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.

The Myeloproliferative Neoplasm Landscape: A Patient’s Eye View

“…A number of other JAK inhibitors have been developed, and although some have entered clinical trials in patients with MPN, their development has been delayed by early toxicity issues, or a lack of benefit over ruxolitinib. Firstly, momelotinib, a JAK1/JAK2 inhibitor, showed similar responses to ruxolitinib with respect to reduction in spleen size, but lesser alleviation of constitutional symptoms in phase 3 trials in patients with MF, although momelotinib was associated with a reduced transfusion requirement relative to ruxolitinib [53,54]. Long-term data failed to show a survival benefit of treatment with momelotinib, and demonstrated a high incidence of peripheral neuropathy [55], and studies of momelotinib in PV and ET were discontinued as a result of limited efficacy [56].…”

Life after ruxolitinib: Reasons for discontinuation, impact of disease phase, and outcomes in 218 patients with myelofibrosis

“…13 A second study of 64 patients treated in a real-life comparison confirmed that responses to salvage treatments are rare. 14 Understanding that the outcome after ruxolitinib is important for identifying patients who may benefit from specific interventions, such as allogeneic stem cell transplantation, 15 second-generation JAK inhibitors, [16][17][18] drugs with alternative mechanisms of action, 19,20 or investigational agents in combination with ruxolitinib. 21 Here, we report the outcome of 218 patients after ruxolitinib.…”

<p>Beyond Ruxolitinib: Fedratinib and Other Emergent Treatment Options for Myelofibrosis</p>

“…46 Comparison with ruxolitinib in the SIMPLIFY-1 trial did not show benefits to treatment with momelotinib with regard to spleen size reduction and symptom improvement (spleen response: 26.5% in momelotinib group and 29% of the ruxolitinib group (p=0.011 for non-inferiority); ≥50% reduction in total symptom score: 28.4% for momelotinib vs 42.2% for ruxolitinib [noninferiority not met; p=0.98]). 46,47 Adverse event profiles were comparable for momelotinib, ruxolitinib, and BAT with peripheral neuropathy (in up to 50% of patients) and myelosuppression being the most frequent adverse events seen with momelotinib. 46,48,49 In single-arm studies of mostly treatment-naïve patients, momelotinib achieved clinical/symptom responses in up to 57.6% and spleen responses in 45% of patients, respectively, and no survival benefit compared to risk-matched patients not receiving momelotinib was seen.…”