A first-in-class JAK/ROCK inhibitor, rovadicitinib, for glucocorticoid-refractory or -dependent chronic GVHD
Abstract
Abstract Rovadicitinib (TQ05105) is a novel, oral dual Janus kinase 1/2 and rho-associated coiled-coil–containing protein kinase-1/2 inhibitor targeting inflammatory and fibrotic components of chronic graft-versus-host disease (cGVHD). This phase 1b/2a, multicenter, open-label study enrolled patients with moderate or severe glucocorticoid-refractory or -dependent cGVHD to evaluate the safety and efficacy of rovadicitinib. The study followed a 3+3 design with 2 escalating doses (rovadicitinib 10 and 15 mg twice daily) and a dose expansion cohort. Primary end points included safety and recommended phase 2 dose (RP2D); the best overall response (BOR) was the key secondary end point. A total of 44 patients were enrolled (29 at 10 mg, 15 at 15 mg twice daily). Rovadicitinib was well tolerated without dose-limiting toxicity at both dosages, and no rovadicitinib-related adverse events (AEs) led to discontinuation. The most prevalent hematological AE was anemia (38.6%), with grade ≥3 of 4.6%. The RP2D was 10 mg twice daily. The BOR was 86.4% (95% confidence interval [CI], 72.6-94.8), with no difference between the 2 dosage cohorts. Besides, BOR was 72.7% in the steroid-refractory cohort and 90.9% in the steroid-dependent cohort. All affected organs exhibited responses regardless of prior therapy. The failure-free survival rate was 85.2% (95% CI, 64.5-94.3) at 12 months. Rovadicitinib reduced corticosteroid doses in 88.6% of patients and improved cGVHD symptoms in 59.1%. Rovadicitinib has favorable tolerability and notable clinical response rates, ameliorating the quality of life and reducing corticosteroid dose requirements in patients with glucocorticoid-refractory or -dependent cGVHD. This trial was registered at www.ClinicalTrials.gov as #NCT04944043.
Article Details
Authors (22)
Yanmin M. Zhao
1Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
Yi Luo
State Key Laboratory of Green Chemical Engineering and Industrial Catalysis
Jimin M. Shi
1Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
Shunqing Q. Wang
4Department of Hematology, Guangzhou First People’s Hospital, Guangzhou, China
Caixia K. Wang
4Department of Hematology, Guangzhou First People’s Hospital, Guangzhou, China
Erlie L. Jiang
5Stem Cell Transplant Center, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
Chen Liang
MOE Key Laboratory for Non-Equilibrium Synthesis and Modulation of Condensed Matter, School of Physics
Xiaoyu Y. Zhu
6Department of Hematology, Anhui Provincial Hospital, Hefei, China
Xuejun J. Zhang
7Department of Hematology, The Second Hospital of Hebei Medical University, Shijiazhuang, China
Fankai K. Meng
8Department of Hematology, Tongji Hospital Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
Hua Jin
Yeqian Q. Zhao
1Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
Jian Yu
Department of Chemistry
Xiaoyu Y. Lai
1Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
Lizhen Z. Liu
1Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
Huarui R. Fu
1Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
Yishan S. Ye
1Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
Congxiao X. Zhang
1Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
Tao Wang
Lifan F. Tu
11Department of Clinical Medicine, Chia Tai Tianqing Pharmaceutical Group Co, Ltd, Nanjing, China
Xunqiang Q. Wang
11Department of Clinical Medicine, Chia Tai Tianqing Pharmaceutical Group Co, Ltd, Nanjing, China
He Huang