ROCKstar: Belumosudil in chronic GvHD – an update from ASH 2020

Inhibition of the Rho-associated coiled-coil kinase 2 (ROCK2) has been shown to inhibit STAT3 signaling, thereby downregulating pro-inflammatory Th17 cells and stimulating expansion of regulatory T cells. An additional function of the ROCK family is the regulation of profibrotic pathways, and ROCK inhibitors have been shown to prevent collagen formation and fibrosis. For these reasons, ROCK2 is an attractive target in the treatment of chronic graft-versus-host disease (cGvHD).¹

The value of an orally available ROCK2 inhibitor, belumosudil, is currently being investigated in the cGvHD setting. In September 2020, a New Drug Application (NDA) for belumosudil was submitted to the U.S. Food and Drug Administration (FDA) for the treatment of cGvHD. The NDA was later granted priority review in November 2020 and will therefore be reviewed within 6 months.²

During the 62nd American Society of Hematology (ASH) Annual Meeting & Exposition, Corey Cutler presented the updated top-line results from the phase II ROCKstar study (NCT03640481) evaluating belumosudil (KD025-213) for the treatment of patients with cGvHD following two to five prior lines of systemic therapy.¹ The GvHD Hub is happy to provide a summary here.

Study design

A phase II, randomized, multicenter trial evaluating the safety and efficacy of once daily (QD, n = 66) or twice daily (BID, n = 66) KD025-213 (200 mg) for the treatment of patients who were 12 years and older, had active cGvHD, and had received two to five prior lines of systemic cGvHD therapy.

For the full study design, patient characteristics, and results as presented at the 46th Annual Meeting of the European Society for Blood and Marrow Transplantation (EBMT), click here. Below is a summary of the additional data presented at ASH 2020.

Results

Efficacy

• The primary end point of achieving an overall response rate (ORR) of > 30% was met with an all-patient ORR of 75% (p < 0.0001).
• Responses improved over time and were 10% higher at the 12-month follow-up compared to data previously reported.
• There was no statistical difference in ORR between belumosudil 200 mg QD vs 200 mg BID (73% vs 77%).
• Clinically meaningful ORRs were seen in all key subgroups as shown in Figure 1, and the following observations were made:
  • Median time to response was 4 weeks.
  • Median duration of response was 50 weeks, with 60% of patients retaining their response for ≥ 20 weeks.
  • Median treatment duration was 11.8 months.
• In total:
  • Seven patients demonstrated a complete response in all affected organs.
  • Failure-free survival was 58%.
  • 64% of patients could reduce their corticosteroid dose and 21% stopped taking corticosteroids.
  • 45% of patients could reduce their calcineurin inhibitor dose and 22% stopped their calcineurin inhibitor therapy.

Safety

The most common Grade ≥ 3 adverse events, occurring in ≥ 5% of patients, were pneumonia (n = 10), hypertension (n = 6), and hyperglycemia (n = 5), which did not differ significantly between treatment groups. A safety overview is shown in Table 1.

Table 1. Safety overview of QD and BID belumosudil in patients with cGvHD¹

AE, adverse event, BID, twice daily; cGvHD, chronic graft-versus-host disease; DRAE, drug-related adverse event; QD, once daily; SAE, serious adverse event.
Safety	Belumosudil 200 mg		Total (N = 132)
	QD	BID
Mean duration of treatment, months	9.4	11.8	10.4
AE any grade, %	99	100	99
Grade ≥3 AE, %	56	52	54
SAE, %	41	35	38
DRAE, %
Related AE any grade, %	74	61	67
Related SAE, %	8	3	5
On study deaths, %	6	6	6

Conclusion

In the phase II ROCKstar study, patients who received both QD and BID belumosudil demonstrated ORRs of > 70% irrespective of a number of disease- and treatment-related factors. Responses were also seen in all affected organs, including organs affected by fibrotic disease. Encouraging patient outcomes, failure-free survival rates, and tolerability suggest that belumosudil may be a suitable option for patients with relapsed or refractory cGvHD.