the patient had dyspnea) compared with seven in the 1.0 mg/kg group and six in the 3.0 mg/kg group.

At higher doses, periorbital edema was a notable side effect of axatilimab, occurring in more than 20% of the higher dose groups, but in just 2.5% of the 0.3 mg/kg group.

When asked whether he had any explanations for the inverse dose response to axatilimab, Wolff said he had been expecting the question.

"It turns out that the high dose leads to a prolonged depletion of monocytes and macrophages, which increases, in turn, the CSF-1 level in the circulation," he said. "And 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, for sure, not the only one."

Developers Syndax Pharmaceuticals and Incyte said that, based on AGAVE-201 results, they intend to submit a to the FDA by the end of 2023.

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