Axatilimab Shakes Up cGVHD Treatment and Looks to Move to Earlier Line in Paradigm

Axatilimab-csfr (Niktimvo) has joined belumosudil (Rezurock) and ruxolitinib (Jakafi) in the treatment paradigm for patients with previously treated chronic graft-vs-host disease (GVHD), and next steps include the examination of the agents in the frontline setting, according to Christopher Graham, MD.

Current therapeutic strategies are informed in part by data from the phase 3 REACH3 study (NCT03112603), phase 2 AGAVE-201 trial (NCT04710576), and phase 2 ROCKstar study (NCT03640481). 1-3 In REACH3, the overall response rate (ORR) through week 24 was 70% in the ruxolitinib arm (n = 165) compared with 57% in the best available therapy arm (n = 164).1 Additionally, the primary end point of AGAVE-201 was met in all patient groups and an overall response rate (ORR) of 74% (95% CI, 63%-83%) was observed in those treated with 0.3 mg/kg of axatilimab (n = 80).2 Finally, patients treated with belumosudil in the ROCKstar study (n = 65) achieved an ORR of 75% (95% CI, 63%-85%).3

“My personal choice based off of [these] strategies [is] I would use belumosudil for more skin predominant [chronic GVHD], and I would use axatilimab for lung, gastrointestinal [GI], and liver [organ-specific disease],” Graham said in an interview with OncLive®.

In the interview, Graham detailed how axatilimab has changed the care of chronic GVHD and highlighted considerations with axatilimab, belumosudil, and ruxolitinib. Graham is a hematologist/oncologist and assistant professor of medicine, hematology, oncology and transplantation at the University of Minnesota Medical School in Minneapolis.

OncLive: What is important to take away from recent notable data on ruxolitinib and axatilimab?

Graham: The REACH3 study data looking at ruxolitinib for the second-line treatment of patients with chronic GVHD [showed a 49.7%] ORR at [week 24] which is impactful. Patients who were on the other arm of best available therapy who crossed over to ruxolitinib had a great response too [of 50.0%] when they were allowed to cross over at 24 weeks, which shows how good ruxolitinib is for patients with chronic GVHD.

The AGAVE-201 trial looked at axatilimab, which blocks CSF1R, [in patients with] chronic GVHD after 2 lines of therapy. Patients [in the lowest dose group of 0.3 mg/kg] also experienced a high response rate, even those who were refractory to prior lines of therapy, including belumosudil, ruxolitinib, and ibrutinib [Imbruvica]. There were very minimal adverse effects [AEs] observed and the most common was elevations of the transaminitis, which was low grade. The lowest dose [given] was the best dose, with a 74% response rate [observed], and this was mostly in [patients with] sclerosis predominant organs. [By baseline organ involvement, the lower GI, upper GI,] esophagus, joints and fascia, [mouth], and lungs, had very high [response] rates [that were all above 45%, and] skin has been very tricky in managing for chronic GVHD [but had an ORR of 26%]. What was very surprising was the responses [seen] in lungs and liver, which have been difficult organs to target for chronic GVHD. Response rates were 47% for the lungs and 40% for the liver, which shows the great utility with very minimal AEs of axatilimab after 2 lines of therapy.

How has axatilimab affected how you treat patients?

[As of late 2024], I haven’t had a chance to get it since it just was approved, but I have some patients who are anxiously awaiting receiving it. At our institution, we should start getting it around the first of January [2025] through our pipeline; once we have it, I’ll start using it more often. Right now, most of the time patients are on ruxolitinib or belumosudil and they have stable disease or still active disease. The complete response rates are not [the] best for a lot of the drugs, [but] with some of the [higher] complete response rates seen in AGAVE-201 [with axatilimab], it would be nice to see how patients respond because this [agent] was also [examined] in patients who previously had received ruxolitinib and belumosudil.

How do you select second-line and beyond therapies for patients with chronic GVHD?

The first-line [treatment] is high dose steroids usually [given at] 0.5 mg/kg to 1 mg/kg, [and] at the time, approximately 70% of patients eventually need another therapy. Before we had ruxolitinib, we had drugs like tacrolimus, sirolimus, and mycophenolate mofetil, and we also have rituximab [Rituxan] and ibrutinib for second-line treatment. Those have historically been some of the second-line therapies, but more people are switching to ruxolitinib in the second-line setting. If patients are already on tacrolimus or sirolimus, they increase that dose and then taper off after starting ruxolitinib. But most of the time, if they’re not on any therapy, you typically start steroids followed by ruxolitinib, and in patients who are refractory to ruxolitinib or did not have great response, historically we have been adding belumosudil. But I believe with the new axatilimab [approval] that choice will be different. You can either choose axatilimab or belumosudil depending on what organs you’re wanting to go after.

Belumosudil data from the ROCKstar study [showed] better skin treatment [with] a little better skin responses [and patients] also had great responses in other organs; [data] are pretty equivalent between axatilimab [and belumosudil]. Axatilimab has a little bit [better]—[although] we can’t do cross trial comparisons—liver and lung involvement response rates based off data from AGAVE-201.

What next steps are needed in chronicGVHD and what can your colleagues look forward to in the future?

One of the difficulties is that some chronic GVHD has a protective effect in that relapse rates are lower in patients who develop chronic GVHD—it’s felt that there’s a graft-vs-leukemia effect. The idea is trying to reduce the moderate to severe chronic GVHD while not increasing the rates of relapse in patients. We can see that with a lot of our prevention strategies; [by] using post-transplantation cyclophosphamide or abatacept we’re actively trying to target a lower chronic GVHD score to make it milder or get rid of the moderate to severe [cases] by reducing the incidence of chronic GVHD while not affecting the risk of relapse.

The phase 3 BMT CTN 1703 study [NCT03959241] and [another trial (NCT04503616) looking at] the CAST protocol have been using prophylaxis to reduce chronic GVHD and the relapse rates have been a lot better [in] both of those trials. I believe there will be more of a push trying to reduce the rates of moderate to severe [cases] without compromising the risk of relapse.

What upcoming research in the chronic GVHD field will be important?

There are some potential phase 3 studies that are coming out looking at earlier lines of therapy. [A phase 2 study (NCT06388564)] is using axatilimab upfront with ruxolitinib and there’s a [phase 3 study] that is looking at belumosudil in the frontline setting [NCT06143891]. Since both drugs are great for chronic GVHD, we’re seeing a push to having them in more upfront settings. There’s active involvement at a lot of institutions for both of those studies.

Chronic GVHD continues to have a significant effect on a patient’s livelihood with a significant financial burden as well as social, economic, and psychological impact. Many patients are refractory to steroids, which is frontline therapy, so the need for additional treatments is there.

References

1. Jakafi. Efficacy. Incyte. Accessed January 8, 2025. https://hcp.jakafi.com/chronic-graft-versus-host-disease/efficacy
2. Wolff D, Cutler C, Lee SJ, et al; AGAVE-201 Investigators. Axatilimab in recurrent or refractory chronic graft-versus-host disease. N Engl J Med. 2024;391(11):1002-1014. doi:10.1056/NEJMoa2401537
3. FDA approves belumosudil for chronic graft-versus-host disease. FDA. Updated February 1, 2022. Accessed January 8, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-belumosudil-chronic-graft-versus-host-disease