December 5, 2020 - Momelotinib improved overall survival and sustained efficacy outcomes in patients with intermediate- or high-risk myelofibrosis.
Momelotinib improved overall survival (OS) 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 trials.1,2
Lead author Srdan Verstovsek, MD, PhD, presented the data during the 62nd American Society of Hematology Annual Meeting. He said momelotinib conveyed a treatment benefit in both patients who had 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, with an overall survival of more than 34.3 months and 37.5 months observed in the 2 treatment arms of SIMPLIFY-2 to compare very favorably with overall survival previously reported in patients who discontinued JAK inhibitor therapy and received salvage therapy,” said Verstovsek, chief of the section for myeloproliferative neoplasms in the Department of Leukemia at The University of Texas MD Anderson Cancer Center.
This analysis includes findings from a total of 558 patients treated in the SIMPLIFY-1 (NCT01969838) and SIMPLIFY-2 (NCT02101268) trials comparing momelotinib versus ruxolitinib (Jakafi) or best available therapy (BAT). Patients in the trials entered a 24-week randomization treatment phase, followed by an opportunity for extended momelotinib treatment for all patients. Patients in SIMPLIFY-1 were naïve to ruxolitinib while patients in the second trial had received prior treatment. Splenic response rate was the primary endpoint in both studies.
In SIMPLIFY-2, the median OS was 34.3 months for patients originally assigned to momelotinib and 37.5 months (HR = .96; P = .86) for those assigned to ruxolitinib/BAT who subsequently crossed over to the experimental drug. Verstovsek called that the best OS reported for patients previously treated with ruxolitinib.
In SIMPLIFY-1, the median OS was not reached for patients initially treated with momelotinib compared with 53.1 months in patients who crossed over from the ruxolitinib arm (HR = .99; P = .97). Forty percent of patients who received momelotinib had a splenic response at any time. Median duration of splenic response was not reached whether patients were initially assigned to momelotinib or crossed over at 24 weeks.
Verstovsek said momelotinib produced robust transfusion independence (TI) in both studies. In SIMPLIFY-1, TI response at week 24 was 67% in the experimental arm compared with 49% in the control arm (P <.001). Furthermore, the median duration of TI has not been reached after more than 3 years of follow up. In SIMPLIFY-2, TI response at week 24 was 43% in the MMB arm and 21% in the control arm (P = .001).
In safety results from SIMPLIFY-2 published in 2018, the most common grade 3 or higher adverse events (AEs) were anemia (14% on momelotinib vs 14% on BAT), thrombocytopenia (7% vs 6%, respectively), and abdominal pain (1% vs 6%). Moreover, peripheral neuropathy occurred in 11% of those on momelotinib, one of which was grade 3, and in no patients on BAT.3
Thirty-five percent of patients in the momelotinib arm experienced serious AEs compared with 23% in the BAT arm. Six patients in the experimental arm experienced AEs leading to death—acute myeloid leukemia (n = 2), respiratory failure (n = 2), cardiac arrest (n = 1), and bacterial sepsis (n = 1). There were 4 such deaths in the BAT arm: 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. Momelotinib is a selective and orally bioavailable inhibitor of JAK1, JAK2, and ACVR1.
Drug maker Sierra Oncology is continuing its investigation of momelotinib in the global, randomized, double-blind phase 3 MOMENTUM clinical trial (NCT04173494). An estimated 180 patients with myelofibrosis who are symptomatic, anemic, and have been previously treated with a JAK inhibitor will be randomly assigned to momelotinib or danazol (Danocrine). Following 24 weeks of therapy, patients on the danazol arm will be permitted to cross over to the momelotinib arm.
The primary endpoint is total symptom score (TSS) response rate of momelotinib compared with danazol at week 24. Sierra Oncology expects to present top-line data in the first half of 2022.