Belumosudil Produces Long-Term Responses Without New Safety Concerns in cGVHD

Corey S. Cutler, MD, MPH, FRCPC

Belumosudil (Rezurock) elicited sustained responses and generated no new safety signals in patients with chronic graft-vs-host disease (cGVHD), according to 3-year follow-up findings from the phase 2 ROCKstar trial (NCT03640481) that were presented at the 50th Annual EMBT Meeting.¹

At a median follow-up of 30 months and a data cutoff of September 1, 2022, the 3-year overall response rates (ORRs) in the populations of patients who received belumosudil at 200 mg once daily (n = 77) and twice daily (n = 75) were 74% (95% CI, 63%-83%; P <.0001) and 76% (95% CI, 65%-85%; P <.0001), respectively.

“Response rates remained extremely stable, without a marked change by the addition of 20 additional patients,” according to lead study author Corey S. Cutler, MD, MPH, FRCPC, of Dana-Farber Cancer Institute in Boston, Massachusetts.

Previous results from ROCKstar, reported in 2021 after a median follow-up of 14 months, showed ORRs of 74% (95% CI, 62%-84%) and 77% (95% CI, 65%-87%) in patients who received the agent once daily and twice daily, respectively.^1,2

In the initial data report, belumosudil was well tolerated, and the observed adverse effects (AEs) were consistent with those expected in patients with cGVHD receiving immunosuppressive therapies, such as corticosteroids.

In 2021, based on preliminary results from ROCKstar, the oral, selective ROCK-2 inhibitor belumosudil was granted full FDA approval for the treatment of patients with cGVHD who had received prior allogeneic hematopoietic cell transplant.³

The open-label, multicenter ROCKstar trial randomly assigned 132 patients at least 12 years of age with persistent cGVHD who had received 2 to 5 prior lines of systemic therapy and were indicated to receive additional systemic therapy to receive belumosudil at either 200 mg once daily (n = 77) or 200 mg twice daily (n = 75). Patients received continuous treatment in 28-day cycles until clinically significant cGVHD progression or unacceptable toxicity. Patients were stratified by prior ibrutinib (Imbruvica) exposure (yes vs no) and severe cGVHD status (yes vs no).¹

ORR served as the primary end point, and key secondary end points included duration of response (DOR), change in Lee Symptom Scale (LSS) summary score, time to next treatment (TTNT), time to response, change in corticosteroid or calcineurin inhibitor dose, failure-free survival (FFS), and overall survival.

The 3-year follow-up analysis of ROCKstar included data from an additional 20 patients who were enrolled in a biomarker cohort after the ROCKstar publication data cutoff of August 19, 2020. The trial’s modified intent-to-treat (mITT) population (n = 152) included all randomly assigned patients who had received at least 1 dose of belumosudil.

In the overall trial population, patients had a median age of 54.5 years (range, 18-77), a median of 28.1 months (range, 1.6-162.4) from cGVHD diagnosis to trial enrollment, and had received a median of 0.19 mg/kg per day (range, 0.02-1.07) of prednisone-equivalent doses of corticosteroids. In total, 69.7% of patients had severe cGVHD at screening, and 52.0% of patients had at least 4 organs involved. Overall, 48.7% of patients had received more than 3 prior lines of therapy, including ibrutinib (34.2%) and ruxolitinib (Jakafi; 36.2%). Seventy-three percent of patients were refractory to their last line of therapy.

At 1 and 3 years of follow-up, the median DORs among responders who received once-daily belumosudil were 50.4 weeks and 69.9 weeks, respectively. These respective values were 74.3 weeks and 85.0 weeks among responders who received twice-daily treatment, and 54.1 weeks and 77.1 weeks in the overall population of responders.

Among the overall mITT population, 61% of patients each at 1 and 3 years of follow-up exhibited a 7-point reduction in LSS score. At 1 and 3 years of follow-up, in the arm of the mITT population that received once-daily dosing, 59% and 58% of patients, respectively, exhibited a 7-point reduction in LSS score. These respective values were 62% and 64% in the arm of the mITT population that received twice-daily dosing.

Among all responders in both arms, 70% and 69% of patients at 1 (n = 100) and 3 (n = 108) years of follow-up, respectively, exhibited a 7-point reduction in LSS score. These respective values were 69% and 68% in responders who received once-daily dosing and 71% each in the responders who received twice-daily dosing.

In the overall population, the median TTNT at 3 years of follow-up was 27.3 months. This value was not available (NA) at 1 year of follow-up. In the arm that received once-daily dosing, the median TTNT was 16.6 months at 1 year of follow-up and 24.2 months at 3 years of follow-up. These respective values were NA and not yet reached among patients who received twice-daily dosing.

A total of 23.4% and 25.3% of patients in the once-daily and twice-daily arms, respectively, successfully stopped all corticosteroid therapy. Furthermore, at 3 years of follow-up, 69% and 29% of patients reduced or discontinued their corticosteroid use, respectively, vs 65% and 21% of patients at 1 year of follow-up.

In the mITT population, the FFS rates were 75%, 56%, and 44% at 6 months, 1 year, and 18 months/2 years/3 years, respectively. In the investigator-assessed responder population, the 3-year FFS rate was 51.8%.

“For over half of the subjects who were given belumosudil for their late-stage cGVHD, belumosudil was the last immunosuppressant drug that they required, telling us that this may induce long-term tolerance, and this in fact may be the end of the journey with prolonged immune suppression for patients with severe cGVHD,” Cutler emphasized in the presentation.

The most common any-grade AEs were fatigue (1 year of follow-up, 38%; 3 years of follow-up, 38%), diarrhea (33%; 39%), nausea (31%; 31%), cough (28%; 28%), upper respiratory tract infection (27%; 26%), dyspnea (25%; 28%), headache (24%; 29%), peripheral edema (23%; 26%), vomiting (21%; 23%), and muscle spasms (20%; 18%). The rates of grade 3 or higher neutropenia and anemia were 1.3% and 3.3%, respectively. No grade 3 or higher thrombocytopenia was observed.

In the mITT population, 8% and 7% of patients in the once-daily and twice-daily arms, respectively, remained on treatment for at least 36 months, and 13.2% of patients discontinued treatment because of AEs. An increase in discontinuation rates because of AEs was observed each year after follow-up. In total, 11.2%, 1.3%, and 0.7% of patients discontinued treatment due to AEs after being on treatment for 1 year or less, 1 to 2 years, and more than 2 years, respectively.

“Treatment with belumosudil is very well tolerated, with a decreasing incidence of AEs over time,” Cutler concluded.

Disclosures: Dr Cutler reports consultant roles with Incyte, Novartis, Rigel, Sanofi, and Syndax; as well as data safety monitoring board membership with Allovir and Angiocrine.

References

1. Cutler C, Lee SL, Pavletic S, et al. Belumosudil for chronic graft-versus-host disease after ≥2 prior lines of systemic therapy: 3-year follow-up of the ROCKstar study. Presented at: EBMT 50th Annual Meeting; April 14-17, 2024. Glasgow, Scotland. Abstract OS13-01.
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 [published correction appears in Blood. 2022 Mar 17;139(11):1772]. Blood. 2021;138(22):2278-2289. doi:10.1182/blood.2021012021
3. FDA approves belumosudil for chronic graft-versus-host disease. FDA. July 16, 2021. Accessed April 17, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-belumosudil-chronic-graft-versus-host-disease#:~:text=On%20July%2016%2C%202021%2C%20the,prior%20lines%20of%20systemic%20therapy.