ROCK2 Inhibition With Belumosudil (KD025) for the Treatment of Chronic Graft-Versus-Host Disease
Madan Jagasia, Aleksandr Lazaryan, Carlos R Bachier, Amandeep Salhotra, Daniel J Weisdorf, Behyar Zoghi, James Essell, Laurie Green, Olivier Schueller, Jeegar Patel, Alexandra Zanin-Zhorov, Jonathan M Weiss, Zhongming Yang, David Eiznhamer, Sanjay K Aggarwal, Bruce R Blazar, Stephanie J Lee, Madan Jagasia, Aleksandr Lazaryan, Carlos R Bachier, Amandeep Salhotra, Daniel J Weisdorf, Behyar Zoghi, James Essell, Laurie Green, Olivier Schueller, Jeegar Patel, Alexandra Zanin-Zhorov, Jonathan M Weiss, Zhongming Yang, David Eiznhamer, Sanjay K Aggarwal, Bruce R Blazar, Stephanie J Lee
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
References
- MacDonald KPA, Hill GR, Blazar BR: Chronic graft-versus-host disease: Biological insights from preclinical and clinical studies. Blood 129:13-21, 2017
- Arora M Cutler CS Jagasia MH, et al. : Late acute and chronic graft-versus-host disease after allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transpl 22:449-455, 2016
- Wingard JR Majhail NS Brazauskas R, et al. : Long-term survival and late deaths after allogeneic hematopoietic cell transplantation. J Clin Oncol 29:2230-2239, 2011
- Wong FL Francisco L Togawa K, et al. : Long-term recovery after hematopoietic cell transplantation: Predictors of quality-of-life concerns. Blood 115:2508-2519, 2010
- Grube M Holler E Weber D, et al. : Risk factors and outcome of chronic graft-versus-host disease after allogeneic stem cell transplantation—Results from a single-center observational study. Biol Blood Marrow Transpl 22:1781-1791, 2016
- Sahebi F Garderet L Kanate AS, et al. : Outcomes of haploidentical transplantation in patients with relapsed multiple myeloma: An EBMT/CIBMTR report. Biol Blood Marrow Transpl 25:335-342, 2019
- Afram G Pérez Simón JA Remberger M, et al. : Reduced intensity conditioning increases risk of severe cGVHD: Identification of risk factors for cGVHD in a multicenter setting. Med Oncol 35:79, 2018
- Zeiser R, Blazar BR: Pathophysiology of chronic graft-versus-host disease and therapeutic targets. N Engl J Med 377:2565-2579, 2017
- Baird K, Cooke K, Schultz KR: Chronic graft versus host disease (GVHD) in children. Pediatr Clin North Am 57:297-322, 2010
- Lee SJ, Vogelsang G, Flowers MED: Chronic graft-versus-host disease. Biol Blood Marrow Transpl 9:215-233, 2003
- Bachier CR Aggarwal SK Hennegan K, et al. : Epidemiology and real-world treatment of chronic graft-versus-host disease post allogeneic hematopoietic cell transplantation: A US claims analysis. Presented at ASH 2019, Orlando, FL, December 7-10, 2019
- Lee SJ Nguyen TD Onstad L, et al. : Success of immunosuppressive treatments in patients with chronic graft-versus-host disease. Biol Blood Marrow Transpl 24:555-562, 2018
- Saillard C Crocchiolo R Furst S, et al. : National Institutes of Health classification for chronic graft-versus-host disease predicts outcome of allo-hematopoietic stem cell transplant after fludarabine–busulfan–antithymocyte globulin conditioning regimen. Leuk Lymphoma 55:1106-1112, 2014
- Data on file : Trinity Data. New York, NY, Kadmon Holdings Inc, 2019
- Pidala J Kurland B Chai X, et al. : Patient-reported quality of life is associated with severity of chronic graft-versus-host disease as measured by NIH criteria: Report on baseline data from the chronic GVHD Consortium. Blood 117:4651-4657, 2011
- Lee SJ Cook EF Soiffer R, et al. : Development and validation of a scale to measure symptoms of chronic graft-versus-host disease. Biol Blood Marrow Transpl 8:444-452, 2002
- Carpenter PA Logan BR Lee SJ, et al. : A phase II/III randomized, multicenter trial of prednisone/sirolimus versus prednisone/sirolimus/calcineurin inhibitor for the treatment of chronic graft-versus-host disease: BMT CTN 0801. Haematologica 103:1915-1924, 2018
- Flowers MED, Martin PJ: How we treat chronic graft-versus-host disease. Blood 125:606-615, 2015
- Couriel D Carpenter PA Cutler C, et al. : Ancillary therapy and supportive care of chronic graft-versus-host disease: National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: V. Ancillary Therapy and Supportive Care Working Group report. Biol Blood Marrow Transpl 12:375-396, 2006
- Imbruvica. Package Insert. Sunnyvale, CA, Pharmacyclics LLC, 2019
- Miklos D Cutler CS Arora M, et al. : Ibrutinib for chronic graft-versus-host disease after failure of prior therapy. Blood 130:2243-2250, 2017
- Waller EK Miklos D Cutler C, et al. : Ibrutinib for chronic graft-versus-host disease after failure of prior therapy: 1-Year update of a phase 1b/2 study. Biol Blood Marrow Transpl 25:2002-2007, 2019
- Zanin-Zhorov A Weiss JM Nyuydzefe MS, et al. : Selective oral ROCK2 inhibitor down-regulates IL-21 and IL-17 secretion in human T cells via STAT3-dependent mechanism. Proc Natl Acad Sci U S A 111:16814-16819, 2014
- Flynn R Paz K Du J, et al. : Targeted rho-associated kinase 2 inhibition suppresses murine and human chronic GVHD through a Stat3-dependent mechanism. Blood 127:2144-2154, 2016
- Riches DWH, Backos DS, Redente EF: ROCK and rho: Promising therapeutic targets to ameliorate pulmonary fibrosis. Am J Pathol 185:909-912, 2015
- Jagasia MH Greinix HT Arora M, et al. : National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. The 2014 Diagnosis and Staging Working Group report. Biol Blood Marrow Transpl 21:389-401.e1, 2015
- Inamoto Y Flowers MED Sandmaier BM, et al. : Failure-free survival after initial systemic treatment of chronic graft-versus-host disease. Blood 124:1363-1371, 2014
- Martin PJ Storer BE Inamoto Y, et al. : An endpoint associated with clinical benefit after initial treatment for chronic graft-versus-host disease. Blood 130:360-367, 2017
- Inamoto Y Storer BE Lee SJ, et al. : Failure-free survival after second-line systemic treatment of chronic graft-versus-host disease. Blood 121:2340-2346, 2013
- Dignan FL Amrolia P Clark A, et al. : Diagnosis and management of chronic graft-versus-host disease. Br J Haematol 158:46-61, 2012
- Lee SJ Wolff D Kitko C, et al. : Measuring therapeutic response in chronic graft-versus-host disease. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: IV. The 2014 Response Criteria Working Group report. Biol Blood Marrow Transpl 21:984-999, 2015
- Baird K Steinberg SM Grkovic L, et al. : National Institutes of Health chronic graft-versus-host disease staging in severely affected patients: Organ and global scoring correlate with established indicators of disease severity and prognosis. Biol Blood Marrow Transpl 19:632-639, 2013
- Imanguli MM Atkinson JC Mitchell SA, et al. : Salivary gland involvement in chronic graft-versus-host disease: Prevalence, clinical significance, and recommendations for evaluation. Biol Blood Marrow Transpl 16:1362-1369, 2010
- Jagasia M Salhotra A Bachier CR, et al. : KD025 for patients with chronic graft-versus-host disease (cGVHD)—Long-term follow-up of a phase 2a study (KD025-208). Presented at ASH 2019, Orlando, FL, December 7-10, 2019
- Jagasia M Salhotra A Bachier CR, et al. : KD025-208: A phase 2a study of KD025 for patients with chronic graft versus host disease (cGVHD)—Pharmacodynamics and updated results. Blood 132:602, 2018. (suppl 1)
Source: PubMed