Belumosudil Continues to Elicit Statistically Significant Responses in cGVHD

The orally available ROCK2 selective inhibitor belumosudil (KD025) continues to elicit clinically meaningful overall response rates (ORRs) with acceptable tolerability in patients with chronic graft-versus-host disease (cGVHD) who have received 2 or more prior lines of systemic therapy, according to results from the phase 2 ROCKstar trial (NCT03640481) presented during the 2020 European Society for Blood and Marrow Transplantation (EBMT) Annual Meeting.¹

Results showed that patients who received a once daily 200-mg dose of the agent experienced an ORR of 73% (95% CI, 60%-83%), while the ORR was 74% in those who received a twice daily 200-mg dose (95% CI, 62%-84%). A total of 4 patients experienced a complete response (CR).

Moreover, responses were reported to be consistent across key subgroups examined, particularly in terms of time from initial diagnosis to trial, in patients who received previous treatment with ibrutinib (Imbruvica) or ruxolitinib (Jakafi), and disease severity.

“The trial met its primary end point in that [belumosudil] demonstrated ORRs of 73%-74% across once- and twice-daily dosing arms, respectively,” Madan Jagasia, MD, MBBS, MS, MMHC, senior vice president of Medical Affairs at Iovance Biotherapeutics, Inc, and colleagues wrote in a poster delivered during the meeting. “Responses were observed across all key subgroups and in all affected organ systems, including in organs with fibrotic disease.”

Belumosudil was developed to downregulate pro-inflammatory Th17 cells while also upregulating Treg cells; the agent also works to reduce collagen deposition and myofibroblast formation and production.

In the open-label, multicenter, phase 2 ROCKstar trial, the ROCK2 selective inhibitor is under examination in adults and adolescents with cGVHD who previously received 2 or more lines of systemic treatment. In the trial, participants were randomized 1:1 to receive belumosudil at a dose of 200 mg daily (n = 66) or 200 mg twice daily (n = 66). Patients were stratified based on previous treatment with ibrutinib and severity of disease and they received treatment until clinically significant disease progression or intolerable toxicity.

To participate, patients had to be 12 years of age or older, have undergone allogenic hematopoietic stem cell transplant, had received 2 or more prior line of systemic treatment, received glucocorticoid therapy with a stable dose over the 2 weeks before screening, had persistent cGVHD manifestations, a Karnofsky performance score of 60 or higher if 16 years of age or older or a Lansky performance score of 60 or higher if less than 16 years, and weigh 40 kg or more.² Patients were not permitted for inclusion if they were not on a stable dose or regimen of systemic cGVHD therapy for 2 or more weeks before screening, they had histological relapse of the underlying disease or posttransplant lymphoproliferative disease at the time of screening, or if they were receiving current treatment with ibrutinib.

The primary end point of the trial is ORR per 2014 National Institutes of Health response criteria, as evaluated by investigators, while secondary end points included the duration of response (DOR), change in Lee Chronic GVHD Symptom Scale Score (LSS), response rate per organ system, partial response rate or CR rate, failure-free survival (FFS), overall survival (OS), time to response, and time to next treatment.

Overall, participants had a median age of 56 years, and 57% of them were male. Patients had received a median of 4 lines of prior treatment and the median time from disease diagnosis to enrollment was 28 months. Moreover, 67% of patients had severe cGVHD per NIH criteria and 52% of patients had 4 or more organs involved. Additionally, 34% of patients received previous treatment with ibrutinib and 72% were refractory to a line of treatment they received prior to enrollment on the study.

A prespecified interim analysis was performed 2 months following the enrollment of the last participant on the trial, and the primary analysis was done 6 months after the last patient was enrolled. The data reported during the primary analysis supported the findings presented at the interim analysis: belumosudil demonstrated a high level of activity in this patient population. Notably, at the time of the earlier assessment, the study met its primary end point of ORR.

Additional data shared at the EBMT meeting showed that 49% of those who responded to treatment with belumosudil maintained their responses for 20 or more weeks. The median DOR had not yet been reached at the time of the data analysis.

With regard to safety, all-grade adverse effects (AEs) that were reported in 20% or more of participants included fatigue (39% in the once-daily arm vs 24% in the twice-daily arm), diarrhea (30% vs 27%, respectively), nausea (26% vs 26%), cough (29% vs 20%), dyspnea (30% vs 17%), upper-respiratory tract infection (21% vs 24%), liver-related investigations (18% vs 24%), and peripheral edema (26% vs 17%).

Overall, patients received treatment with the agent for a median duration of 4.3 months and 95% of patients experienced an AE; 38% of these patients experienced toxicities that were grade 3 or 4 in severity, and 28% experienced serious toxicities. Any drug-related AEs occurred in 50% of patients and treatment-related serious AEs were reported in 3% of patients.

A total of 5 deaths occurred on the study; 4 were determined to not be related to the study drug. One patient on the once-daily treatment arm experienced severe nausea, diarrhea, and vomiting, which resulted in multiple organ dysfunction syndrome.

“[Belumosudil] was well tolerated with AEs consistent with those expected in patients with cGVHD,” the authors concluded. “No cytomegalovirus infection or re-activation [was observed.”

Additional end point data from the trial, including DOR, FFS, OS, LSS reductions, corticosteroid dose reductions, pharmacokinetic and pharmacodynamic data, are anticipated later in 2020.

In May 2020, Kadmon Holdings, Inc, the developer of the agent, reported the submission of a new drug application for belumosudil to the FDA under the Real-Time Oncology Review pilot program based on early data ROCKstar.

References

1. Analysis of the ROCKstar study: a phase 2, randomized, multicenter study to evaluate the efficacy and safety of belumosudil (KD025) in subjects with cGVHD. Presented at: 2020 European Society for Blood and Marrow Transplantation Annual Meeting; August 20-September 2, 2020; Virtual.
2. Efficacy and safety of KD025 in subjects with cGVHD after at least 2 prior lines of systemic therapy. ClinicalTrials.gov. Updated July 8, 2020. Accessed September 1, 2020. https://clinicaltrials.gov/ct2/show/NCT03640481.