Momelotinib, a selective and orally bioavailable inhibitor of Janus kinase (JAK) 1, JAK2, and ACVR1, improved overall survival and sustained efficacy outcomes in patients with intermediate- or high-risk myelofibrosis, according to updated findings from the phase 3 SIMPLIFY-1 and SIMPLIFY-2 clinical trials presented at ASH 2020. Momelotinib was of benefit to patients who previously received treatment with ruxolitinib (Jakafi) and those who had not received a JAK inhibitor.
“In both the JAK inhibitor-naïve and previously ruxolitinib-treated patients, an overall survival of more than 34.3 months and 37.5 months observed in the 2 treatment arms of SIMPLIFY-2 compare very favorably with overall survival previously reported in patients who discontinued JAK inhibitor therapy and received salvage therapy,” said lead investigator Srdan Verstovsek, MD, PhD, Chief, Section for Myeloproliferative Neoplasms, Department of Leukemia, M.D. Anderson Canwqcer Center, Houston, TX.
The analysis Dr Verstovsek presented was based on a total of 558 patients in the SIMPLIFY-1 and SIMPLIFY-2 clinical trials. Both studies compared momelotinib versus ruxolitinib or best available therapy. Both studies had a 24-week randomization treatment phase, followed by extended momelotinib treatment for all patients. Patients in SIMPLIFY-1 were naïve to ruxolitinib and patients in SIMPLIFY-2 received previous treatment with ruxolitinib. The primary end point of the 2 studies was splenic response rate.
In SIMPLIFY-2, the median overall survival was 34.3 months for patients originally assigned to momelotinib and 37.5 months for those assigned to ruxolitinib or best available therapy who subsequently crossed over to the experimental drug. Dr Verstovsek emphasized that this was “the best overall survival reported for patients previously treated with ruxolitinib.”
In SIMPLIFY-1, the median overall survival was not reached for patients who initially received momelotinib compared with 53.1 months in patients who crossed over from the ruxolitinib arm to momelotinib (not significantly different). Of the patients who received momelotinib, 40% had a splenic response at any time. The median duration of splenic response was not reached, whether patients were initially assigned to momelotinib or crossed over at 24 weeks.
Momelotinib led to encouraging rates of transfusion independence in both studies. In SIMPLIFY-1, the transfusion independence response at week 24 was 67% in the experimental arm compared with 49% in the control arm (P <.001). The median duration of transfusion independence has not been reached after >3 years of follow-up. In SIMPLIFY-2, the transfusion independence response at week 24 was 43% in the momelotinib arm and 21% in the control arm (P = .001).
In all, 35% of patients in the momelotinib arm had serious adverse events compared with 23% in the best available therapy arm. In addition, 6 patients in the experimental arm had adverse events leading to death, including acute myeloid leukemia (N = 2), respiratory failure (N = 2), cardiac arrest (N = 1), and bacterial sepsis (N = 1). There were 4 deaths in the best available therapy arm, resulting from sepsis (N = 2), lung adenocarcinoma (N = 1), and myelofibrosis (N = 1).
Myelofibrosis results from dysregulated JAK-STAT signaling and is characterized by constitutional symptoms, splenomegaly, and progressive anemia.
The global, randomized, double-blind phase 3 MOMENTUM clinical trial is enrolling an estimated 180 patients with myelofibrosis who are symptomatic, anemic, and have previously received a JAK inhibitor.
Patients will be randomized to momelotinib or to the steroid danazol (Danocrine). Crossover to momelotinib will be allowed after 24 weeks of therapy. The primary end point is total symptom score response rate with momelotinib compared with danazol at week 24. Top-line data are expected in the first half of 2022.