JAK/Rock Inhibitor Rovadicitinib for Glucocorticoid-Refractory or -Dependent Chronic Graft-Versus-Host Disease：Updated Results of Multicenter, Phase 1b/2a Trial

Introduction:

Chronic graft-versus-host disease(cGVHD) is an immune-mediated inflammatory and fibrotic disorder, which is a leading cause of morbidity, and mortality after allogeneic stem cell transplantation. The Janus kinase (JAK) and signal transducers and activators of transcription (STAT) and rho-associated coiled-coil-containing protein kinase-2 (ROCK2) signaling pathways play an important role in the progression of cGVHD. Rovadicitinib is a novel, oral dual JAK1/2 and ROCK1/2 inhibitor targeting inflammatory and fibrotic components of cGVHD. We report updated results, including efficacy and safety, after median treatment duration of 27.7 months.

Methods:

This phase1b/2, multicenter, open-label study of Rovadicitinib (NCT04944043) enrolled moderate or severe glucocorticoid-refractory or -dependent cGVHD patients who had received at least one prior line of therapy (LOTs). The primary endpoint of Phase 1b portion of the study was safety and RP2D. The key secondary endpoints were the best overall response (BOR, complete or partial response) defined per the 2014 NIH Consensus criteria, failure-free survival (FFS) at 6 months and improved score on the modified Lee Symptom Scale(LSS).

Results:

From May 19, 2021, through December 31, 2023, 44 patients were enrolled. Median patient age was 34 years (16-59), 61.4% male. The median time from cGVHD diagnosis to enrollment was 27.9 months. Patients enrolled in 10mg BID (n=29) and 15mg BID (n=15) had received a median of 3 prior lines of cGVHD therapy. 63.6% of patients had severe cGVHD, and 36.4% had moderate cGVHD.75.9% of patients in 10mg BID and 93.3% in 15mg BID had involvement of ≥4 organs. The most frequently involved organs in 10mg BID and 15mg BID, respectively, are Joints and/or fascia (100%, 100%), eyes (82.8%, 86.7%), mouth (69.0%, 93.3%), lungs (48.3%, 80.0%), and skin (62.1%, 53.3%).

Rovadicitinib was well tolerated without dose-limiting toxicities in two dosages. Commonly reported treatment-related adverse events (TRAEs) (≥20%) were upper respiratory tract infection (34.1%), Epstein-Barr virus infections (31.8%), lung infection or pneumonia (27.3%), neutropenia (27.3%), anemia (27.3%), leukopenia (25.0%), thrombocytosis (20.5%). Grade 3 or higher TRAEs were lung infection or pneumonia (17.2%), upper respiratory tract infection (10.3%) in 10mg BID. In 15mg BID were lung infection or pneumonia (33.3%), upper respiratory tract infection (20.0%), neutropenia (6.7%), anemia (6.7%). 8 and 5 patients experienced serious adverse events (SAEs) in 10mg BID and 15mg BID, respectively. There were seven patients discontinued study treatment due to AE, two of them were in 10mg BID.

Of the 44 patients, the BOR was 96.6% in 10mg BID and 80.0% in 15mg BID, and responses were rapid, with 72.4% and 66.7% of responders achieving a response at 4 weeks, respectively. Overall response (ORR) at week 24 was 75.9% in 10mg BID and 46.7% in 15mg BID. Responses were achieved across key subgroups in 10mg BID and 15mg BID, with BOR of 100% (22 of 22) and 78.6% (11 of 14) in patients with ≥ 4 organs involved, 95.5% (21 of 22) and 78.6% (11 of 14) in patients who had received ≥ 2 prior systemic LOTs, 93.8% (15 of 16) and 75% (9 of 12) in patients with severe cGVHD. The BOR was 83.3% in patients prior to ruxolitinib therapy. The median duration of response was not reached. The FFS rate was 87.7% (95%CI 73.0, 94.7) at 12 months. Additionally, Organ-specific analyses demonstrated the BOR of 100% (5/5) in the liver, 90.91% (10/11) in the lower GI tract, 78.95% (15/19) in the esophagus, 65.38% (17/26) in the skin, 64.71% (11/17) in the joints/fascia, 54.05% (20/37) in the eyes, 44.12% (15/34) in the mouth, 40% (2/5) in the upper GI tract, and 23.08% (6/26) in the lungs. In the summary LSS, a clinically meaningful improvement of least 7 points was observed in 61.4% (27/44) of the total population. During rovadicitinib treatment, 88.6% patients reduced corticosteroids (CS) dose, and 13.6% patients discontinued CS.

Conclusion:

Rovadicitinib was well tolerated in patients with cGVHD, eliciting a high rate of clinical response, improved quality of life, and CS dose reduction. Rovadicitinib may be effective in patients with glucocorticoid-refractory or -dependent cGVHD, and a phase 3 randomized study for registration will be launched soon. (Funded by Chia Tai Tianqing Pharmaceutical Group Co., Ltd. ClinicalTrials.gov number, NCT04944043.)