Belumosudil: Poised to Become Necessity in Chronic GVHD

Corey S. Cutler, MD, MPH, FRCPC, discusses the potential clinical implications should belumosudil gain FDA approval in chronic GVHD.

The novel ROCK2 inhibitor belumosudil (formerly KD025) has demonstrated promising results in patients with chronic graft-versus-host disease (GVHD) who have received 2 or more prior lines of therapy and could soon become a very crucial agent available in the paradigm, explained Corey S. Cutler, MD, MPH, FRCPC.

In November 2020, the FDA granted priority review status to belumosudil for use in this patient population and setting, based on results of the phase 2 ROCKstar study (NCT03640481).1 Updated data from an analysis of the trial, which were presented at the 2020 ASH Annual Meeting and Exposition, indicated that the objective response rates (ORR) at the 200-mg dose once daily and twice daily were 73% and 74%, respectively.2 Additionally, the agent elicited high responses across all patient subgroups, regardless of length of time from diagnosis to treatment, severe chronic disease, involvement of 4 or more organs, and refractory status to prior lines of therapy.

“Having a third agent approved for [the treatment of chronic] GVHD would be tremendous,” Cutler said. “We know that many of our patients require multiple lines of therapy and many [of them] progress despite [previous treatment with] ibrutinib[Imbruvica] which is FDA approved, and ruxolitinib, [Jakafi], which is pending FDA approval in chronic GVHD. In the ROCKstar study, response rates were excellent among patients who had previously received either of these 2 agents.”

In an interview with OncLive, Cutler, who is the medical director of the Adult Stem Cell Transplantation Program, director of clinical research in Stem Cell Transplantation, director of the Stem Cell Transplantation Survivorship Program, and institute physician at Dana-Farber Cancer Institute, as well as an associate professor of medicine at Harvard Medical School, discussed the potential clinical implications should belumosudil gain FDA approval in chronic GVHD.

OncLive: What sets belumosudil apart from other agents used to treat patients with chronic GVHD?

Cutler: Ibrutinib and belumosudil differ in several ways. First, ibrutinib is a BTK inhibitor and, as such, only inhibits B-cell pathways. However, there are other targets of ibrutinib in T cells, as well, but their role in GVHD is a little less clear. Belumosudil, on the other hand, is an inhibitor of ROCK2, which rebalances immunity at the level of the germinal center by downregulating Th17 cells and upregulating regulatory T cells. It also inhibits fibrotic pathways; it's part of the cascade in terms of laying down collagen and fibrosis. They work on very different pathways and have very different mechanisms of action.

What is the current state of effective therapeutics for patients with chronic GVHD?

Very clearly, what we have now is insufficient. While ibrutinib being the first approved therapy in this disease was a great step forward for us, it's not effective in all patients. Many patients who initially respond to ibrutinib eventually progress and require later [lines of] therapy. Having more than 1 option for these patients is really something that our patients need.

What were the preliminary data from the phase 2 ROCKstar study, and what has since been learned with the 1-year updated analysis?

Previously, we had presented an early analysis at the 2020 Transplantation and Cellular Therapy Meeting where we showed response rates of about two-thirds in patients 2 months after the last patient was [enrolled] on the trial. We now have 1-year data on pretty much [all patients].

At this point, the response rates are significantly higher—they are up in the mid 70% [range]—which suggests that, over time, there are additional patients who will respond to therapy. We have nice data on subgroups in terms of patients who had previously received other agents. We divided the patients by how many lines of prior therapy they had and how many organs they have involved.

We have a nice update on the data. There are no surprises. Everything is, in fact, a little bit better than how it was at the first early interim analysis.

Was this efficacy demonstrated across all patient subgroups?

It was. Individuals who had received prior ibrutinib had a response rate of about 74% and those who had received prior ruxolitinib had a response rate of 68%. There were responses across all the groups that we could tell, even among those who were refractory to their prior line of therapy. The responses were 73% and 74% for those who were refractory and those who were not, [respectively].

The one other important thing about this analysis was that the responses were really durable. The median duration of response was about 1 year at 50 weeks, and 60% of responders had a response for 20 weeks or greater. That number is likely to go up over time based on the shorter degree of follow-up [we have available] for some patients, but it's really nice that subjects are not necessarily coming off of therapy. We know that our 1-year failure-free survival is about 60%, which is quite good in this disease.

Were there any late onset toxicities?

We didn't see anything additional, surprising, or new in terms of toxicities. Overall, it was very well tolerated. What was interesting was that the infection rate was actually quite low. Problems with cytomegalovirus reactivation, for example, were exceedingly rare. These are patients who are heavily immunosuppressed, [which] suggests to us that this [agent] is not immunosuppressive in the traditional sense of the word.

Where do you believe future research efforts should be focused in GVHD?

Like any drug in GVHD that we have tested in the past, we tend to use these agents in patients who have very few options left for their therapy. The natural thing to think about for the compound—and really any other compound following development—is to look at its activity in earlier stages of chronic GVHD. [This includes] either frontline steroid failures or frontline [in combination with] steroids, potentially even frontline [use] instead of steroids. There is always the idea of whether this is an appropriate agent to use for prophylaxis of chronic GVHD or not.

We're also particularly interested in studying belumosudil in subtypes of chronic GVHD that have fibrosis as 1 of their prominent features. There stands to be at least a reasonable chance that this drug can reverse established fibrosis.

We would like to see this agent tested earlier in the treatment of patients with chronic GVHD, perhaps in direct comparison to other commonly used agents. We would also like to see it tested in larger groups of patients with chronic GVHD–induced fibrosis to determine how effective it can be in reversing established fibrosis. Finally, there may be a role for this agent in the prevention of patients with chronic GVHD.

There still will be a need for other agents in this space. Some patients will not respond to this drug, and others may require a combination of therapies to maximize the likelihood of successful chronic GVHD outcomes.


  1. Kadmon announces FDA acceptance of nda for belumosudil in patients with chronic graft-versus-host disease. News release. Kadom Holdings, Inc. November 30, 2020. Accessed March 3, 2021.
  2. Cutler C, Lee SJ, Arai S, et al. Belumosudil for chronic graft-versus-host disease (cGVHD) after 2 or more prior lines of therapy: the Rockstar study (KD025-213). Presented at 62nd Annual ASH Annual Meeting and Exposition; December 5-8, 2020; virtual. Abstract 353.