ROCK2 Inhibition With Belumosudil (KD025) for the Treatment of Chronic Graft-Versus-Host Disease

Abstract

Purpose: The rho-associated coiled-coil-containing protein kinase-2 (ROCK2) signaling pathway regulates the Th17/regulatory T cells balance and controls profibrotic pathways. Selective ROCK2 inhibition with belumosudil (KD025) may offer a novel approach to the management of chronic graft-versus-host disease (cGVHD).

Patients and methods: A phase IIa, open-label, dose-finding study of belumosudil enrolled 54 patients with cGVHD who had received one to three prior lines of therapy (LOTs). The primary end point was overall response rate (ORR).

Results: The median time from cGVHD diagnosis to enrollment was 20 months. Seventy-eight percent of patients had severe cGVHD, 50% had ≥ 4 organs involved, 73% had cGVHD refractory to their last LOT, and 50% had received ≥ 3 prior LOTs. With an overall median follow-up of 29 months, the ORR (95% CI) with belumosudil 200 mg once daily, 200 mg twice daily, and 400 mg once daily was 65% (38% to 86%), 69% (41% to 89%), and 62% (38% to 82%), respectively. Responses were clinically meaningful, with a median duration of response of 35 weeks, and were associated with quality-of-life improvements and corticosteroid (CS) dose reductions. CS treatment was discontinued in 19% of patients. The failure-free survival rate was 76% (62% to 85%) and 47% (33% to 60%) at 6 and 12 months, respectively. The 2-year overall survival rate was 82% (69% to 90%). Belumosudil was well-tolerated, with low rates of cytopenia. There were no unexpected adverse events and no apparent increased risk of infection, including cytomegalovirus infection and reactivation.

Conclusion: Belumosudil treatment resulted in a high ORR and overall survival rate and demonstrated quality-of-life improvements, CS dose reductions, and limited toxicity. Data from the study indicated that belumosudil may prove to be an effective therapy for patients with treatment-refractory cGVHD.

Trial registration: ClinicalTrials.gov NCT02841995.

Conflict of interest statement

Madan JagasiaEmployment: Iovance BiotherapeuticsStock and Other Ownership Interests: Iovance BiotherapeuticsConsulting or Advisory Role: Kadmon Aleksandr LazaryanStock and Other Ownership Interests: AbbVie, PfizerConsulting or Advisory Role: EUSA Pharma Carlos R. BachierEmployment: HCA HealthcareConsulting or Advisory Role: Kadmon, Viracyte, WUGEN, crispr therapeutics, Novartis, Juno/CelgeneResearch Funding: Bristol-Myers Squibb Amandeep SalhotraConsulting or Advisory Role: Kadmon, Syros PharmaceuticalsResearch Funding: Bristol-Myers Squibb Daniel J. WeisdorfConsulting or Advisory Role: Incyte, Fate TherapeuticsResearch Funding: Incyte James EssellConsulting or Advisory Role: AbbVie/Genentech, Celgene/Bristol-Myers SquibbSpeakers' Bureau: Kite/Gilead Laurie GreenEmployment: Kadmon Olivier SchuellerEmployment: Kadmon Jeegar PatelEmployment: Kadmon Corporation LLCStock and Other Ownership Interests: Kadmon Corporation LLCTravel, Accommodations, Expenses: Kadmon Alexandra Zanin-ZhorovEmployment: Kadmon HoldingsStock and Other Ownership Interests: Kadmon Holdings Jonathan M. WeissEmployment: KadmonStock and Other Ownership Interests: KadmonConsulting or Advisory Role: StellateResearch Funding: KadmonTravel, Accommodations, Expenses: Kadmon Zhongming YangEmployment: KadmonStock and Other Ownership Interests: Kadmon David EiznhamerEmployment: KadmonStock and Other Ownership Interests: Kadmon Sanjay K. AggarwalEmployment: Kadmon, Angiocrine BioscienceLeadership: Angiocrine BioscienceStock and Other Ownership Interests: Kadmon, Angiocrine Bioscience, Amgen, AlnylamConsulting or Advisory Role: Kadmon Bruce R. BlazarStock and Other Ownership Interests: Five Prime Therapeutics, BlueRock Therapeutics, Tmunity Therapeutics, Inc, Magenta TherapeuticsHonoraria: Kadmon, IncyteConsulting or Advisory Role: Kadmon, BlueRock Therapeutics, Magenta TherapeuticsResearch Funding: Fate Therapeutics, BlueRock Therapeutics, Alpine Immune Sciences, AbbViePatents, Royalties, Other Intellectual Property: Inducible regulatory T cell generation for hematopoietic cell transplants (UMN Z09026), U.S. 9,228,172, Inducible regulatory T cell generation for hematopoietic cell transplants (UMN Z09026), U.S. 9,228,172, TALEN based gene correction, Patent No. 9,393,257, Generation of natural killer cells and lymphoid tissue inducer-like (LTI-like) NK-22 cells, 9,862,928, Method for correcting a genetic sequence, 10,648,002Travel, Accommodations, Expenses: Incyte, Magenta Therapeutics, Rheos Medicines Stephanie J. LeeHonoraria: Wolters KluwerConsulting or Advisory Role: Incyte, Pfizer, EMD Serono, Kadmon, MSD Oncology, Sanofi, Genzyme, Regeneron, 4SCResearch Funding: Kadmon, Takeda, Amgen, Bristol-Myers Squibb, EMD Serono, MSD, Novartis, Incyte, Syndax, Pfizer, AstraZenecaPatents, Royalties, Other Intellectual Property: Patent pending for high affinity T cell receptors that target the Merkel polyomavirusNo other potential conflicts of interest were reported.

Figures

FIG 1.

CONSORT diagram. cGVHD, chronic graft-versus-host disease; LTFU, long-term follow-up.

FIG 2.

Forest plot for subgroup analyses of ORR in the safety population. Note that subgroups were defined based on baseline assessment. cGVHD, chronic graft-versus-host disease; ORR, overall response rate.

FIG 3.

Durability of response to belumosudil in patients with cGVHD. Kaplan-Meier curves of estimated (A) DOR for responders, (B) time to next cGVHD systemic treatment (TTNT) in the safety population, (C) FFS in the safety population (including reasons for failure), and (D) overall survival in the safety population. DOR was defined as the time from response until documented progression. FFS was defined as the time from first dose of study drug to the start of another cGVHD systemic treatment, relapse of the underlying disease, or death., cGVHD, chronic graft-versus-host disease; DOR, duration of response; FFS, failure-free survival; TTNT, time to next treatment.

FIG 4.

Changes in percentage of CD4+ Tregs following treatment with belumosudil compared with baseline. (A) Tregs (all), (B) Tregs (responders), and (C) Tregs (nonresponders). Predose peripheral blood samples were collected on C1D1, C2D1, C4D1, C7D1, and end-of-treatment visits. C1D1, cycle 1 day 1; C2D1, cycle 2 day 1; C4D1, cycle 4 day 1; C7D1, cycle 7 day 1; Tregs, regulatory T cells.

FIG A1.

Best individual response by organ system among responders. n = number of responder population for global severity rating and number of specific organs involved at baseline. The percentages are calculated based on the corresponding n. CR, complete response; PR, partial response.

FIG A2.

Response and progression heat map for all patients in the safety population. (A) Best response by organ. (B) Organ responses at time of progression or end of study. Of 11 patients with progression in joints, seven had a reduction in P-ROM of just one unit. cGVHD, chronic graft-versus-host disease; CR, complete response; GSR, Global Severity Rating; PR, partial response; P-ROM, photographic range of motion.

FIG A3.

Time to response among belumosudil responders. Percentages are calculated based on the number of responder population.

FIG A4.

Time to response by selected organs among responders. Percentages are calculated based on the number of responder population.