Asian patients with pretreated chronic GVHD respond well with belumosudil

The selective Rho-associated coiled-coil kinase 2 (ROCK2) inhibitor belumosudil mesylate appears to induce durable responses in Japanese patients with steroid-dependent/resistant chronic graft-versus-host disease (cGVHD) when used in the second or subsequent line of therapy, according to the results of a single-arm phase III study.

Forty-eight–week data from 21 patients showed that the best overall response rate (ORR), the primary endpoint, was 85.7 percent (95 percent confidence interval [CI], 63.66–96.95), reported lead author Dr Yasushi Onishi from the Department of Hematology at Tohoku University Hospital in Sendai, Miyagi, Japan. [EHA 2024, abstract S262]

Onishi added that all 18 patients showed partial response. The median duration of treatment with belumosudil was 13.8 months.

The median duration of response (DOR) was 68.1 weeks, and eight of 18 patients maintained response at data cutoff. Kaplan-Meier estimates of DOR were 0.77 (95 percent CI, 0.49–0.91) at week 24 and 0.57 (95 percent CI, 0.30–0.77) at week 48.

ORR by organ involvement, time point

Organ-specific analyses indicated a best ORR of 100 percent in the upper gastrointestinal (GI) tract (n=1), 80 percent in the joints/fascia (4 of 5 patients), 72.2 percent in the mouth (13 of 18 patients), 54.5 percent in the skin (6 of 11 patients), 50 percent in the oesophagus (1 of 2 patients), and 26.7 percent in the eyes (4 of 15 patients). Neither the six patients with lung involvement nor the single patient with upper GI tract involvement showed response with belumosudil.

When assessed by time point, ORR was 47.6 percent (10 of 21 patients) at week 4, 75.0 percent (15/20 patients) at week 24, and 66.7 percent (12 of 18 patients) at week 48.

For all 18 responders, the median time to response was 4.10 weeks.

Symptoms, survival, safety

According to Onishi, more than half of patients (57.1 percent) experienced clinically meaningful symptom improvement, defined by a ≥7-point reduction in the Lee symptom scale (LSS) score, at least once throughout the study, while 47.6 percent of patients did so on two consecutive assessments.

The median total duration of clinically meaningful symptom improvement was 38.2 weeks.

Subsequently, 66.7 percent of patients were able to reduce their corticosteroid dose, with a median maximum dose reduction of 26.32 percent from baseline, Onishi pointed out.

Survival endpoints—median failure-free and overall survival—were not calculable at data cutoff, he added.

“No new safety concerns were identified [with daily belumosudil], and there were no notable increases in treatment-emergent adverse events (TEAEs) with continued administration,” Onishi said.

TEAEs occurred in 90.5 percent of patients, and drug-related TEAEs were documented in 38.1 percent. The most common TEAEs were cataract (23.8 percent), diarrhoea (19 percent), and COVID-19 (19 percent). The most frequent drug-related TEAEs were headache, herpes zoster, and muscle spasms. Nine patients experienced grade ≥3 TEAES, with cataract being the most common (14.3 percent). Two patients died during the study period, one due to acute myeloid leukemia (AML) and the other due to recurrent AML, but neither was associated with the study drug.

“Although six patients had discontinued treatment at data cutoff, none were due to drug-related TEAEs, further supporting the good tolerability [profile] of belumosudil,” Onishi said.

Of the 21 patients included in the study, one was a minor and five were older adults. The median age of the overall population was 50 years, and 66.7 percent were male. Chronic GVHD was steroid-dependent in 85.7 percent of patients and severe in 42.9 percent. The median duration of cGVHD was 23.7 months. These patients had received a median of one prior line of treatment for cGVHD, including ibrutinib. Belumosudil 200 mg was administered daily.

Approved to treat cGVHD in several countries—including the US, the UK, Canada, and Japan—belumosudil has immunomodulatory and antifibrotic effects, with a mechanism of action that differs from that of currently available therapies, the author said.