Newly-Approved Belumosudil Yields High Overall Response Rate in Patients with Chronic Graft-Versus-Host-Disease

Corey Cutler, MD, MPH, FRCPC

Data from the phase 2 trial ROCKstar clinical trial (NCT03640481) demonstrated that patients with chronic graft-versus-host-disease (GVHD) and were treated with belumosudil (Rezurock) experienced clinically meaningful, durable responses. These results were consistent among patients despite differences in prior treatments, severity of disease and number of organs affected, according to the published study in Blood. ¹

The best overall response rate (ORR) achieved with belumosudil at a once-daily dose of 200 mg was 74% (95% CI, 62%-84%) and 77% (95% CI, 65%-87%) when given at a twice-daily dose of 200 mg. High ORRs, ranging from 61% to 85%, were reported in all subgroups analyzed.

The efficacy demonstrated with belumosudil was maintained, regardless of previous treatment with ibrutinib (Imbruvica; n = 46) or ruxolitinib (Jakafi; n = 38). The ORRs in the ruxolitinib and ibrutinib subsets were 68% (95% CI, 51%-83%) and 74% (95% CI, 59%-86%), respectively.

Additionally, best ORR was observed across all affected organs. The ORRs observed in the skin, eyes, mouth, liver, lungs, joint/fascia, upper gastrointestinal (GI) tract, lower GI tract, and the esophagus at 37%, 42%, 55%, 39%, 26%, 71%, 52%, 69%, and 45%, respectively.

“Belumosudil is very effective in inducing responses across all organs affected by chronic GVHD and is safe and well tolerated. It is exciting to see the development of new interventions that can help patients,” study investigator Corey Cutler, MD, MPH, FRCPC, associate professor of medicine at Harvard Medical School and medical director of the Adult Stem Cell Transplantation Program at Dana-Farber Cancer Institute, stated in a press release.²

An oral selective inhibitor of ROCK2, belumosudil was designed to reduce type 17 and follicular helper T cells through downregulation of STAT3 and to strengthen regulatory T cells through the upregulation of STAT5.

In July 2021, the FDA approved belumosudil for use in adult and pediatric patients aged 12 years and older with chronic GVHD following failure of at least 2 prior lines of systemic therapy.³ The regulatory decision was supported by data from ROCKstar.

In the multicenter registration phase 2 trial, investigators examined 2 doses of belumosudil, at 200 mg daily (n = 66) and 200 mg twice daily (n = 66) in patients with chronic GVHD who had previously received 2 to 5 lines of treatment.

To be eligible for participation, patients needed to have received an allogeneic hematopoietic cell transplant, be at least 12 years of age, and have persistent chronic GVHD manifestations following 2 to 5 previous systemic lines of therapy. Patients needed to be on stable corticosteroids for 2 weeks before screening, and they needed to have a Karnofsky or Lansky Performance Status Scale score of 60 or higher.

If patients experienced a relapse of their underlying malignancy, had a National Institutes of Health (NIH) lung symptom score of 3, and had developed lymphoproliferative disease following transplant, they were excluded. Other exclusion criteria included liver transaminases greater than 3 times the upper limit of normal (ULN), a total bilirubin of more than 1.5 times the ULN for any reason, current receipt of ibrutinib.

Study participants received belumosudil at either once-daily 200 mg or twice-daily 200 mg in patients with chronic GVHD. Patients were stratified 1:1 by chronic GVHD severity and previous exposure to ibrutinib. Patients received belumosudil continuously until significant disease progression or intolerable toxicity.

The primary end point of the trial was best ORR at any time, and important secondary end points comprised duration of response (DOR), time to response (TTR), changes in Lee Symptom Scale (LSS), failure-free survival (FFS), corticosteroid dose reductions, overall survival, and safety.

A total of 132 patients were enrolled to the trial between October 2018 and August 2019. Baseline demographics and clinical characteristics were found to be comparable across the arms. The median age of participants was 56 years (range, 21-77), and the overall median time from diagnosis to enrollment was 28 months (range, 2-162).

At the time of screening, 31% of patients had moderate disease and 67% had severe disease. Moreover, 52% had involvement of 4 or more organs. Additionally, 36% of patients were found to have lung involvement at baseline; 38% of these patients had a NIH lung symptom score of 2. Patients received a median of 3 prior systemic lines of treatment. Additionally, 72% of patients had disease that was refractory to their last systemic line of treatment received, 34% had prior ibrutinib, 29% had prior ruxolitinib, and 72% had 3 or more prior lines of therapy. The median corticosteroid dose at baseline was 0.2 mg/kg/day of prednisone equivalent; the mean dose was 0.25 mg/kg/day.

At the time of the data analysis, 37% of patients were still on belumosudil treatment. Patients who discontinued treatment did so because of disease progression (n = 21), voluntary withdrawal (n = 13), toxicities (n = 16), physician decision (n = 11), progression of an underlying malignancy (n = 5), death because of an underlying malignancy or progression (n = 4), other (n = 7), and nonadherence to treatment (n = 3).

Additional data from the study showed that 7 patients experienced a complete response (CR) in all affected organs. Of 12 patients with lung responses based on normalization of FEV1, 3 achieved a CR and there were an additional 3 CRs based on a reduction in NIH lung symptom score from 1 to 0. Six additional patients achieved a partial response (PR).

Of the 41 patients who experienced skin responses, 11 were noted to have a decrease in sclerotic features, 15 had a decrease in body surface area (BSA) involvement, and 13 had improvements in both BSA involvement and sclerotic features.

Responses were found to occur rapidly. The median TTR was 5 weeks (range, 4-66). Within 6 months of treatment, 91% of patients experienced responses; the remaining 9% of patients experienced responses after 6 to 12 months of treatment. Notably, 59% of patients who responded to belumosudil continued to respond for 20 weeks or longer. The median DOR was 54 weeks in responders. The FFS rates achieved with the agent at 6 months and 12 months were 75% (95% CI, 66%-81%) and 56% (95% CI, 47%-64%), respectively.

With belumosudil, 65% of patients reduced their corticosteroid dose. The mean dose resulted in a 45% reduction in the modified intention-to-treat (mITT) population; the mean dose reduction was 54% in responders. Moreover, 21% of patients discontinued treatment with corticosteroids. Twenty-two percent of patients were able to discontinue treatment with calcineurin inhibitors; 20% discontinued sirolimus (Rapamune) and 21% discontinued mycophenolate mofetil.

Lastly, treatment with belumosudil at a daily-dose of 200 mg and a twice-daily dose of 200 mg improved the 7-day LSS summary score by 59% and 62%, respectively, from baseline in the mITT population. Among responders, the rates with the once-daily and twice-daily doses were 69% and 71%, respectively; in nonresponders, these rates were 29% and 33%, respectively.

Belumosudil was well tolerated, with toxicities consistent with those expected in patient with chronic GVHD who were receiving corticosteroid therapy. Thirty-eight percent of patients experienced 1 or more serious adverse effects (AEs), with pneumonia being the most frequently reported (7%). The most common grade 3 or 4 toxicities comprised pneumonia (8%), hypertension (6%), and hyperglycemia (5%).

Of 83 patients who discontinued treatment with belumosudil, 21% did so because of toxicity, 12% because of potential drug-related toxicities, 4% because of progression of underlying malignant disease, and 16% because of progression of chronic GVHD.

“Based on the similar efficacy and safety observed in this study, 200 mg once daily is the preferred dosage for the treatment of chronic GVHD. Although the 200-mg twice-daily dose showed higher responses in certain organs, such as the skin, and slightly fewer AEs, the difference compared with the 200-mg twice-daily dose was not deemed significant,” the studfy authors concluded. “Because of its unique mechanism of action, belumosudil may have broad therapeutic potential beyond chronic GVHD and is currently being studied in systemic sclerosis, with plans for additional studies in other immune disorders.”

References

1. Cutler CS, 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. Blood. Published online July 15, 2021. doi:10.1182/blood.2021012021
2. Kadmon announces pivotal trial data published in the journal Blood for REZUROCK (belumosudil) in chronic graft-versus-host disease (cGVHD). News release. Kadmon Holdings, Inc. July 19, 2021. Accessed July 19, 2021. https://bit.ly/3ivvImY
3. US FDA grants full approval of REZUROCK (TM) (belumosudil) for the treatment of patients with chronic graft-versus-host disease (cGVHD). News release. Kadmon Holdings, Inc. July 16, 2021. Accessed July 19, 2021. https://bit.ly/3z14sTW

This article was originally published as “Belumosudil Represents Promising Newly-Approved Option for Chronic GVHD”