S246: jak/rock inhibitor tq05105 for glucocorticoid-refractory or -dependent chronic graft-versus-host disease: updated results of a phase 1b/2 study

Background: 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. TQ05105 is a novel, oral dual JAK1/2 and ROCK1/2 inhibitor targeting inflammatory and fibrotic components of cGVHD. Selective JAK/ROCK inhibition with TQ05105 may offer a novel approach to the management of cGVHD. Aims: Selective JAK/ROCK inhibition with TQ05105 may offer a novel approach to the management of cGVHD. Methods: This phase1b/2, multicenter, open-label study of TQ05105 (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. Results: At data cutoff (September 30, 2022), 30 patients were enrolled. The median age was 34 years (16-59), 53.3% male. Patients enrolled had received a median of 3 prior lines of cGVHD therapy. Twelve patients had previously received ruxolitinib. 70% of patients had severe cGVHD. 47% of patients in 10mg BID and 73% in 15mg BID had involvement of ≥ 4 organs. TQ05105 was well tolerated without dose-limiting toxicities in two dosages. Commonly reported adverse events(AEs) (≥20%) were Epstein-Barr virus infections(33.3%), hypercholesterolemia(30.0%), lung infection or pneumonia(26.7%), upper respiratory tract infection(26.7%), leukopenia(23.3%), neutropenia(23.3%), anemia (23.3%), thrombocytopenia(20.0%). Grade 3 or higher AEs were soft tissue infection(6.7%), neutropenia(6.7%), thrombocytopenia(6.7%) in 10mg BID. In 15mg BID were lung infection(26.7%), upper respiratory tract infection(20.0%). 4 and 6 patients experienced serious adverse events(SAEs) in 10mg BID and 15mg BID, respectively. There were five patients discontinued study treatment due to AE and two patients due to others, one of them was in 10mg BID. Of the 30 patients, the BOR was 93.3% in 10mg BID and 80.0% in 15mg BID, and the median duration of response was not reached. Responses were rapid, with 73.3% and 60.0% of responders achieving a response at 4 weeks, respectively. Responses were achieved across key subgroups in 10mg BID and 15mg BID, with BOR of 85.7% (6 of 7) and 81.8% (9 of 11) in patients with ≥ 4 organs involved, 90% (9 of 10) and 78.6% (11 of 14) in patients who had received ≥ 2 prior systemic LOTs, 100% (9 of 9) and 75% (9 of 12) in patients with severe cGVHD. The FFS rate was 94.1% (95%CI, 65.0-99.1) at 6 months. Organ-specific analyses demonstrated a response of 100% in the liver, 87.5% in the lower GI tract, 66.7% in the skin. During TQ05105 treatment, 80% in 10mg BID and 66.7% in 15mg BID reduced corticosteroids (CS) dose, 46.7% and 33.3% patients discontinued CS. Summary/Conclusion: In this updated data analysis, TQ05105 demonstrated a tolerable safety and significant efficacy profile consistent with preliminary study. The two dosages showed similar efficacy and slightly fewer AEs in 10mg BID, which is the preferred dosage as RP2D. Targeting JAK and ROCK pathways with TQ05105 is a therapeutically promising novel strategy with a favorable safety profile for glucocorticoid-refractory or -dependent cGVHD.Keywords: Chronic graft-versus-host