Patients with chronic graft-vs-host disease (GVHD) frequently require multiple lines of therapy for persistent symptoms after hematopoietic cell transplant. Multiple drugs are now approved for this purpose. In a virtual Case-Based Roundtable event for physicians in the central US, Michael R. Bishop, MD, director of the Hematopoietic Cellular Therapy Program, director of the David and Etta Jonas Center for Cellular Therapy, and professor of medicine at the University of Chicago, discussed the trial data for 4 drugs including the most recently approved, axatilimab (Niktimvo). Bishop looked at the organ-specific responses that could influence treatment of different manifestations of GVHD as well as discussing the outcomes based on different dose and schedules of that were investigated in the trial.
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Targeted Oncology: Could you discuss the trial that supported the approval of axatilimab?
Michael R. Bishop, MD: This is the AGAVE-201 trial [NCT04710576]. It was a phase 2 randomized trial, and they looked at 3 different dosing schedules for axatilimab at 0.3 mg/kg every other week, 1 mg/kg every other week, and 3 mg/kg every 4 weeks. It has similar eligibility criteria as the other [chronic GVHD] trials, although this allowed older children and young adults. The primary end point was overall response after 6 cycles, and a cycle was considered 4 weeks, and [the lower bound of the 95% CI] had to be at least above a 30% response rate. Secondary end points were the Lee symptom scale, duration of response, failure-free survival, overall survival, and safety, which is always important.
What were the outcomes of the trial AGAVE-201 trial for patients with GVHD?
Interestingly, as patients went up on the dose, they saw a decline in response. [However], if you look at The New England Journal of Medicine paper, the complete response [CR] rate was slightly higher at the 1 mg/kg dose every other week, as compared with the 0.3 mg/kg every other week.1 However, the toxicity was significant as compared with the 0.3 mg/kg. In the 3 mg/kg dose, not only did you get less response, but you got a lot more toxicity. So, what ended up being approved is a 0.3 mg/kg dose every other week.
The organ response is interesting. Nearly 90% of patients with lower gastrointestinal [GI] GVHD achieved a CR. Similarly, upper GI—small bowel, stomach—was 82%, almost all CRs. If we look at the esophagus, we’re getting 78% and the overwhelming majority of those [are CRs]. In the joints and fascia, there was a good response rate at 76%, but similar to what we saw with belumosudil [Rezurock] there was a low CR rate. In the mouth, [overall response] was 52%, then we see lungs at 47% and then liver at 40%. At least surprising to me, eyes and [skin] were really low [in response]. They do comment that the sclerotic changes in the skin were improved in about 60% of patients. But it’s remarkable what you see in terms of GI and then again, a little similar in the other organs, is what we’ve seen with the other drugs.
When looking over time, the responses keep getting better. That’s another important thing. If we get out to 6 months, we see the response rates continue to improve, and we see skin up to 71%.2 [Originally], they were looking at the 6 cycles and continued improvement; this was updated evaluation of the patients on AGAVE-201.
How did the dose level affect the tolerability of axatilimab?
When looking at adverse events, if we look at grade 3 with the 1 mg/kg and 3 mg/kg doses, it was 60% and 71% of grade 3, [respectively]. Forty-one percent and 48% were serious adverse events [with the higher doses vs only] 38% of that with the 0.3 mg/kg.1 Fatalities were higher and there was a higher degree of interruption and dose reduction at these higher doses and with no improvement in response, as compared with 0.3 mg/kg. So more is not necessarily better or less is more when it comes to axatilimab.
What do you suggest for patients who have a response to axatilimab but live far from the infusion center?
These are important logistical points, having to travel back and forth. The infusion is relatively quick and simple, but you still have to get there. What do you do for long distance [patients]? It is an indefinite therapy, similar to all the other agents, but when they’re a pill, you can weigh that back and forth; at least it’s a little bit easier to administer. That means they’re going to have to come back. I know people are looking at whether there is the ability to decrease the frequency, but it’s still an intravenous formulation, and it’s not like they can get it at their local hospital, because they have to carry it on formulary.
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DISCLOSURES: Bishop previously reported research funding from AbbVie, Ascentage, Kite, a Gilead Company, Kura, and Takeda.
References:
1. 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
2. Choe H, Salhotra A, Farhadfar N, et al. Dynamics of overall and organ-specific responses to axatilimab in chronic graft-versus-host disease: analysis from the Agave-201 study. Blood. 2024;144(suppl 1):98. doi:10.1182/blood-2024-209965