A Phase II study conducted in China has demonstrated promising results for belumosudil in treating chronic graft-versus-host disease (cGVHD) in patients who have previously failed corticosteroid therapy. The study, a multicenter, single-arm, open-label trial, revealed a 73.3% overall response rate (ORR) among Chinese patients, aligning with findings from Western populations. This suggests belumosudil could offer a valuable treatment option for cGVHD patients in China, where there is currently no approved second-line treatment.
The trial enrolled 30 patients with a median age of 30.6 years, all of whom had received prior systemic treatments for cGVHD. A significant proportion of patients (66.7%) had severe cGVHD, and over half (53.3%) had at least four organs involved. Patients received 200 mg of oral belumosudil once daily, and the primary endpoint was investigator-assessed ORR based on the 2014 National Institutes of Health (NIH) consensus criteria.
Efficacy and Safety Outcomes
The study not only met its primary efficacy endpoint but also demonstrated clinically meaningful improvements in secondary endpoints. The median time to response (TTR) was 4.3 weeks, with nearly a quarter of responders showing improvement at 20 weeks or beyond. Furthermore, the treatment facilitated a reduction in corticosteroid dosage for 56.7% of patients, with some even discontinuing corticosteroid use altogether. This is particularly significant given the long-term toxicities associated with corticosteroid use, such as bone loss and metabolic disorders.
"The high ORR among patients with at least four organs involved and severe cGVHD suggested that belumosudil can benefit patients with severe disease," the researchers noted in the study published in BMC Medicine. They also observed improvements in Lee Symptom Scale (LSS) scores, indicating enhanced physical and social functioning, which translates to a better quality of life.
The safety profile of belumosudil in the Chinese cohort was consistent with previous global studies. The majority of treatment-emergent adverse events (TEAEs) were mild to moderate. The most common drug-related TEAEs included sinus tachycardia (30.0%), upper respiratory tract infection (13.3%), and increased alanine aminotransferase (6.7%). Serious adverse events (SAEs) were reported in 36.7% of patients, with pneumonia being the most frequent grade ≥3 TEAE (16.7%).
Belumosudil's Mechanism and Place in Therapy
Belumosudil is a first-in-class selective rho-associated, coiled-coil-containing protein kinase 2 (ROCK2) inhibitor. It works by restoring the balance between type 17 T helper cells and regulatory T (Treg) cells and reducing fibrosis, which are key factors in cGVHD pathology. This mechanism differs from other therapies like ruxolitinib and ibrutinib, which have different side effect profiles and are not yet approved for cGVHD in China.
Study Limitations and Future Directions
The study's limitations include its single-arm design and relatively small sample size, which preclude direct comparisons against other treatments or quantitative assessments of treatment-related AEs. However, the researchers emphasize that the study design was ethical, given the lack of approved second-line treatments for cGVHD in China. They also suggest that future research should explore optimal treatment sequencing and combinations with other therapies to improve clinical outcomes further.
"Another approach to improve response rates and overcome the development of resistance against belumosudil is to combine this new agent with other therapies with a different modality to harness synergy from the different agents," the researchers suggested.
Overall, the findings from this Phase II study support belumosudil as a promising treatment option for Chinese patients with cGVHD who have failed corticosteroid therapy, offering a potential improvement in response rates, quality of life, and corticosteroid-sparing effects.
