Scenario 2: Belumosudil and Axatilimab as Treatment Options in cGVHD


Considerations for belumosudil and axatilimab as treatment options for steroid-refractory chronic graft-versus-host disease.


Nelson Chao, MD:Let’s go on to the third drug, which is belumosudil. This drug was approved in July 2021 for patients and pediatric patients 12 years and older with chronic GVHD [graft-vs-host disease] after failure of at least 2 prior lines of systemic therapy. I’m going to turn this over to Dr Cutler, who’s the lead investigator of this trial.

Corey Cutler, MD, MPH, FRCPC: Thanks, Dr Chao. This was the second trial performed using this novel compound. Just of note, this is the first compound developed and specifically approved in chronic GVHD. Based on a phase 1 dose-escalation trial that enrolled just under 60 patients, we chose 2 potential recommended doses for a randomized trial in the ROCKstar study. In this trial, we enrolled 132 subjects and randomized them between 2 dosages of belumosudil: 200 mg once daily or 200 mg twice daily. Similar to the design of the REACH3 trial, we included some stratification factors, which included the prior use of Ibrutinib. At that time, it was the only FDA-approved compound available. We stratified by moderate to severe chronic graft-vs-host disease. This was a real-world trial population. These were sick patients, more than 2 years after the onset of their chronic GVHD, and most had multiple origins and had 3 or more lines of therapy. This was a sick advanced group of patients with chronic GVHD. What’s shown is the response rates. The overall response rates for the 2 arms were approximately 75%. We did not notice differences between the 200-mg daily and the 200-mg twice-daily dosing in this study.

What was very important as well was that we noticed significant responses that were no different from the overall response rate in patients who are previously exposed to ibrutinib or ruxolitinib. This wasn’t part of the original design, we did analyze it at the end. It didn’t matter if patients had previously had 3, 4, or more lines of therapy. The response rates were all the same, no matter how we cut the data. On the basis of this study, the FDA granted a full approval to belumosudil for the management of patients with 2 or more lines of prior therapy in chronic graft-vs-host disease.

We also looked at things like quality of life and organ-specific responses. We were able to demonstrate very nice broad organ responses across the board, including responses in the lung, which we had not previously seen. The drug was very safe. The adverse-effect profile is seen on these slides. The standard adverse effects that one would expect in a trial of patients with advanced chronic GVHD were seen. But the incidence of grade 3 or higher adverse effects that were found commonly were only pneumonia, hypertension, and hyperglycemia—things also associated with chronic corticosteroid use.

Nelson Chao, MD:One interesting point you brought up is to see the responses in the lung. That’s probably 1 of the more encouraging aspects. Up to this point, it’s been very difficult to see responses in the lung. Other drugs are out there, including axatilimab, which is a monoclonal antibody that targets the CSF1R receptor protein in monocytes and macrophages. There are increasing data to suggest that a lot of the inflammatory and profibrotic responses we see in chronic graft-vs-host disease may be from monocytes and macrophages. This might be a quite interesting way to have a novel mechanism of action that’s targeting a cell that’s different from what we’ve been focused on in the past, which had been T cells or B cells. For phase 1/2 open-label dose escalations studies, 40 patients had 2 or more prior lines of therapy, including ibrutinib, ruxolitinib, and belumosudil. The median involved 4 organs. Overall responses have been 66% to 70%, and 4 of 13 patients had responses to the lung. Median time to the first response was 0.9 month. It was well tolerated overall, which is something else to keep in mind.

There are other clinical trials. There’s a lot of interest in the potential of combination therapies. These are some of the trials that are recruiting. Trials using ruxolitinib and belumosudil with 2 mechanisms of action, for example, may be quite interesting with patients who have severe chronic graft-vs-host disease.

Transcript edited for clarity.

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