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ROCKstar: Belumosudil in chronic GvHD, an update from EBMT 2021

May 19, 2021
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The Rho-associated coiled-coil kinase 2 (ROCK2) pathway is accountable for the regulation of Th17/regulatory T (Treg) cells and directing profibrotic pathways. ROCK2 inhibitors are known to rebalance the immune responses through the downregulation of pro-inflammatory Th17 cells and increasing Treg cells. This makes ROCK2 an attractive treatment target for chronic graft-versus-host disease (cGvHD). Belumosudil is an oral selective ROCK2 inhibitor that has previously demonstrated to significantly reduce lung and skin fibrosis in animal models.

The ROCKstar trial (NCT03640481) is a phase II trial evaluating the safety and efficacy of once daily versus twice daily belumosudil (KD025) for patients with cGvHD. The GvHD Hub has previously reported on the data from the ROCKstar trial presented at the 62nd American Society of Hematology (ASH) Annual Meeting and Exposition,1 which can be found here. The key finding from this presentation was that both the once daily and twice daily doses of belumosudil led to clinically meaningful overall response rates (ORRs) of >70%.

At the 47th Annual Meeting of the European Society for Blood and Marrow Transplantation (EBMT), Corey Cutler presented the 12-month updated results from the ROCKstar trial,2 summarized below.

Study design2

The phase II, randomized, multicenter trial evaluating the safety and efficacy of once daily (n = 66) or twice daily (n = 66) belumosudil (200 mg) for the treatment of patients who were ≥12 years old, had active cGvHD, and had received two to five prior lines of systemic cGvHD therapy.

  • Primary endpoint was ORR (per 2014 National Institutes of Health criteria) and secondary endpoints included safety, duration of response (DOR), corticosteroid dose reduction, failure-free survival (FFS), Lee symptom score (LSS), and overall survival (OS).

Results2

Baseline characteristics

The median age across both arms was 55 years, and the baseline characteristics were well balanced (as seen in Table 1).

Table 1. Baseline characteristics*

 

Belumosudil 200 mg

 

QD (n = 66)

BID (n = 66)

Median age, years (range)

53 (21–77)

57 (21–77)

Male, %

64

50

Median prior lines of treatment, n

3

4

Median time from cGvHD, months

25

30

Severe cGvHD, %

70

64

Prior ibrutinib, %

33

35

Prior ruxolitinib, %

30

27

≥4 organs involved, %

50

53

Refractory to prior line, % (n/N)

79 (44/56)

65 (35/54)

BID, twice daily; cGvHD, chronic graft-versus-host disease; QD, once daily.
*Data from Cutler et al.2

Efficacy

The median duration of response was 50 weeks with responses being maintained for ≥20 weeks in more than half of the patients (60%).

  • The primary endpoint of achieving an ORR was significantly high at 75% in both arms (see Table 2).
  • Complete response (CR) was seen in all organ systems (as seen in Figure 1), including in organs with fibrotic disease, and the responses were consistent across key subgroups.
  • FFS was seen in 58% of patients at 1 year, and 60% of patients experienced a clinically meaningful improvement (≥7-point reduction) in LSS.

Nearly half of the patients (44%) remained on belumosudil for >1 year. 21% of the patients discontinued corticosteroids and 22% discontinued calcineurin inhibitors, while dose reductions of corticosteroids and calcineurin inhibitors were achieved in 64% and 45% of patients, respectively.

Table 2. Responses across all subgroups*

Subgroups

ORR, % (95% CI)

All patients (n = 132)
              Belumosudil 200 mg QD
              Belumosudil 200 mg BID

75 (67–82)
73 (60–83)
77 (65–87)

Severe GvHD at screening
              Yes (n = 89)
              No (n = 43)


74 (64–83)
77 (61–88)

Best response to last prior line of systemic therapy
              Refractory (n = 79)
              Nonrefractory (n = 31)


73 (62–83)
74 (55–88)

Duration of cGvHD before enrollment
              >50th percentile (n = 66)
              ≤50th percentile (n = 66)


68 (56–79)
82 (70–90)

Number of organs involved at baseline
              ≥4 (n = 68)
              <4 (n = 64)


71 (58–81)
80 (68–89)

No. of prior lines of systemic therapy
              ≥4 (n = 65)
              <4 (n = 67)


72 (60–83)
78 (66–87)

Prior ibrutinib (n = 46)

74 (59–86)

Prior ruxolitinib (n = 38)

68 (51–83)

BID, twice daily; cGvHD, chronic graft-versus-host disease; CI, confidence interval; ORR, overall response rate; QD, once daily.
*Data from Cutler et al.2


Figure 1. ORR by organ system*

CR, complete response; GI, gastrointestinal; PR, partial response.

*Data from Cutler et al.2

 

Safety

Adverse events (AEs) reported in >20% patients in both arms included fatigue (38%), diarrhea (33%), nausea (31%), cough (28%), upper respiratory infections (27%), dyspnea (25%), headache (24%), and peripheral edema (23%). A minimum of one serious AE was observed in 38% patients (as seen in Table 3). There were a total eight deaths during the study. Overall, both once daily and twice daily belumosudil was well tolerated in patients.

Table 3. Safety*

 

Belumosudil 200 mg

 

 

QD (n = 66)

BID (n = 66)

Total (N = 132)

Median duration of treatment, months

9.4

11.8

10.4

Any AE, %

99

100

99

Grade ≥3 AE, %

56

52

54

SAE, %

41

35

38

Drug-related AE %
              Any related AE, %
              Related SAE, %

74
8
6

61
3
6

67
5
6

Deaths, %

6

6

6

AE, adverse event; BID, twice daily; QD, once daily; SAE, serious adverse event.
*Data from Cutler et al.2

Conclusion

High ORRs were demonstrated in both once daily and twice daily belumosudil arms, meeting the primary endpoint as per 2014 National Institutes of Health criteria. The responses observed were durable and clinically meaningful, irrespective of organ involvement, patient and cGvHD characteristics.  

Update: The result of this trial have now been published in the journal Blood.3

  1. Cutler C, Lee SJ, Arai S, et al. Belumosudil for chronic graft-versus-host disease (cGVHD) after 2 or more prior lines of therapy: The Rockstar study (KD025-213). Oral abstract #353. 62nd American Society of Hematology (ASH) Annual Meeting & Exposition; Dec 6, 2020; Virtual.
  2. Cutler C, Lee SJ, Arai S, et al. Belumosudil for chronic graft-versus-host disease (cGVHD) after 2 or more prior lines of therapy: The Rockstar study (KD025-213). Oral abstract. EBMT 47th Annual Meeting; March 14th, 2021; Virtual.
  3. Cutler C, Lee SJ, Arai S, et al. Belumosudil for chronic graft-versus-host disease (cGVHD) after 2 or more prior lines of therapy: The ROCKstar Study (KD025-213). Blood. 2021; Online ahead of print. DOI: 10.1182/blood.2021012021

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