Axatilimab After Second-Line Therapy Generates ORR Benefit in Steroid-Refractory cGVHD

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Treatment with axatilimab-csfr (Niktimvo) following second-line therapy yielded consistent overall response rates (ORRs) regardless of number and type of prior lines of therapy in patients with hematologic malignancies and steroid-refractory chronic graft-vs-host disease (cGVHD), according to data from a post hoc analysis of the phase 2 AGAVE-201 trial (NCT04710576) that were presented at the 51st Annual EBMT Meeting.1

Across all studied dose levels of axatilimab, the agent produced similar ORRs between patients who had received 2 prior lines of therapy (n = 35; 51.4%; 95% CI, 34.0%-6.6%), 3 prior lines of therapy (n = 49; 61.2%; 95% CI, 46.2%-74.8%), 4 prior lines of therapy (n = 49; 63.3%; 95% CI, 48.3%-76.6%), and 4 or more prior lines of therapy (n = 157; 66.9%; 95% CI, 58.9%-74.2%).

In the overall population, the agent also induced similar ORRs between patients with best responses to their most recent prior treatment of complete response (CR) or partial response (PR; 64.6%; 95% CI, 53.3%-74.9%), no response (62.1%; 95% CI, 52.6%-70.9%), and disease progression (62.5%; 95% CI, 35.4%-84.8%). In the overall population (n = 241), the ORR was 63.5% (95% CI, 57.1%-69.9%).

Of note, the most common prior cGVHD therapies received during any line of therapy included prednisone (76.8%), ruxolitinib (Jakafi; 54.8%), extracorporeal photopheresis (56.4%), tacrolimus (40.2%), ibrutinib (Imbruvica; 31.1%), mycophenolate mofetil (29.5%), sirolimus (Rapamune; 29.5%), rituximab (Rituxan; 26.1%), belumosudil (Rezurock; 23.2%), ruxolitinib phosphate (19.5%), and ciclosporin (17.8%).

Among patients in the overall population treated with ruxolitinib in their last line of therapy (n = 68), the ORR was 61.8% (95% CI, 49.2%-73.3%), with a median time to response (TTR) of 1.9 months (range, 0.9-5.8) and a sustained response rate of 43.0% (95% CI, 31%-55%). Those treated with belumosudil in their last line of therapy (n = 34) achieved an ORR of 50.0% (32.4%-67.6%), with a median TTR of 1.9 months (range, 0.9-3.9) and a sustained response rate of 26% (95% CI, 13%-44%). Patients who received any other cGVHD treatment in their last line of therapy (n = 173) achieved an ORR of 64.2% (95% CI, 56.5%-71.3%).

Furthermore, in the overall population, the ORR was 57.4% (95% CI, 43.2%-70.8%) in patients who had been randomly assigned to AGAVE-201 less than 2 years after initial cGVHD diagnosis (n = 54) and 65.2% (95% CI, 57.9%-72.0%) in those who had been randomly assigned at least 2 years after diagnosis (n = 187).

“In AGAVE-201, ORRs were consistent with axatilimab regardless of the number of prior lines of therapy received. Responses were more sustained with ruxolitinib as last prior therapy,” Carrie L. Kitko, MD, and colleagues wrote in a poster of the data. “Patients who received axatilimab immediately after a regimen with ruxolitinib demonstrated rapid, durable clinical responses.”

Kitko is an associate professor of pediatrics and hematology/oncology, holds the Ingram Professorship in Pediatric Oncology in the Department of Pediatrics, and is the medical director of the Pediatric Stem Cell Transplantation Program at Vanderbilt University Medical Center in Nashville, Tennessee.

Background and AGAVE-201 Design

In August 2024, the FDA granted approval to axatilimab for the treatment of adult and pediatric patients with cGVHD after at least 2 lines of systemic therapy who weigh at least 40 kg.2 The regulatory decision was based on efficacy data from the AGAVE-201 study, and the recommended dose of axatilimab is 0.3 mg/kg in patients who weigh at least 40 kg up to a maximum dose of 35 mg as an intravenous (IV) infusion over 30 minutes every 2 weeks until disease progression or unacceptable toxicity.

The randomized, open-label, multicenter study included patients at least 2 years of age who had active cGVHD per NIH 2014 consensus criteria and had previously received at least 2 prior lines of systemic therapy.1 Patients were stratified based on disease severity (mild or moderate vs severe) and previous use of ibrutinib, ruxolitinib, or belumosudil (yes vs no). After stratification, patients were randomly assigned 1:1:1 to receive axatilimab IV at 0.3 mg/kg every 2 weeks (n = 80), 1 mg/kg every 2 weeks (n = 81), or axatilimab IV at 3 mg/kg every 4 weeks (n = 80). Responses were assessed post hoc by the number of prior lines of therapy and last therapy; lines of therapy were clinically adjudicated for the analysis.

The primary end point of the study was ORR; secondary end points included organ-specific responses, sustained response rate, and safety, with an exploratory end point of TTR. The objective of the current post hoc analysis was to evaluate the effects of prior lines of therapy on clinical outcomes in patients treated with axatilimab for cGVHD in AGAVE-201.

Patient Baseline Characteristics

In the overall patient population, across all axatilimab dose cohorts, the median age was 53.0 years (range, 7-81), and most patients were male (62.7%). The median time from cGVHD diagnosis to random assignment was 4.0 years (range, 0.4-17.6). At baseline, the median number of organs involved was 4.0, with a maximum of 8. In total, 79.7% of patients had severe disease, and the median number of prior lines of therapy was 4.0 (range, 2-15). Prior cGVHD therapy was given to 84.6% of patients, which included ruxolitinib (74.3%; last prior line of therapy, 28.2%; first line of therapy, 6.2%; second line of therapy, 24.5%; third line of therapy, 24.1%; fourth or later line of therapy, 40.2%), belumosudil (23.2%; 14.1%; 1.2%; 5.8%; 17.0%), and ibrutinib (31.1%; 5.8%; 2.5%; 4.1%; 5.0%; 22.4%).

Response Data in the 0.3 mg/kg Cohort

Notably, among patients who received axatilimab in the 0.3 mg/kg cohort, the ORR was 73.8% (95% CI, 62.7%-83.0%). The ORRs were 63.3% (95% CI, 43.9%-80.1%) among patients with CR or PR to their most recent prior treatment, 81.3% (95% CI, 63.6%-92.8%) among those with no response, and 83.3% (95% CI, 35.9%-99.6%) among those with disease progression.

When patients were stratified by number of prior lines of therapy, the ORRs were 63.6% (95% CI, 30.8%-89.1%) among those who had received 2 prior lines (n = 11), 53.3% (95% CI, 26.6%-78.7%) among those who had received 3 prior lines (n = 15), 82.4% (95% CI, 56.6%-96.2%) among those who had received 4 prior lines (n = 17), and 81.5% (95% CI, 68.6%-90.7%) among those who had received 4 or more prior lines (n = 54).

When patients were stratified by type of last line of therapy, the ORRs were 70.6% (95% CI, 44.0%-89.7%) among those who received ruxolitinib as their last line of therapy (n = 17), 75.0% (95% CI, 42.8%-94.5%) among those who received belumosudil as their last line of therapy (n = 12), and 74.6% (95% CI, 62.1%-84.7%) among those who received other cGVHD agents in their last line of therapy (n = 63).

Additionally, the ORR was 70.6% (95% CI, 44.0%-89.7%) in patients in this cohort who had been randomly assigned to AGAVE-201 less than 2 years after initial cGVHD diagnosis (n = 17) and 74.6% (95% CI, 62.1%-84.7%) in those who had been randomly assigned at least 2 years after diagnosis (n = 63).

Organ-Specific Responses and Safety Data

Organ-specific responses with axatilimab stratified by last prior therapy included those in the joints/fascia (prior ruxolitinib, 69.8% [n = 43]; prior belumosudil, 45.8% [n = 24]; other, 63.9% [n = 119]), mouth (42.3% [n = 26]; 25.0% [n = 20]; 47.7% [n = 86]), lungs (34.1% [n = 44]; 18.2% [n = 11]; 42.2% [n = 64]), eyes (31.4% [n = 51]; 28.0% [n = 25]; 30.3% [n = 132]), and skin (21.8% [n = 55], 6.9% [n = 29], 19.6% [n = 138]).

“Across all organs, response rates were numerically similar between patients who received ruxolitinib as last line of therapy compared with all other prior therapies,” the study authors wrote. “Organ-specific response rates were generally greater with ruxolitinib as last line of therapy compared with belumosudil as last line of therapy, except in the eyes, where responses were numerically similar.”

Regarding safety, treatment-emergent adverse effects (TEAEs) of any grade occurred in 96.2% of patients from the 0.3 mg/kg cohort and 97.9% of patients across all doses. Grade 3 or greater TEAEs occurred in 49.4% and 60.3% of patients in these respective dose groups. Opportunistic infections—including cytomegalovirus, Epstein-Barr virus, and invasive fungal infections—occurred in 4.2% of patients across all doses but did not occur in any patients in the 0.3 mg/kg arm. TEAEs that led to discontinuation of axatilimab occurred in 6.3% and 15.5% of patients in the 0.3 mg/kg cohort and the overall population, respectively.

“These findings warrant further investigation and may be attributable to the novel mechanism of action of axatilimab or line of therapy,” the study authors concluded. “Small patient numbers and mixed treatment regimens may limit interpretation.”

Disclosures: Kitko reported serving as an advisory committee member for Incyte Corporation, Sanofi, and Mesoblast; and membership of the GVHD adjudication teams for Alexion, CSL Behring, DSMC, and Incyte Corporation.

References

1. Kitko CL, Mehta R, Popradi G, et al. The effects of prior lines of therapy on clinical outcomes for patients with chronic graft-vs-host-disease receiving axatilimab: a post hoc analysis of AGAVE-201. Presented at: 51st Annual EBMT Meeting; March 30-April 2, 2025; Florence, Italy. Abstract B039.
2. FDA approves axalitimab-csfr for chronic graft-versus-host-disease. FDA. August 14, 2025. Accessed April 2, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-axatilimab-csfr-chronic-graft-versus-host-disease