Dosage, IV Administration Considered in Use of Axatilimab for cGVHD

A significant number of patients who develop chronic graft-vs-host disease (cGVHD) following hematopoietic cell transplantation continue to need treatment after multiple prior therapies, and current trials are focusing on this refractory population. During a virtual Case-Based Roundtable event, Hannah Choe, MD, an associate professor of Internal Medicine in the Division of Hematology at The Ohio State University, discussed outcomes of the AGAVE-201 trial (NCT04710576) of axatilimab (Niktimvo). She examined the multiple dose levels investigated and the implications of its organ-specific efficacy and intravenous (IV) administration in comparison to other options at this stage.

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This article is part 3 of a 3-part series from a Case-Based Roundtable event.

Targeted Oncology: How did the AGAVE-201 trial investigate the use of axatilimab?

Hannah Choe, MD: AGAVE-201 with axatilimab is a phase 2 [trial], [and axatilimab is] already FDA approved. Similar to belumosudil [Rezurock] in the ROCKstar study [NCT03640481], this was done in patients who were refractory to multiple lines of therapy as well, more than 2 prior lines of therapy, and not directly comparable to REACH3 [NCT03112603] with ruxolitinib [Jakafi].

The AGAVE-201 study with axatilimab was in younger patients.¹ The cutoff for ruxolitinib was 12 years old, and then belumosudil was with 18-year-old [patients], and then now axatilimab [was investigated] with [patients as young as] 2 years. Their indications and the uses were slightly different, too.

[Whereas the ROCKstar trial investigated] twice daily vs daily [doses] with belumosudil…axatilimab had 3 different doses that they compared within the same study. They can do that because it’s a phase 2 study. They tried using it at 0.3 mg/kg every 2 weeks, 1 mg/kg every 2 weeks, and then a higher dose, at 3 mg every 4 weeks, and they had [approximately 80] patients in each of these arms.

The primary end point was overall response rate in the first 6 cycles as defined by [NIH 2014 Consensus Criteria] for grading, and the end point was met the lower bound [of 95% CI] was higher than 30%...because if you compare the response rates to therapies that were existing at the time, that were in practice, for multiple lines of therapy failures, then 30% was the minimum. Even getting 30% in this setting for only approved therapies [is good]? It was going to be reached regardless, as long as you got at least 30% in this study for any of these doses. The secondary and exploratory end points for the study were clinically meaningful improvement in the patient-reported outcome report with the modified Lee Symptom Scale of 7 points or more. They also looked at organ-specific response rates—but not comparing them between each arm—for failure-free survival, duration of response, and then safety, as you would expect. I want to clarify that ruxolitinib, belumosudil and ibrutinib [Imbruvica] are oral, [but] axatilimab is an [intravenous (IV)] infusion which takes about 30 minutes…in an infusion center.

What were the response outcomes overall and by organ?

The overall response from this study met its primary end point for all 3 arms with regards to the dose, 0.3 mg/kg every 2 weeks, 1 mg/kg every 2 weeks, or 3 mg/kg every 4 weeks. What’s interesting, though, is that the [lowest] dose had the higher overall response rate: 74% of patients in the 0.3 mg/kg every-2-weeks dose was much better than 67% [with 1 mg/kg] vs the 50% [with 3 mg/kg every 4 weeks] but all of them met the primary end point.

When you look at organ-specific response rates—and this is not focusing on only the 0.3 mg/kg dose, because we’ve only determined that that is the dose that works the best in terms of response rate—across organ systems, the organ systems are similar to what we saw in ROCKstar, which was also in patients with multiple lines of previous therapy that had failed.^1,2 You see lower gastrointestinal [GI] tract responses [89%], upper GI [82%], esophageal responses [78%], [and] joints and fascia responses [76%].¹ Then you see mouth [52%] and then as expected, [responses were] low in the lungs [47%], liver [40%], eyes [30%], and skin [26%], but still in a very refractory setting, very high response rates for difficult to treat immune systems, particularly the lungs, and particularly the skin too, because these were actually more sclerotic manifestations. I think 41% to 44% of these patients had sclerotic manifestations of skin involvement, and regardless of that, they still had more than a quarter of these patients respond.

In a very refractory setting, these were very encouraging data to see. We have this [agent] that, [although] it’s IV, it’s a totally different mechanism of action. Whereas ruxolitinib or belumosudil target the T cells and maybe target the B cells, they also might target a little bit of scar tissue formation is as well. But axatilimab, in fact, targets monocytes and tissue macrophages, and so by blocking macrophages, or by blocking the activity at the scar tissue formation level, you can have responses not just in the more inflammatory manifestations, such as the GI tract and esophagus, but more sclerotic responses and more sclerotic manifestations with the lungs, eyes, and the skin. The more sclerotic manifestations have more partial responses than complete responses.

[Looking at] the organ-specific response rate based on the duration, we see that patients that had lower GI tract, upper GI, joints, fascia, esophagus, liver, tend to respond much faster within the first 2 to 3 months, as compared to the more sclerotic lung, ocular, and skin manifestations, which might have taken at least 4 months or so, or even 6 months to get to that point where the other organ systems had already responded.³ Once you start therapy, it might take some time to get that response.

What stood out in terms of tolerability of axatilimab?

It’s interesting that we had the highest response with the lowest dose, [but] it makes more sense that we don’t see as many adverse events.¹ This 0.3 mg/kg every 2 weeks the clear winner for this study, There are fewer serious or fatal adverse events with the 0.3 mg/kg dose and fewer dose reductions, though not necessarily dose interruptions. That’s because the dose interruptions can happen for laboratory changes. The discontinuation was significantly less with the lower dose because of better tolerability.

Does the IV administration pose challenges for using axatilimab?

I have been reached out to by one physician out of the many patients that we have on axatilimab to ask questions about management of the axatilimab locally. Once you start giving it, it’s easier to manage than rituximab [Rituxan], in my opinion. You have to watch out for infusion reactions, because it’s a monoclonal antibody, but the rate of infusion reactions is, anecdotally, very few, and it’s only a half-hour infusion. Patients are open to it after they’ve started it. They’re not excited starting it, because they go from an oral therapy like ruxolitinib or belumosudil to all of a sudden needing an IV therapy and having to drive to an infusion center. But once they’ve started and see how tolerable it is, generally, patients will stay on it….

_{DISCLOSURES: Choe previously reported relationships with Incyte Corporation, Sanofi, Ironwood Pharmaceuticals, AbbVie, Actinium Pharmaceuticals, Inc., and Regimmune.}

_REFERENCES:

_{1. Wolff D, Cutler C, Lee SJ, et al. Axatilimab in recurrent or refractory chronic graft-versus-host disease. N Engl J Med. 2024;391(11):1002-1014. doi:10.1056/NEJMoa2401537}

_{2. Cutler C, Lee SJ, Arai S, et al. Belumosudil for chronic graft-versus-host disease after 2 or more prior lines of therapy: the ROCKstar Study. Blood. 2021;138(22):2278-2289. doi:10.1182/blood.2021012021}

_{3. 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}