Introduction:

Rovadicitinib (R, TQ05105) is a novel, oral small-molecule JAK/ROCK inhibitor that has demonstrated significant clinical benefits in myelofibrosis (MF) patients (pts) (NCT04339400 / NCT05020652). TQB3617 is an oral small-molecular inhibitor of the bromodomain and extra-terminal (BET) protein family. In a previous phase I study, TQB3617 monotherapy was well-tolerated and showed encouraging efficacy in pts with lymphoma or MF (NCT05110807). Here, we report the primary results of a phase Ib/II study investigating R in combination with TQB3617 in MF pts (NCT06122831).

Methods: The phase Ib study used a “3 + 3” dose escalation design for the combination of R and TQB3617, which is intended for pts with suboptimal response to JAKi treatment. The phase II study included three cohorts: Cohort 1 and Cohort 2 involve the combination of the two drugs, used to treat MF pts who are JAKi-naïve or have suboptimal response to JAKi, respectively. Cohort 3 involves TQB3617 monotherapy for pts with suboptimal response to JAKi. Pts aged ≥ 18 years with PMF, post-PV MF, or post-ET MF, and with DIPSS intermediate or high risk, were enrolled. Pts must have palpable splenomegaly. In phase Ib, eligible pts received R at 10 mg BID or 15 mg BID (administered consecutively for 21 days, 21/21) and TQB3617 at 0.05mg QD or 0.1mg QD (14 days on and 7 days off, 14/21) in each 21-day cycle. Based on the RP2D determined in the phase Ib study, pts in Cohorts 1 and 2 of the phase II study will receive treatment at the RP2D. Pts in Cohort 3 will receive TQB3617 at 0.1 mg QD (14/21). The primary outcomes were the RP2D in phase Ib, and in phase II, the proportion of pts with at least a 35% reduction in spleen volume (SVR35) at week 24 compared with baseline.

Results: Between December 13, 2023, and June 30, 2025, 12 pts in phase Ib and 39 pts in phase II were assessed for eligibility and enrolled. Among them, 36 pts had a suboptimal response to JAKi treatment, while 15 were JAKi-naïve. The median age of the pts was 58 years (IQR 50-62). There were 23 (45.1%) female pts.​ In terms of disease subtypes, 38 pts (74.51%) had PMF, 9 (17.65%) had post-ET MF, and 4 (7.84%) had post-PV MF. Based on the DIPSS, 30 pts (58.82%) were classified as intermediate-1, 16 (31.37%) as intermediate-2, and 5 (9.80%) as high risk.​ Bone marrow biopsy results showed that 33 pts (64.71%) had MF-3 and 15 (29.41%) had MF-2. Genetic mutation analysis revealed that 36 pts (70.59%) carried the JAK2 V617F, 12 (23.53%) had CALR, and 2 (3.92%) had MPL W515L/K. Additionally, 22 pts (43.14%) had high-risk mutations.​ The median spleen volume was 1351 cm³ (IQR 1057-2308); and the median MPN-SAF-TSS was 15 (IQR 11-19). In phase Ib, no dose-limiting toxicity (DLT) was experienced. Based on the safety profile and spleen shrinkage efficacy, the starting dose of R 10 mg BID (21/21) in combination with TQB3617 0.1mg (14/21) was identified as RP2D and after six weeks, the dose of R will be increased to 15 mg BID (21/21) based on the pt's platelet and neutrophil counts. At week 24, 50% (6/12) of pts achieved SVR35, and 67% (8/12) achieved TSS50. Meanwhile, the mean HGB level in 11 pts improved from a baseline of 114 g/L to 130 g/L at week 24. Additionally, the JAK2 V617F allele burden decreased in 40% (4/10) pts, and MF grade improved in 45% (5/11) pts at week 24. In phase II, At week 24, 91.67% (11/12) of pts achieved SVR35, and 45.45% (5/11) achieved TSS50 in cohort 1; 25% (1/4) of pts achieved SVR35, and 100% (4/4) achieved TSS50 in cohort 2. 92.2% (47/51) pts occurred treatment-related adverse events (TRAEs). The most common TRAEs were platelet count decrease (56.9%), anemia (25.5%), lymphocyte count decrease 15.7%), WBC count decrease (11.8%), fibrinogen decrease (11.8%) and hyperuricemia (11.8%). Grade ≥3 TRAEs were reported in 29.4% pts, were platelet count decrease (13.7%) and anemia (5.9%). There was no death related to R or TQB3617. TRAEs were generally manageable.

Conclusions:Rovadicitinib in combination with TQB3617 was generally safe, well-tolerated, and showed clinical activity in pts with MF who were either JAKi-naïve or had a suboptimal response to JAKi treatment. This regimen may represent a new treatment option for such patients with MF. A phase III study is currently being planned in pts with MF who had a suboptimal response to JAKi treatment.

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2025
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