Rovadicitinib in Patients with Myelofibrosis Who Were Refractory or Relapsed or Intolerant to Ruxolitinib: A Single Arm, Multicenter, Open-Label, Phase Ib Study

Introduction:

Rovadicitinib (TQ05105) is a novel, oral, small molecule JAK/ROCK inhibitor. The target activity of ROCK was significantly better than that of ruxolitinib in preclinical studies. Rovadicitinib demonstrated significant clinical benefits in myelofibrosis patients for spleen response or improved symptom response (NCT04339400/NCT05020652). Here we report the primary results of the phase Ib study of rovadicitinib in patients with myelofibrosis who were refractory or relapsed or intolerant to ruxolitinib (NCT06388759).

Methods:

We conducted a single arm, multicenter, open-label, phase Ib trial at 3 sites in China. Aged ≥18 with PMF, post-PV MF or post-ET MF, dynamic international prognostic scoring system (DIPSS) intermediate or high risk, were enrolled. Patients were refractory or relapsed or intolerant to ruxolitinib, and must have palpable splenomegaly (≥5 cm below the left costal margin). Eligible patients received rovadicitinib 15 mg BID of each 28-day cycle. Treatment continued until progressive disease or unacceptable toxicity. The primary outcomes was the proportion of patients whose reduction of at least 35% in spleen volume (SVR35) at week 24 compared with baseline. The main secondary end point was proportion of patients whose Total Symptom Score decreased ≥ 50% (TSS50) at week 24.

Results:

Between August 1, 2022, and September 14, 2023, 9 patients were assessed for eligibility and enrolled. All patients were treated with ruxolitinib, 5 (56%) patients were intolerant, 2 (22%) patients were refractory and 2 (22%) patients were relapsed. The median age was 57 years (IQR 52-60), and 7 (78%) patients were aged 65 years or younger. 6 (67%) patients were female. 7 (78%) patients were PMF and 2 (22%) were post-PV MF. 2 (22%) patients were DIPSS high risk statues and 2 (22%) patients were DIPSS intermediate-2. Mutations of JAK2, CALR, and MPL were analyzed, 7 (78%) patients with JAK2 V617F mutations, two (22%) patients with MPL W515L/K mutations. The median spleen volume was 1102 cm³ (IQR 788-3202). The median white blood cell count was 12.3 x 10⁹/L (IQR 5.9-17.4), the median blood platelet count was 232 x 10⁹/L (IQR 80-295), the median hemoglobin was 90 g/L (IQR 84-129). Eight patients were treated with rovadicitinib more than 24 weeks. The proportion of patients who had SVR35 was 25% (2/8) at week 24, and 75% (6/8) patients achieved SVR35 during the study period. At week 24, 62.5% (5/8) patients achieved SVR20, inclued two patients were primary drug resistance to ruxolitinib. One patient achieved SVR35 at first assesment and duration more than 60 weeks. The proportion of patients who had TSS50 was 37.5% (3/8) at week 24. 50% (4/8) patients achieved TSS50 during the study period. 78% (7/9) patients occurred treatment-emergent adverse events (TEAEs). The most common TEAEs were platelet count decrease (4/9, 44.4%), hyperpotassemia (2/9, 22.2%), weight decrease (2/9, 22.2%), upper respiratory infection (2/9, 22.2%) and anemia (1/9, 11.1%). Grade ≥3 TEAEs were reported in 4 (44.4%) patients, were platelet count decrease (3/9, 33.3%) and anemia (1/9, 11.1%). There was only one death, due to disease progression and not related to rovadicitinib. TEAEs were generally manageable.

Conclusions:

Rovadicitinib was generally safe, well-tolerated and showed clinical activity in patients with myelofibrosis who were refractory or relapsed or intolerant to ruxolitinib. ROCK target activity may play a potential role in myelofibrosis treatment, which needs to be confirmed in the future. Rovadicitinib may be a new treatment option for those patients who failed ruxolitinib. Meanwhile, a phase Ib/II study is ongoing, aiming to assess the efficacy and safety of Rovadicitinib combined with TQB3617 (a novel oral BET inhibitor) in patients with myelofibrosis (NCT06122831).