Rovadicitinib Shows Safety, Clinical Activity After Ruxolitinib Intolerance in Myelofibrosis

The novel, oral, small molecule JAK/ROCK inhibitor rovadicitinib (TQ05105) was generally well-tolerated and demonstrated clinical activity, including splenic and symptom responses, in patients with myelofibrosis who were relapsed/refractory or intolerant to ruxolitinib (Jakafi), according to primary results from a phase 1b study (NCT06388759) presented during the 2024 ASH Annual Meeting.

All patients treated with rovadicitinib for longer than 24 weeks (n = 8) experienced a decrease in spleen volume compared with baselines. Throughout the study period, 6 patients (75%) achieved a spleen volume reduction of at least 35% (SVR35). Of these patients, 3 achieved SVR35 by their 12-week assessment. At week 24, 2 patients (25%) achieved SVR35, and 5 patients (62.5%) experienced a spleen volume reduction of at least 20% (SVR20). Notably, 2 of the patients who achieved SVR20 displayed primary ruxolitinib resistance. One patient achieved SVR35 at first assessment and had a duration of more than 72 weeks.

Total symptom score reduction of 50% or greater (TSS50) occurred in half of patients during the study. Three patients (37.5%) achieved TSS50 at week 24, and clinical symptoms disappeared in 2 patients.

“Rovadicitinib may be a new treatment option for those patients who [progressed on] ruxolitinib,” presenting author Professor Hu Zhou, MD, stated. “ROCK target activity may play a potential role in myelofibrosis [management], which needs to be confirmed in the future.”

Zhou serves as chief physician in the Department of Hematology at The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital in Zhengzhou, Henan, China.

Background and Study Overview

Prior research has demonstrated substantial clinical benefit in the form of spleen or improved symptom response with rovadicitinib in myelofibrosis. This approach was also identified as a potentially viable strategy for addressing glucocorticoid-refractory or -dependent chronic graft-vs-host disease (GVHD). Additionally, in a preclinical model of acute GVHD, potential synergy was observed with the addition of a ROCK inhibitor to ruxolitinib.

This single arm, multicenter, open-label phase 1b study enrolled patients at least 18 years of age with primary myelofibrosis, post–polycythemia vera myelofibrosis, or post–essential thrombocytosis myelofibrosis that was relapsed, refractory or intolerant to prior ruxolitinib. Patients were required to have intermediate-1 or high-risk disease according to the dynamic international prognostic scoring system (DIPSS); have palpable splenomegaly (at least 5 cm below the left costal margin); have a platelet count of 100 x 109/L or greater; and have a hemoglobin count of more than 80 g/L.

A total of 9 patients were deemed eligible for study enrollment between August 1, 2022, and September 14, 2023. Patients were treated with 15 mg of rovadicitinib twice daily during each 28-day cycle. Treatment continued until progressive disease or unacceptable toxicity. The median dose intensity of rovadicitinib was 20 mg daily.

The proportion of patients who achieved SVR35 at week 24 compared with baseline served as the study’s primary end point. Secondary end points included TSS50 at week 24 vs baseline, best spleen response rate, symptom response, and safety.

Regarding baseline characteristics, the median age of all patients was 57 years (range, 50-70), with 77.78% of patients being 65 years of age or older. The majority of patients were female (66.67%) and had primary myelofibrosis (77.28%). Over half (55.56%) of patients had intermediate-1 risk according to DIPSS; intermediate-2 and high-risk disease each occurred in 22.22% of patients. JAK2 V617F and MPL W515L/K mutations were reported in 77.78% and 22.22% of patients, respectively. The mean spleen volume at baseline was 1102 cm3 (range, 524-4759). The mean TSS according to the Myeloproliferative Neoplasm Symptom Assessment Form was 11 (range, 3-66). White blood cell, hemoglobin, and platelet counts were 12.30 x 109/L (range, 5.17-56.64), 90 g/L (range, 71-146), and 232 x 109/L (range, 12-507), respectively.

At the data cutoff of September 3, 2024, 4 patients were continuing on the study and 5 patients had withdrawn.

Safety Data and Next Steps

The safety profile for rovadicitinib was manageable, and no new safety signals were reported. Any-grade treatment emergent adverse effects (TEAEs) were reported in 77.78% of patients (n = 7/9). The most common TEAEs included platelet count decrease (44.4%), hyperpotassemia (22.2%), weight decrease (22.2%), upper respiratory infection (22.2%), and anemia (11.1%).

Grade 3 or higher TEAEs were present in 44.4% of patients, the most common of which were platelet count decrease (33.3%) and anemia (11.1%). Serious TEAEs occurred in 33.33% of patients. TEAEs led to dose reduction, interruption, or discontinuation in 33.33%, 11.11%, and 11.11% of patients, respectively. Only one death occurred due to disease progression; this was deemed unrelated to rovadicitinib.

These data support 2 ongoing phase 1b/2 studies evaluating the efficacy and safety of rovadicitinib plus the novel BET inhibitor TQB3617 (NCT06122831) or in combination with the novel BCL2 inhibitor TQB3909 (NCT06245941) for patients with myelofibrosis.

Reference

Chang C, Zhang M, Gao S, et al. Rovadicitinib in patients with myelofibrosis who were refractory or relapsed or intolerant to ruxolitinib: A single arm, multicenter, open-label, phase Ib study. Blood. 2024;144(suppl 1):484. doi:10.1182/blood-2024-203242