Belumosudil for chronic graft-versus-host disease after 2 or more prior lines of therapy: the ROCKstar Study

Abstract

Belumosudil, an investigational oral selective inhibitor of rho-associated coiled-coil-containing protein kinase-2 (ROCK2), reduces type 17 and follicular helper T cells via downregulation of signal transducer and activator of transcription 3 (STAT3) and enhances regulatory T cells via upregulation of signal transducer and activator of transcription 5 (STAT5). Belumosudil may effectively treat patients with cGVHD, a major cause of morbidity and late nonrelapse mortality after an allogeneic hematopoietic cell transplant. This phase 2, randomized, multicenter registration study evaluated belumosudil 200 mg QD (n=66) and 200 mg BID (n=66) in subjects with cGVHD who had received 2 to 5 prior lines of therapy. The primary end point was best overall response rate (ORR). Duration of response (DOR), changes in Lee Symptom Scale score, failure-free survival, corticosteroid dose reductions and overall survival were also evaluated. Overall median follow-up was 14 months. The best ORR (95% CI) of belumosudil 200 mg QD and 200 mg BID was 74% (62%-84%) and 77% (65%-87%), respectively, with high response rates observed in all subgroups. All affected organs demonstrated complete responses. The median DOR was 54 weeks; 44% of subjects have remained on therapy for ≥1 year. Symptom reduction with belumosudil 200 mg QD and 200 mg BID was reported in 59% and 62% of subjects, respectively. Adverse events (AEs) were consistent with those expected in patients with cGVHD receiving corticosteroids and other immunosuppressants. Sixteen subjects (12%) discontinued belumosudil due to possible drug-related AEs. Belumosudil, a promising therapy for cGVHD, was well tolerated with clinically meaningful responses. (Funded by Kadmon Corporation, LLC; ClinicalTrials.gov number, NCT03640481.)

Belumosudil: First Approval

“…The efficacy of belumosudil for the treatment of cGVHD was demonstrated in the randomized, multicentre, phase II ROCKstar trial in allogeneic haematopoietic cell transplant (alloHCT) recipients (NCT03640481) [ 14 ]. After a median follow-up of 14 months, the best overall response rate (ORR, defined as complete response or partial response; primary endpoint) was 74% (95% CI 62–84%) with belumosudil 200 mg once daily and 77% (95% CI 65–87%) with belumosudil 200 mg twice daily.…”

“…The overall failure-free survival (FFS) rate was 75% at 6 months and 56% at 12 months. The overall survival (OS) rate at 2 years was 89% [ 14 ].…”

T Cell Subsets in Graft Versus Host Disease and Graft Versus Tumor

“…Responses were clinically meaningful, with a median duration of response of 35 weeks, and were associated with quality-of-life improvements and corticosteroid (CS) dose reductions (86). Furthermore, the ROCKstar study showed that belumosudil showed responses for cGVHD after 2 or more prior lines of therapy (87). Based on these findings, belumosudil was recently FDA approved for patients 12 years and older who have received 2 or more prior lines of therapy (88).…”

Pulmonary Complications After Pediatric Stem Cell Transplant

“…However, these studies evaluated those 12 years of age or older; studies evaluating effectiveness/dosing in children younger than 12 and dosing are ongoing (81,83). Other agents that are currently under investigation include belumosudil and ibrutinib, though further investigation is needed for use in pediatrics (84,85). Despite aggressive treatment, most patients have acute flares with mortality rate being between 12% and 27% at 5 years due to secondary infection or respiratory complications (8,51,78).…”