SIMPLIFY-1: A Phase III Randomized Trial of Momelotinib Versus Ruxolitinib in Janus Kinase Inhibitor-Naïve Patients With Myelofibrosis

Abstract

Purpose We evaluated the efficacy and safety of momelotinib, a potent and selective Janus kinase 1 and 2 inhibitor (JAKi), compared with ruxolitinib, in JAKi-naïve patients with myelofibrosis. Patients and Methods Patients (N = 432) with high risk or intermediate-2 risk or symptomatic intermediate-1 risk myelofibrosis were randomly assigned to receive 24 weeks of treatment with momelotinib 200 mg once daily or ruxolitinib 20 mg twice a day (or per label), after which all patients could receive open-label momelotinib. The primary end point was a ≥ 35% reduction in spleen volume at 24 weeks of therapy. Secondary end points were rates of symptom response and effects on RBC transfusion requirements. Results A ≥ 35% reduction in spleen volume at week 24 was achieved by a similar proportion of patients in both treatment arms: 26.5% of the momelotinib group and 29% of the ruxolitinib group (noninferior; P = .011). A ≥ 50% reduction in the total symptom score was observed in 28.4% and 42.2% of patients who received momelotinib and ruxolitinib, respectively, indicating that noninferiority was not met ( P = .98). Transfusion rate, transfusion independence, and transfusion dependence were improved with momelotinib (all with nominal P ≤ .019). The most common grade ≥ 3 hematologic abnormalities in either group were thrombocytopenia and anemia. Grade ≥ 3 infections occurred in 7% of patients who received momelotinib and 3% of patients who received ruxolitinib. Treatment-emergent peripheral neuropathy occurred in 10% of patients who received momelotinib (all grade ≤ 2) and 5% of patients who received ruxolitinib (all grade ≤ 3). Conclusion In JAKi-naïve patients with myelofibrosis, 24 weeks of momelotinib treatment was noninferior to ruxolitinib for spleen response but not for symptom response. Momelotinib treatment was associated with a reduced transfusion requirement.

Fig 1.

Change in spleen volume and spleen response rate (percentage of patients with a ≥ 35% reduction in spleen volume) at week 24. MMB, momelotinib; RUX, ruxolitinib; SRR, spleen response rate.

Fig 2.

(A) Change in Total Symptom Score (TSS) from baseline and TSS response rate (percentage of patients with ≥ 50% reduction in TSS) at week 24. (B) Absolute and percent changes in individual symptoms of the Myeloproliferative Neoplasm Symptom Assessment Form from baseline to week 24. MMB, momelotinib; RUX, ruxolitinib.

Fig 3.

Comparison of momelotinib (MMB) and ruxolitinib (RUX) effects on transfusion requirements at week 24. (A) RBC transfusion independence rate (no RBC transfusion and no hemoglobin [Hb] < 8 g/dL in the prior 12 weeks; nominal P < .001). (B) RBC transfusion dependence rate (≥ 4 units of RBC transfusion or Hb < 8 g/dL in the prior 8 weeks; nominal P = .019). (C) Rate of RBC transfusions through week 24 (nominal P < .001).

Fig 4.

Patients (n, %) who achieved spleen response (≥ 35% reduction in spleen volume), Total Symptom Score (TSS) response (≥ 50% reduction in score), and transfusion independence (TI; no RBC transfusion and no Hb < 8 g/dL in the prior 12 weeks) at week 24. MMB, momelotinib; RUX, ruxolitinib.

Fig A1.

Patient disposition and availability for assessments. AE, adverse effect; ET, essential thrombocythemia; SSR24, spleen response rate at 24 weeks; TSS24, Total Symptom Score at 24 weeks.