Behind the FDA Approval: Belumosudil for Chronic Graft Versus Host Disease

Belumosudil (Rezurock) was approved by the FDA for the treatment of patients 12 years and older with chronic graft-versus-host disease (GVHD) after 2 prior lines of systemic therapy in July of 2021. Since its approval, belumosudil has joined ibrutinib (Imbruvica) as the only 2 options available for this patient population.

The approval belumosudil was based on results from 2 clinical trials. The first phase 2 trial (NCT02841995) has an estimated enrollment of 88 participants and the second phase 2 trial (NCT03640481) has an estimated enrollment of 166 participants.

The first phase 2 trial was a small, dose escalation trial that tested 3 dose levels, 200 mg once daily, 200 mg twice daily, and 400 mg once daily. Due to safety signals, the lower 2 doses were chosen for further study.

The second phase 2 trial was a dose expansion trial with a primary outcome of overall response rate. Secondary end points include duration of response, change in Lee symptom scale score, overall survival, and time to response. The overall response rate was 75%, and more than 40% of patients remained on treatment for more than 1 year.

In an interview with Targeted Oncology™, Corey S. Cutler, MD, MPH, FRCPC, the medical director of the Adult Stem Cell Transplantation Program, director of Clinical Research, Stem Cell Transplantation, director of Stem Cell Transplantation Survivorship Program, institute physician at the Dana-Farber Cancer Institute, and associate professor of Medicine at Harvard Medical School, discussed the impact belumosudil has made on the chronic GVHD space.

TARGETED ONCOLOGY: Can you discuss the mechanism of action of belumosudil and what makes is effective for patient with chronic GVHD?

CUTLER: Belumosudil is a ROCK2 inhibitor. It's a compound that helps rebalance immunity at the level of the germinal center. And it also works by preventing or inhibiting some of the final steps required to lay down collagen and to make scar or fibrosis. So, it works in two different fashions in chronic GVHD.

What impact do you think the FDA approval has had on chronic GVHD?

First of all, this is an extraordinarily active compound with a very high response rate. So, patients who have steroid resistant disease are going to have yet another option for therapy, and now an option that actually works in a high proportion of patients. It's going to be a game changer for some of our patients with steroid resistant disease.

Can you provide an overview on the data supporting this approval?

The data is based on 2 trials. The first is a phase 1 dose escalation study, a small trial with about 55 patients who were enrolled. And we tested 2 dose levels, 200 mg once a day, 200 mg twice a day and 400 mg once a day. And the lower 2 doses were chosen for further study based on safety signals. And so, in the Pivotal trial, we tested 200 mg, once a day versus 200 mg, twice a day. In a randomized fashion, we enrolled 132 patients, and the overall response rate there was 75%. So, three out of four patients had a meaningful response. Duration of response by the protocol defined criteria was 54 weeks. And over 40% of subjects remained on therapy for over a year. So, it was a very well tolerated based on that median time on therapy statistic, and very effective with a 75% overall response rate, including a small number of patients that actually had a complete response.

What is the safety profile of belumosudil?

It was very safe. The only three side effects in the randomized trial that had an incidence greater than 5% for grade 3 or higher was pneumonia, hypertension, and hyperglycemia. These are things that are very commonly seen in our patients with chronic GVHD. And there was only a small proportion of patients who stopped the compound for side effects. So, very safe.

What unmet need does this drug fill?

The drug is labeled with a steroid refractory and one other line of therapy indication. Right now, the only [other] drug that's approved and chronic GVHD is ibrutinib for steroid refractory disease. So, there's not a lot of drugs that have been tested formally that are approved and are known to be very active. There are lots of other drugs, but they mostly work in smaller proportion of patients. So, here you have a drug with a label. This is the first drug that was ever designed and tested and labeled initially for chronic GVHD. We're going to be using a lot of this, I suspect, and I think our patients are going to benefit greatly. We're going to learn how to use it, and we're going to test it in other settings. We'll test it formally in other settings and hope We'll find an even greater role in chronic GVHD over time.

One thing to say is this drug is not for everybody. But for those in whom it works, it works for a long period of time. And I think we're going to figure out the best patients to use it in. Who's most likely to respond? And who is most likely to derive benefit from it? And that's our next challenge, is not giving it to everybody, but to give it to the patients who specifically will respond the best.

_REFERENCE:

_{Cutler C, Arai S, Zoghi B, et al. Interim analysis of KD025-213: a phase 2, randomized, multicenter study to evaluate the efficacy and safety of kd025 in subjects with chronic graft versus host disease (cGVHD) after at least 2 prior lines of systemic therapy (the ROCKstar study; NCT03640481). Presented at: 2020 Transplantation & Cellular Therapy Meetings; February 19-23, 2020. Orlando, FL. Abstract LBA2.}