Axatilimab Elicits Responses With Manageable Safety in Recurrent/Refractory cGVHD

Supplements And Featured Publications2023 ASH Meeting Reporter: Updates in GVHD
Volume 1
Issue 1

Axatilimab induced rapid and durable responses with an acceptable toxicity profile at all doses analyzed with highest efficacy observed at the 0.3-mg/kg dose in patients with recurrent or refractory chronic graft-vs-host disease.

Daniel Wolff, MD, PhD

Daniel Wolff, MD, PhD

Axatilimab induced rapid and durable responses with an acceptable toxicity profile at all doses analyzed with highest efficacy observed at the 0.3-mg/kg dose in patients with recurrent or refractory chronic graft-vs-host disease (cGVHD), according to data from the phase 2 trial (NCT04710576) presented in a Plenary Session during the 2023 ASH Annual Meeting.1

The agent elicited an objective response rate (ORR) of 74% (95% CI, 63%-83%) when given at a dose of 0.3 mg/kg every 2 weeks (n = 80). When given at a dose of 1.0 mg/kg every 2 weeks (n = 81) or 3.0 mg/kg every 4 weeks (n = 80), axatilimab resulted in ORRs of 67% (95% CI, 55%-77%) and 50% (95% CI, 39%-61%), respectively. The primary end point of the trial, which was ORR in the first 6 cycles as defined by National Institutes of Health (NIH) 2014 Consensus criteria, was met in all cohorts.

The median time to response in the 0.3-mg/kg, 1.0-mg/kg, and 3.0-mg/kg cohorts with axatilimab was 1.7 months (range, 0.9-8.1), 1.9 months (range, 0.9-8.6), and 1.4 months (range, 0.9-5.6), respectively. Moreover, 60% (95% CI, 43%-74%), 60% (95% CI, 43%-74%), and 53% (95% CI, 30%-71%) of patients in these cohorts, respectively, had responses that continued for at least 1 year.

“Axatilimab, with its unique mechanism of action, may represent a new therapeutic strategy in chronic GVHD,” Daniel Wolff, MD, PhD, of the University Hospital of Regensburg in Germany, said in a presentation of the data. “The AGAVE-201 trial met its primary end point in all 3 doses assessed, but the highest ORR and the least toxicity was observed with the lowest dose; that underlines the crucial importance of sufficiently powered studies in this vulnerable patient population.”

cGVHD represents a major cause of late morbidity, affecting 30% to 50% of patients who undergo transplant, Wolff noted. It is a multiorgan, inflammatory, fibrotic, difficult-to-treat disease that frequently requires several lines of treatment with decreasing efficacy, he added. cGVHD also impairs quality of life (QOL) and results in significant disease burden in those who are otherwise cured from underlying malignancies. As such, new effective and tolerable options are needed.

“CSF-1R–dependent monocytes and macrophages mediate inflammation and fibrosis. Axatilimab is an investigational monoclonal antibody that targets CSF-1R on monocytes and macrophages,” Wolff said. Data from a phase 1/2 study (NCT03604692) showed that in all evaluable patients, axatilimab elicited an ORR of 67% (95% CI, 50%-81%) in the first 6 cycles of treatment.2 The agent was also reported to have a favorable safety profile.

The phase 2 AGAVE-201 trial enrolled patients with active cGVHD defined as 2014 NIH Consensus criteria who were at least 2 years of age who had received at least 2 prior lines of systemic treatment.1 They also needed to have “Karnofsky performance equal to or above 60% and adequate bone marrow and organ function,” Wolff said. Although concomitant use of corticosteroids (65%), calcineurin inhibitors (28%), and mTOR inhibitors (12%) was permitted, it was not required. No additional systemic treatment for cGVHD was allowed.

Study participants were enrolled at a total of 121 clinical sites in 16 countries and 4 continents (North America, n = 51; Europe/Middle East, n = 58; Asia, n = 10; Australia, n = 2). A total of 241 patients were randomized to 1 of 3 doses/schedules: 0.3 mg/kg every 2 weeks, 1.0 mg/kg every 2 weeks, and 3.0 mg/kg every 4 weeks.

In addition to the primary end point being ORR in the first 6 cycles by NIH 2014 Consensus criteria, secondary and exploratory end points included clinically meaningful improvement in modified Lee Symptom Scale (mLSS), organ-specific response rates, duration of response, failure-free survival (FFS), overall survival, and safety.

Baseline characteristics and demographics were well balanced across the cohorts, according to Wolff. In the total population, the median age was 53 years (range, 7-81). Most patients were male (63%), White (83%), and had severe disease (80%). The median time from diagnosis of cGVHD to randomization was 4 years. The median number of organs involved at baseline was 4, and 54% of patients had 4 or more organs involved.

Notably, the median number of previous systemic treatments received for cGVHD was 4; 55% of patients were refractory to their last cGVHD treatment. Eighty-five percent of patients previously received ruxolitinib (Jakafi; 74%), ibrutinib (Imbruvica; 31%), and/or belumosudil (Rezurock; 23%).

“Surprisingly, [none] of the patient characteristics impact[ed] the response rate, including age—in fact, only 7 patients in the whole study were below the age of 17—and severity [of cGVHD at screening,” Wolff noted. “Most importantly, high response rates were seen in patients who received prior FDA-approved agents, including belumosudil, underlying the distinct mechanism of action of axatilimab.”

In those younger than 17 years of age (n = 4), the ORR with the agent was 75% (95% CI, 19%-995); in those who were at least 17 years but under 65 years (n = 55), the ORR was 78% (95% CI, 65%-88%). In those who were 65 years of age or older (n = 21), the ORR was 62% (95% CI, 38%-82%). In those with mild or moderate cGVHD at the time of screening (n = 17), the ORR with the agent was 65% (95% CI, 38%-86); in those with severe cGVHD at screening (n = 63), the ORR was 76% (95% CI, 64%-86%). In those who previously received ibrutinib (n = 27), ruxolitinib (n = 57), or belumosudil (n = 16), the ORRs with axatilimab were 82% (95% CI, 62%-94%), 79% (95% CI, 66%-89%), and 75% (95% CI, 48%-93%), respectively.

“In terms of organ-specific response, complete remission [CR] was seen across all organs involved,” Wolff said. Responses with axatilimab at 0.3 mg/kg every 2 weeks were also seen in fibrosis-dominated organs. CRs were observed in the following organs: lower gastrointestinal (GI; n = 9; 89%), upper GI (n = 11; 82%), esophagus (n = 23; 65%), joints/fascia (n = 55; 20%), mouth (n = 40; 42%), lungs (n = 32; 42%), liver (n = 10; 20%), eyes (n = 59; 10%), and skin (n = 64; 9%).

Forty-four percent of patients had reduction in body surface area involved by sclerosis and 66% experienced an improvement in skin and joint tightening severity, Wolff added. “The discrepancy is best explained by the fact that 94% of the patients enrolled in the trial has steroidal skin lesions and the nature of the NIH response criteria require complete resolution of deep sclerosis for a remission documentation.”

The median FFS with axatilimab was 17.3 months (95% CI, 14.2-not evaluable). “Only 2 patients in the 0.3-mg/kg cohort died. Both had severe lung GVHD; 1 died as a direct consequence of progressive lung disease and the other had a preceding lung infection which led to death,” Wolff said.

In terms of symptom burden as assessed by mLSS, 55% of patients experienced a clinically meaningful change of equal to or above 7 points. “Eighty-seven percent of patients experienced improvement compared with baseline,” Wolff noted. Moreover, 73% of patients experienced improved mLSS skin thickened score vs baseline, “underlying the crucial importance of capturing patient-reported outcomes in this patient population,” he said. “Symptom improvement was fairly rapid and followed the trajectory seen in the overall response.”

In the 0.3-mg/kg cohort, adverse effects (AEs) led to dose decrease for 6.3% of patients and discontinuation for 6.3% of patients. The most common any-grade AEs experienced in at least 20% of patients in this cohort included fatigue (22.8%), headache (19.0%), periorbital edema (2.5%), and COVID-19 (16.5%).

Laboratory abnormalities included increased aspartate aminotransferase (13.9%), increased creatinine phosphokinase (11.4%), increased lipase (11.4%), increased lactate dehydrogenase (13.9%), increased alanine aminotransferase (12.7%), and increased amylase (3.8%).

Additionally, 17.7% of patients experienced at least 1 related grade 3 or higher AE and 1 patient had an AE that proved to be fatal.

“At higher doses, periorbital edema was a very specific AE of axatilimab,” Wolff concluded. “…AEs were mostly low grade, reversible, and increased with higher doses.”


  1. Wolff D, Cutler C, Lee SJ, et al. Safety and efficacy of axatilimab at 3 different doses in patients with chronic graft-versus-host disease (AGAVE-201). Blood. 2023;142(suppl 1):1. doi:10.1182/blood-2023-186963
  2. Kitko CL, Arora M, DeFilipp Z, et al. Axatilimab for chronic graft-versus-host disease after failure of at least two prior systemic therapies: results of a phase I/II study. J Clin Oncol. 2023;41(10):1864-1875. doi:10.1200/JCO.22.00958
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