Belumosudil shows promise for chronic GVHD
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Belumosudil conferred high overall response rates at two dose levels among patients with chronic graft-versus-host disease, according to results of the phase 2 ROCKstar study presented at the virtual ASH Annual Meeting and Exposition.
The open-label, randomized, muticenter study showed durable and clinically meaningful responses across patient subgroups, including among those previously treated with ruxolitinib (Jakafi, Incyte) and ibrutinib (Imbruvica; Pharmacyclics, Janssen).
There is a great unmet need for treatments for patients with chronic GVHD, according to Corey S. Cutler, MD, MPH, FRCPC, medical director of the adult stem cell transplantation program, director of clinical research in stem cell transplantation and director of the stem cell transplantation survivorship program at Dana-Farber Cancer Institute, and associate professor of medicine at Harvard Medical School.
“With one approved agent (ibrutinib) and a second likely to have an expanded label in chronic GVHD in 2021 (ruxolitinib), a substantial number of patients remain resistant to therapy,” Cutler told Healio. “In addition, a third agent with an entirely separate mechanism of action and major activity in ruxolitinib- and ibrutinib-refractory patients is extremely important.”
Belumosudil (KD025, Kadmon Holdings) — a novel oral selective rho-associated coiled-coil kinase 2 (ROCK2) inhibitor — was developed specifically for the treatment of chronic GVHD.
“ROCK2 inhibition can do two important things in chronic GVHD,” Cutler said. “It can rebalance STAT3/STAT5 signaling in the germinal center, reducing TH17 cells and increasing regulatory T cells. In addition, blocking ROCK2 signaling can prevent fibrosis and scarring, common occurrences in advanced chronic GVHD.”
Cutler and colleagues evaluated data of 132 patients (median age, 56 years; 57% men) with chronic GVHD who had received two to five prior lines of therapy.
Median time from chronic GVHD diagnosis to enrollment was 29 months.
Most patients (72%) had received at least three prior lines of therapy, including ibrutinib (n = 46) or ruxolitinib (n = 38), and 73% were refractory to their last line of therapy.
Sixty-seven percent of patients had severe chronic GVHD, and 52% had four or more involved organs.
The researchers assigned patients to 200 mg belumosudil once (n = 66) or twice (n = 66) daily.
ORR, defined using the 2014 NIH Consensus Criteria, served as the study’s primary endpoint. Additional endpoints included duration of response, Lee Symptom Scale score, failure-free survival, corticosteroid dose reductions and OS.
The current analysis occurred 12 months after the last patient was accrued on the trial.
Researchers reported an ORR of 73% (95% CI, 60-83) with the daily dose and 77% (95% CI, 65-87) with the twice-daily dose.
Researchers also reported high ORRs combined for both doses among patients who previously received ruxolitinib (68%; 95% CI, 51-83) and ibrutinib (74%; 95% CI, 59-86).
Other subgroups also showed similar ORRs, including those who had four or more involved organs (71%; 95% CI, 58-81), were refractory to their last line of treatment (73%; 95% CI, 62-83) and had severe chronic GVHD (74%; 95% CI, 64-83).
Median time to response was 4 weeks, but Cutler noted that some responses occurred as long as 40 weeks after initiation of therapy. Median duration of response was 50 weeks, with 60% of responders maintaining their response for 20 or more weeks.
Failure-free survival rate, which considered relapse, mortality and new treatment for chronic GVHD, was 58% at 1 year. Two-year OS was 89% (95% CI, 82-93).
Further, 64% of patients reduced their corticosteroid dose and 21% of patients discontinued corticosteroids. Forty-five percent of patients reduced their dose of calcineurin inhibitors and 13% discontinued them.
Researchers reported a clinically meaningful, 7-point or greater reduction in Lee Symptom Scale score among 42% of patients in the once-daily dose group and 36% of patients in the twice-daily dose group. Improvements in quality of life occurred among both responders and nonresponders, Cutler said.
All adverse events were consistent with what would be expected in a cohort of patients with chronic GVHD, Cutler said during his presentation, adding that there were no noticeable differences in toxicity between the two dosing cohorts.
Grade 3 or higher adverse events occurred among 67% of patients. Those that occurred in 5% or more of patients included pneumonia (8%), hypertension (6%) and hyperglycemia (5%).
Common adverse events of any grade included fatigue (38%), diarrhea (33%), nausea (31%), cough (28%), upper respiratory tract infection (27%), dyspnea (25%) and headache (24%).
Eight patients died while on study, most of which were related to infection and respiratory compromise.
Based on these promising results, additional research should be conducted to evaluate belumosudil among more patients with chronic GVHD, Cutler told Healio.
“KD025 should be tested earlier in the chronic GVHD disease course and in patients with advanced fibrosis and sclerosis, as it might be able to reverse some of these manifestations,” he said.
Perspective
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Belumosudil has a different mechanism of action than ruxolitinib and ibrutinib, and it also is an antifibrotic agent, which makes it very interesting to study. This randomized study showed no difference in response rate between the two doses studied, once or twice a day, and the response rate, which exceeded 70%, was very high and clinically meaningful. The duration of response was nearly a year, and 60% maintained a response for more than 20 weeks. These data led to FDA breakthrough designation for this agent, which likely will become commercially available in 2021.
Based on these results and data presented on ruxolitinib at this year’s ASH meeting, many of us are now asking important questions. Should we be combining these agents? Is one better than the other? How should we sequence them?
Considering these response rates, it makes sense to compare these agents head-to-head or, more importantly, combine them. The biggest toxicities for patients with chronic GVHD are infectious complications that result from chronic steroid therapy. Having a steroid-free regimen will be a significant benefit to patients. We now have three, if you consider ibrutinib, belumosudil and ruxolitinib, that potentially can be steroid-free or steroid-sparing regimens for the treatment of chronic GVHD. That will make a significant impact on the quality of life for patients.
Reference:
Zeiser R, et al. Abstract 77. Presented at: ASH Annual Meeting and Exposition (virtual meeting); Dec. 5-8, 2020.
Memorial Sloan Kettering Cancer Center
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Cutler CS, et al. Abstract 353. Presented at: ASH Annual Meeting and Exposition (virtual meeting); Dec. 5-8, 2020.
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