Momelotinib superior to danazol in symptomatic and anemic myelofibrosis
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Momelotinib demonstrated statistically significant improvement in anemia measures, splenic response and total symptom score compared with danazol among patients with previously treated myelofibrosis, according to study results.
The findings of the randomized phase 3 MOMENTUM trial, presented during ASCO Annual Meeting, additionally showed no new adverse events associated with momelotinib (Sierra Oncology).
Rationale and methods
“We conducted the MOMENTUM study to complete the body of data that would definitively address the degree of benefit achievable with momelotinib. Prior studies had strongly suggested that the agent could provide substantial benefit for patients with myelofibrosis, but those prior studies were not as definitive as we had hoped,” Ruben A. Mesa, MD, FACP, executive director of Mays Cancer Center at UT Health San Antonio MD Anderson Cancer Center, and a HemOnc Today Editorial Board member, told Healio.
“Physicians and health authorities were interested in taking a deeper look at the potential benefit of momelotinib for patients with myelofibrosis who were previously treated with an approved Janus kinase (JAK) inhibitor and were symptomatic and anemic, which is an area of great unmet need,” he said.
Investigators randomly assigned patients 2:1 to 200 mg/day momelotinib plus danazol placebo or 600 mg/day danazol plus momelotinib placebo for 24 weeks followed by the option of open-label momelotinib.
Total symptom score response rate at 24 weeks served as the primary endpoint, and secondary endpoints included red blood cell transfusion independence rate, splenic response rate, change from baseline in total symptom score and rate of zero transfusions since baseline.
Key findings
“The goal of the study was to demonstrate that momelotinib was significantly better than danazol in improving symptoms and splenomegaly and could address anemia at least as well as danazol in patients who were symptomatic, anemic and previously treated with a JAK inhibitor,” Mesa said. “The study was very successful in doing so and met the primary and all key secondary endpoints.”
Results showed most patients in the momelotinib group experienced symptom improvement, and 24.6% achieved at least a 50% improvement in total symptom score by week 24 compared with 9.2% in the danazol group (P = .0095).
Moreover, the momelotinib group had higher rates of transfusion independence (30.8% vs. 20%; one-sided P = .0064), and splenic response rates of 35% or greater (23.1% vs. 3.1%) and 25% or greater (40% vs. 6.2%).
Momelotinib also demonstrated a trend toward improved OS up to week 24 and overall.
“All of this was achieved in a very advanced, vulnerable patient population. Patients were generally highly symptomatic and anemic, and many were also thrombocytopenic,” Mesa said.
Grade 3 or worse adverse events during the randomized treatment period occurred in 15% of those in the momelotinib group vs. 17% in the danazol group, and serious treatment adverse events occurred in 35% vs. 40%. The most frequent nonhematologic adverse events included diarrhea, nausea, asthenia, pruritus and increased blood creatinine.
“The effects of the agent on symptoms, anemia and the spleen were consistent with previous studies and confirmed the importance of the JAK inhibitor taper and washout for the study of patients with previously treated myelofibrosis,” Mesa said. “There had been limited data previously on danazol in patients with myelofibrosis, and the study demonstrated that danazol was an active comparator with some effect on symptoms and the spleen, in addition to the expected impact on need for transfusions.”
Looking ahead
These results support future FDA approval of momelotinib and likely approval by health authorities in other countries, Mesa said.
“If this occurs, it means that momelotinib could be commercially available for patients with myelofibrosis and anemia some time in 2023,” Mesa said. “Anemia of myelofibrosis is strongly correlated with reduced quality of life and a decrease in OS. Half of all patients with myelofibrosis present with anemia at diagnosis and virtually all become anemic over time.”
Currently approved JAK inhibitors address symptoms and the spleen but have had limited efficacy for improving anemia or may worsen it, he added.
“It’s wonderful to know that we may soon have a new treatment option for patients to effectively and holistically address the key manifestations of disease regardless of baseline anemia or, largely, thrombocytopenia,” Mesa said. “Based on the positive data from MOMENTUM, as well as data from the previous phase 3 studies, the manufacturer is actively working on the new drug application for submission to the FDA, which will be followed by a mobile medical app submission to European Medicines Agency. There is also ongoing preparation for commercial launch in the U.S. in 2023 following anticipated FDA approval.”
Given momelotinib’s ability to address anemia, symptoms and the spleen without impacting platelet counts, researchers are interested to see how the agent may combine with other innovative therapies, such as BET inhibitors, to potentially improve outcomes in patients with myelofibrosis, Mesa added.
“We are actively exploring a potential study of momelotinib in combination with SRA515, our recently acquired BET inhibitor, for this patient population and are also exploring potential options to study momelotinib as monotherapy or in combination for other indications,” he said.
For more information:
Ruben A. Mesa, MD, FACP, can be reached at mesar@uthscsa.edu.
Perspective
Back to TopCaitlin O’Neil, MD
Mesa and colleagues conducted this study as a follow-up of SIMPLIFY-2, a randomized phase 3 study of momelotinib vs. best available therapy among patients with myelofibrosis previously treated with a JAK inhibitor. Results of SIMPLIFY-2 suggested momelotinib may improve anemia, transfusion requirements and symptom burden in patients who have failed or are unable to tolerate ruxolitinib (Jakafi, Incyte).
In the MOMENTUM study, the authors concluded that in patients with symptomatic and anemic myelofibrosis patients, momelotinib was superior to danazol for symptom responses, transfusion requirements and spleen responses, with comparable safety and favorable survival.
These results are encouraging, as they show momelotinib to be an effective second-line agent for patients with myelofibrosis who fail or are unable to tolerate other JAK inhibitors and for whom limited options exist outside of a clinical trial or hematopoietic stem cell transplant. Of particular interest is the reduction in transfusion requirements and the low rate of new or worsening anemia with momelotinib, as cytopenias are a common toxicity of JAK inhibitors and often lead to treatment discontinuation.
Long-term studies will be needed to assess duration of response to momelotinib and the overall survival benefit in this population.
Reference:
Harrison CN, et al. Lancet. 2017;doi:10.1016/S2352-3026(10)30237-5.
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Mesa RA, et al. Abstract 7002. Presented at: ASCO Annual Meeting; June 3-7, 2022; Chicago.
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