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Evaluation of Efficacy and Safety of Momelotinib for Patients With Myelofibrosis and Thrombocytopenia
Jean-Jacques Kiladjian, MD, PhD, from the University of Paris in France, and colleagues analyzed the MOMENTUM, SIMPLIFY-1, and SIMPLIFY-2 trials to determine the safety and efficacy of momelotinib for patients with myelofibrosis (MF) and thrombocytopenia (platelet counts <100 × 109/L). There are key differences between each trial: in the SIMPLIFY-1 trial, patients who were JAK inhibitor naïve were included, in the SIMPLIFY-2 trial, patients who were previously exposed to ruxolitinib were included, and in the MOMENTUM trial, patients who were exposed to any JAK inhibitor were included. Momelotinib was compared to the data found in each of these studies to determine whether the treatment’s safety and efficacy levels had a statistically significant difference in comparison with other JAK inhibitors (ruxolitinib, fedratinib, etc) for patients with MF and thrombocytopenia.
In the MOMENTUM study, patients with symptomatic and anemic primary MF (PMF), post-polycythemia vera (post-PV) MF, and post-essential thrombocythemia (post-ET) MF that was treated previously with a JAK inhibitor were included. Patients were required to have a baseline platelet count ≥25 × 109/L to be eligible for this study. Patients with MF were randomly assigned once a day to receive 200 mg of momelotinib and a danazol placebo or 300 mg of danazol and a momelotinib placebo. In the SIMPLIFY-1 study, patients who were intermediate or high-risk PMF, post-PV MF, and post-ET MF with baseline platelet counts ≥50 × 109/L were included. Patients were randomly assigned 200 mg of momelotinib plus a ruxolitinib placebo or were given ruxolitinib twice a day with a momelotinib placebo. The dose of ruxolitinib was dependent on the individual patient’s baseline platelet counts. The SIMPLIFY-2 trial included patients with intermediate or high-risk PMF, post-PV MF, and post-ET MF and those who experienced hematologic toxicity when they were treated with ruxolitinib. There was no minimum baseline platelet count in this study, like the studies previously mentioned. Patients with MF were randomly given 200 mg of momelotinib or BAT, which included ruxolitinib (88.5% of patients), other standard treatments, or no treatment at all. All studies took place over a 24-week treatment period.
In their statistical analyses for the MOMENTUM study, the study authors established a primary endpoint of ≥50% reduction in Myelofibrosis Symptom Assessment Form Total Symptom Score (TSS) response rate at week 24, with secondary end points of 24-week rates of spleen volume reduction ≥25% (SVR25), spleen volume reduction ≥35% (SVR35), transfusion independence, zero transfusions, and a change in mean TSS from baseline. In the SIMPLIFY-1 and SIMPLIFY-2 studies, the primary endpoint was an SVR35 rate at 24 weeks and the secondary endpoints were mean TSS response rate and red blood cell (RBC) transfusion independence rate at 24 weeks. All three studies had previously established primary efficacy analyses that Dr Kiladjian used to analyze the safety/efficacy of momelotinib.
In the results for all three studies, 210 of 783 patients were found to have baseline platelet counts of <100 × 109/L and 47 (6%) had baseline platelet counts of <50 × 109/L. Within the 210 patients with a baseline platelet count of <100 × 109/L, 126 received momelotinib in the 24-week period and 84 received treatment in the control arms. Additionally, 62 patients switched over to open-label momelotinib from the control arm after the 24-week period was over. Within these 62 patients, 23 switched from danazol, 17 switched from ruxolitinib, and 22 switched from BAT. In MOMENTUM, SIMPLIFY-1, and SIMPLIFY-2, the SVR35 rate at week 24 was numerically comparable or higher in the sub-100 groups treated with momelotinib compared to the broader study populations. No patients in the SIMPLIFY-1 study achieved an SVR35 with ruxolitinib.
Dr Kiladjian found in their data regarding safety for all three trials, the top three treatment emergent adverse effects were diarrhea, thrombocytopenia, and anemia. Rates of hemorrhage were found to be higher in the MOMENTUM and SIMPLIFY-2 trials. Less patients discontinued treatment because of thrombocytopenia in the SIMPLIFY-1 trial on momelotinib than on ruxolitinib. For efficacy, they found that the SVR35 rate at week 24 was higher in the sub-100 baseline platelet groups that took momelotinib than in the overall study populations for all three clinical trials. The response rate for TSS in the sub-100 group receiving ruxolitinib was about half of the rate seen in the overall SIMPLIFY-1 population’s ruxolitinib arm (22% compared to 42%, respectively). They also found that all patients in the MOMENTUM trial in the sub-100 group were anemic upon screening, and in the SIMPLIFY-1 and SIMPLIFY-2 trials, most patients were mildly anemic at baseline. Patients on momelotinib in the sub-100 group with anemia had SVR35, transfusion independence, and TSS response rates that were numerically higher than the control group across all three trials. Overall, patients in MOMENTUM, SIMPLIFY-1, and SIMPLIFY-2 had consistent efficacy results when they were evaluated.
”Despite thrombocytopenia being the most common grade ≥3 TEAE among sub-100 patients in the phase 3 randomized studies of momelotinib, few patients had dose reductions due to thrombocytopenia with momelotinib. Across all 3 studies, very few sub-100 patients treated with momelotinib discontinued therapy due to thrombocytopenia,” the authors wrote.
In conclusion, Dr Kiladjian and colleagues determined in their analysis that the MOMENTUM, SIMPLIFY-1, and SIMPLIFY-2 clinical trials demonstrated the safety and efficacy of momelotinib for the treatment of patients with MF and moderate-to-severe thrombocytopenia. Momelotinib was found to demonstrate statistically significant clinical benefits in comparison with treatments such as ruxolitinib, BAT, and danazol for MF and thrombocytopenia.
Source:
Kiladjian JJ, Vannucchi AM, Gerds AT, et al. Momelotinib in Myelofibrosis Patients With Thrombocytopenia: Post Hoc Analysis From Three Randomized Phase 3 Trials. Hemasphere. 2023 Oct 27;7(11):e963. doi:10.1097/HS9.0000000000000963.
