Belumosudil: A Rising Star for the Management of Chronic Graft-Versus-Host Disease and the First FDA-Approved ROCK2 Inhibitor

Chronic graft-versus-host disease (cGVHD) is a multiorgan disorder marked by inflammation and fibrosis and a leading cause of morbidity, mortality, and impaired quality of life among allogeneic hematopoietic cell transplantation recipients. Front-line therapy for cGVHD consists of corticosteroids with or without calcineurin inhibitors. Several agents have been studied as second-line therapy, when disease becomes steroid refractory (SR).^1,2  Ibrutinib was the first U.S. Food and Drug Administration (FDA)–approved second-line therapy for cGVHD, and the recent REACH3 trial demonstrated favorable outcomes for ruxolitinib.³  Despite these successes, infection rates on these immunosuppressive therapies remain high, and there is no clear optimal therapy for SR-cGVHD. Other commonly used agents include calcineurin inhibitors, mTOR inhibitors, mycophenolate mofetil, rituximab, extracorporeal photopheresis, pentostatin, proteasome inhibitors, and tyrosine kinase inhibitors.^1,2  There is a need for treatment options that spare steroid use with minimal toxicity.

Belumosudil is a selective Rho-associated kinase 2 (ROCK2) inhibitor. The ROCK2 pathway is involved in inflammation and fibrosis, both central to the pathogenesis of cGVHD. ROCK2 inhibition blocks STAT3 phosphorylation and upregulates STAT5 phosphorylation, leading to decreased levels of Th17 transcription factors, decreased secretion of proinflammatory cytokines IL-21 and IL-17, and increased CD4 regulatory T cell number and inhibitory activity.⁴  In murine cGVHD models, belumosudil prevented the development of bronchiolitis obliterans and scleroderma manifestations of cGVHD, decreased activation of STAT3, RORγ and BCL6, and increased STAT5.⁵ 

The randomized, multicenter phase II ROCKstar trial was conducted to evaluate the safety and efficacy of belumosudil for cGVHD after two to five prior lines of therapy. The trial included patients aged 12 years and older who had cGVHD as a complication of hematopoietic cell transplantation. Subjects were randomized to belumosudil 200 mg daily or 200 mg twice daily until cGVHD progression or unacceptable toxicity. Exclusion criteria included disease relapse, post-transplant lymphoproliferative disorder, FEV1 less than 40 percent, alanine aminotransferase or aspartate aminotransferase greater than three times the upper limit of normal, or current ibrutinib therapy. The primary endpoint was best overall response rate (ORR). Secondary endpoints included duration of response, time to response, changes in Lee Symptom Scale summary score for characterizing quality of life related to cGVHD symptoms, corticosteroid dose reductions, and overall survival.

One hundred thirty-two patients were enrolled, with median follow-up time of 14 months (range, 1-22 months). Patients were 57 percent men, had a median age of 57 years (range, 21-77 years), and received a median of three prior lines of therapy. Thirty-one percent had moderate cGVHD and 67 percent had severe cGVHD. Thirty-four percent previously received ibrutinib and 29 percent received ruxolitinib. Median duration of treatment was 10 months (range, 1-22 months) with 44 percent of patients receiving more than one year of therapy. Best ORR was 74 percent and 77 percent for 200 mg once daily and 200 mg twice daily, respectively, with all subgroups demonstrating a similar ORR, including 74 percent of those previously treated with ibrutinib and 68 percent of those previously treated with ruxolitinib. Organ-specific analysis demonstrated improvement in skin, eye, mouth, liver, lung, joint/fascia, upper and lower gastrointestinal, and esophageal symptoms. Median time to response was five weeks with 59 percent of responders maintaining response for more than 20 weeks and a median duration of response of 54 weeks. Nonrelapse mortality and relapse were relatively low at 7 percent and 3 percent, respectively. Sixty-five percent of patients decreased steroid dose by an average of 45 percent, and 21 percent of patients discontinued steroid therapy. Fifty-nine percent to 62 percent of patients experienced at least a seven-point reduction in their seven-day Lee Symptom Scale summary score. Fifty-four percent of patients experienced grade 3 or 4 adverse events (AEs) with the most common being pneumonia (8%), hypertension (6%), and hyperglycemia (5%). Serious AEs occurred in 38 percent of patients. Twelve percent of patients discontinued belumosudil due to drug-related AEs.