In an interview with Targeted Oncology, Aaron T. Gerds, MD, MS, discussed phase 3 MOMENTUM study and how it has impacted the clinical trial development of momelotinib for the treatment of patients with myelofibrosis.
Momelotinib, a JAK1/JAK2 inhibitor, has shown promising efficacy in various clinical trials including SIMPLIFY-1 (NCT01969838), SIMPLIFY-2 (NCT02101268), and most recently, in the phase 3 MOMENTUM study (NCT04173494).
Initially, momelotinib was designed for patients with myelofibrosis as a treatment option to help address enlarged spleens and symptom burden. Across multiple studies of momelotinib, investigators found the inhibitor to improve cases of anemia in this patient population.
Within MOMENTUM, momelotinib was compared with danazol in patients with myelofibrosis who had received prior treatment with a JAK inhibitor. The phase 3 trial included 195 patients who were symptomatic and anemic, and randomized them in a 2:1 ratio to receive momelotinib at a dose of 200 mg daily or danazol at a daily dose of 600 mg. The primary end point was total symptom score (TTS) response rate at week 24, with the key secondary end points of the trial including transfusion independence and splenic response rates at week 24.
Data presented during the 2022 American Society of Clinical Oncology showed that in the TSS response rate at week 24 was 24.6% (95% CI, 17.49%-32.94%) in the 130 patients who received momelotinib vs 9.2% (95% CI, 3.46%-19.02%) in those who were given danazol (n = 65; P = .0095). Participants were required to achieve at least a 50% reduction in TSS compared with baseline in order to establish superiority.
The baseline rates of transfusion independence were 13.1% with momelotinib vs with 15.4% with danazol. Momelotinib was shown to be superior when compared with danazol in regard to spleen response rate at week 24, at both the 25% and 35% reduction thresholds. Further, 40% (95% CI, 31.51%-48.95%) of patients who received momelotinib reached a 25% or higher reduction in spleen volume vs 6.2% (95% CI, 1.70%-15.01%) of the patients administered danazol (P < .0001).
Up to week 24, a trend of improved overall survival (OS) was seen with momelotinib vs danazol at 0.734 (95% CI, 0.382-1.409; P = .3510), with the hazard ratio for OS in the investigative and control arms up to week 24 meeting significance at 0.506 (95% CI, 0.238-1.076; P = .0719). A total of 23.1% (95% CI, 16.14%-31.28%) of patients administered momelotinib achieved reduction in spleen volume of at least a 35% vs 3.1% (95% CI, 0.37%-10.68%) for those enrolled in the danazol arm (P = .0006).
In an interview with Targeted OncologyTM, Aaron T. Gerds, MD, MS, assistant professor in Medicine (Hematology and Medical Oncology) at the Cleveland Clinic, further discussed phase 3 MOMENTUM study and how it has impacted the clinical trial development of momelotinib for the treatment of patients with myelofibrosis.
Targeted Oncology: How has momelotinib been previously examined for the treatment of patients with myelofibrosis? How have these trials impacted the development of this inhibitor?
Gerds: The MOMENTUM study is an important study in the development of momelotinib for the treatment of myelofibrosis. There have been other randomized phase 3 trials, the SIMPLIFY-1 and 2 trials, as well as a phase 2 scientific study that have been all completed. Again, MOMENTUM really represents the last stage in this drug development with an eye towards regulatory approval.
Early on, momelotinib was being developed as another JAK 1/2 inhibitor, with the goal of treating enlarged spleens and symptom burden in patients with myelofibrosis. Over the early phases of development, it was also noticed that patients treated with momelotinib have often had improvements in their anemia. Of course, anemia is a big problem in myelofibrosis. It's one of the diagnostic criteria for diagnosing myelofibrosis as well as it's very common and leads to significant reductions in quality of life and requires some time transfusions, which are course are intensive. Lastly, anemia is associated with a worse survival in patients with myelofibrosis. It represents a massive unmet need.
Current JAK inhibitors that are approved for the treatment of myelofibrosis do not necessarily improve anemia and often make anemia worse as a side effect. Again, all the more reason to explore this agent that could potentially improve anemia, and that was like the main focus of the MOMENTUM study.
What changes have been seen in the myelofibrosis space? What can be expected for the future?
This is the first of a series of randomized phase 3 trials are being completed in myelofibrosis. Myself and many others in the field expect the next couple of years to be a period of rapid growth and change.
In February, we already had a new drug approved, pacritinib, momelotinib is on docket for early 2023. We have pelabresib [CPI-0610] coming along in phase 3 trials, and navitoclax coming along with phase 3 trials. All these trials should be finishing in the next year or 2, and potentially moving us beyond JAK inhibitors for the space. Not only would we have 4 potential JAK inhibitors approved to treat patients, but we may have therapeutics outside of JAK inhibitors to treat these patients, which will be a massive change in the field.
Can you explain the methods and design of the phase 3 MOMENTUM trial?
It included patients with myelofibrosis who are symptomatic and had splenomegaly but were also anemic, many of which were transfusion dependent coming on the study. The key end points included freedom from transfusions as well as transfusion independence rate. The comparator arm was danazol and danazol was selected because it is often used to treat anemia in patients with myelofibrosis as recommended by both the the National Comprehensive Cancer Network and European Society for Medical Oncology guidelines. In this trial, 130 patients were randomized to mobilize they've been 65 are randomized to danazol and this was a prospective, blinded, randomized, control trial.
How do you interpret the findings of the study?
For the key end points, if we looked at transfusion independence rate, it was a non-inferiority analysis, meaning was momelotinib no worse than danazol at the proportion of patients at week 24 that were independent of transfusions. And in fact, that was not inferior.Thirty percent of patients were transfusion independent at that time, 0.20% of patients of danazol were independent at that point.
Another way of looking at getting no transfusions from the time one enrolled to the 24 week, primary evaluation, was a superiority analysis which showed that 35% of patients treated with momelotinib had 0 transfusions vs almost 17% of patients on the danazol arm requiring zero transfusions. This was some kind of nod to the anti-anemia effect of momelotinib, as well as danazol.
What were some of the key takeaways from the trial?
One of the other main things about this study is that this is the largest prospective and only blinded study of danazol ever completed. It was a comparator arm so not only are we getting important information about momelotinib, but we're getting important information about danazol as well.
The thing that really sticks out about momelotinib, in addition to the anemia responses that we were seeing, is the fact that the symptom burden improvements and spleen volume responses were on par with prior studies done with momelotinib. It is, first and foremost, a JAK inhibitor. We saw that 23% of patients had a reduction in speel volume of 35 of those treated with momelotinib vs 3.1% of patients treated with danazol. We saw that the total symptom score response rate, which was the primary end point of the study, 24% of patients treated with momelotinib had a TSS of 50%, where only 9.2% of patients treated with danazol had a TSS of 50%. This hit those key JAK inhibitor end points as well.
How does momelotinib compare with other JAK inhibitors currently being used in this space?
At the end of the day, the thing that catches your eye is the fact that not only is this a JAK inhibitor that performs on par with currently available JAK inhibitors, but it also has this anemia response. As we practice now, we often put patients on a JAK inhibitor, and then we'll have to give another medicine to improve the anemia, like an erythropoiesis stimulating agentin combination with the JAK inhibitor.
But this might be a one stop shop, 1 pill to rule them all where we can give JAK inhibition, along with treating the anemia, or at least trying to prevent the anemia from getting worse. I think it is a notable step forward in treatments for myelofibrosis and we all look forward to potentially having this drug commercially available sometime next year.
What further conclusions are investigators keeping an eye out for in regard to this research?
This was kind of a first pass at the primary end point for this study. There is the 24 week assessment, there's currently a data lock going on for the 48 week assessments, so we'll get longer term data. We want longer term data from this from this analysis and that's first and foremost. There was a hint at perhaps better survival for the momelotinib patients vs the danazol, but of course, more follow up is needed to parse that out. That would bring home the idea that anemia is associated with inferior survival. If we can do something to improve the anemia, we may improve survival. We want to bring that story full circle, so with this study. That's the next thing that we are all looking at.
The other big next step for this drug is the regulatory submission with anticipation of approval sometime early next year in 2023. That is beyond this study, as the 0% transfusion rate was not 100% from momelotinib nor was the transfusion in the independent rate 100%. There's still a long way to go to work on anemia. A simple concept would be, can we combine momelotinib nib, which treats the anemia of inflammatory disease with something that could promote erythropoiesis, likeluspatercept [Reblozyl], and try to make even more inroads on anemia, while still treating the symptoms of myelofibrosis, being enlarged spleens and cytokine mediated symptoms.
What advice can you offer to community oncologists wanting to learn more about this research?
As this drug moves closer to approval and becomes approved, partnering with tertiary centers that have experienced using momelotinib will be key in helping to identify which patients may benefit from this therapy.
Mesa RA, Gerds AT, Vannucchi A, et al. MOMENTUM: Phase 3 randomized study of momelotinib (MMB) versus danazol (DAN) in symptomatic and anemic myelofibrosis (MF) patients previously treated with a JAK inhibitor. J Clin Oncol 2022; 40 (suppl 16); 7002. doi: 10.1200/JCO.2022.40.16_suppl.7002