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Novel agents to treat MF with suboptimal response to ruxolitinib: Long-term outcome with momelotinib

Janus kinase (JAK)–signal transducer and activator of transcription (STAT) pathway dysregulation is central to the pathogenesis of myelofibrosis (MF), giving rise to progressive anemia, splenomegaly, and other, constitutional symptoms in patients with MF.1 The JAK1/JAK2 inhibitor (JAKi), ruxolitinib, was approved for the treatment of patients with primary and secondary intermediate-/high-risk MF in 2011, based on results showing significantly reduced spleen volume, improved MF-related symptoms and quality of life, and prolonged overall survival (OS).2 However, there remains an unmet clinical need for the effective management of patients with MF who need to discontinue JAKi therapy due to toxicity, as OS after JAKi discontinuation is short.

During the 62nd American Society of Hematology (ASH) Annual Meeting and Exposition, there were a number of presentations on the novel agents and treatment combinations under evaluation for patients with MF. The MPN Hub is happy to present a summary on the JAK1/JAK2 inhibitor and activin A receptor type I (ACVR1) activator, momelotinib, which has been proposed as a potentially promising treatment option for patients with MF, particularly those experiencing hematological toxicity and myelosuppression during JAKi therapy. At ASH 2020, Srdan Verstovsek, University of Texas MD Anderson Cancer Center, discussed the long-term outcome data from the phase III SIMPLIFY-1 (NCT01969838) and SIMPLIFY-2 (NCT02101268) trials evaluating momelotinib for patients with JAKi-naïve and JAKi-treated MF, respectively.

Study design

  • SIMPLIFY-1 and SIMPLIFY-2 (Figure 1) were non-inferiority and superiority studies, respectively, and each shared the same study endpoints:
    • Primary – splenic response rate at Week 24
    • Secondary – total symptom score and transfusion independence (TI) rate
  • Patients were initially randomized to receive ruxolitinib (best available treatment [BAT] was used in SIMPLIFY-2) or momelotinib. Open label momelotinib was available to all patients from Week 24 as shown in Figure 1.
  • Previous data have suggested that momelotinib improves constitutional symptoms, reduces transfusion burden and anemia, and has a favorable safety profile.3,4

Figure 1. Treatment schema for SIMPLIFY-1 and SIMPLIFY-2 evaluating momelotinib for MF1

 BAT, best available treatment; BID, twice daily; JAKi, Janus kinase inhibitor; LTFU, long-term follow-up; MF, myelofibrosis; QD, once daily; R/R, relapsed and/or refractory; SVR, spleen volume reduction.

Results

  • Encouraging OS results were observed across both the SIMPLIFY-1 and SIMPLIFY-2 studies, irrespective of whether patients were initially randomized to ruxolitinib/BAT or momelotinib as shown in Table 1.

Table 1. OS of patients enrolled in SIMPLIFY-1 and SIMPLIFY-21

HR, hazard ratio; NR, not reached; OS, overall survival.*Patients crossed over from treatment with ruxolitinib (or BAT in SIMPLIFY-2) to momelotinib at Week 24.
†Patients originally randomized to momelotinib.

Trial

Patient population

Median OS, months

HR

p

Ruxolitinib followed by  momelotinib*

Momelotinib

SIMPLIFY-1

JAKi-naïve

53.1

NR

0.99

0.97

SIMPLIFY-2

Ruxolitinib-exposed

37.5

34.3

0.96

0.86

  • Further analysis of SIMPLIFY-1 showed:
    • Stable hemoglobin and platelet levels during therapy allowed for full dose intensity treatment with momelotinib, whereas high rates of dose reductions were seen with ruxolitinib.
    • Spleen response rates were 27% for momelotinib and 29% for ruxolitinib, demonstrating non-inferiority to ruxolitinib at Week 24 (p < 0.001). Furthermore, 40% of patients achieved a splenic response with momelotinib at any time. Splenic responses were durable irrespective of whether patients were initially randomized to ruxolitinib/BAT or momelotinib, and the median duration of response was not reached at > 3 years of follow-up.
    • Landmark analysis of TI at 24 weeks showed better rates for momelotinib (67%) versus ruxolitinib (49%; p < 0.001). Median duration of TI response was not reached after 3 years.

Conclusion

Momelotinib demonstrated robust OS outcomes in both JAKi-naïve and JAKi-treated patients with MF that did not discriminate according to initial therapy. JAKi-naïve patients treated with momelotinib achieved splenic responses and sustained transfusion independence while showing only mild myelosuppression and no cumulative toxicity. This compares well with ruxolitinib, where thrombocytopenia-induced treatment interruption or discontinuation is more frequent.

The global effort to identify optimal therapies to manage patients with MF continues, and novel druggable targets and agents are being investigated in the MF setting. At ASH 2020, novel combination regimens with ruxolitinib were presented using navitoclax and KRT-232: read a summary here. For an overview of the novel agents for MF, read our review article here.

Additional resources

For more information on the long-term safety analyses of momelotinib in patients with MF, as determined in the SIMPLIFY-1/2 studies, click here.

During ASH 2020, the MPN Hub spoke to Steering Committee member Ruben Mesa, UT Health San Antonio, San Antonio, US, who discussed the long-term benefit of momelotinib in the SIMPLIFY-1+2 trials.

SIMPLIFY-1+2 trial: What is the long-term benefit of momelotinib treatment in R/R MF?

Watch the video below for an interview with Abdulraheem Yacoub, University of Kansas Medical Center, Kansas City, US, on the clinical value and potential of momelotinib for anemic patients with MF.

What is the clinical value and potential of momelotinib for anemic patients with myelofibrosis?

  1. Verstovsek S, Egyed M, Lech-Marańda E, et al. Robust overall survival and sustained efficacy outcomes during long term exposure to momelotinib in JAK inhibitor naïve and previously JAK inhibitor treated intermediate/high risk myelofibrosis patients. Oral abstract #54. 62nd ASH Annual Meeting and Exposition; Dec 5, 2020; Virtual.
  2. Verstovsek S, Gotlib J, Mesa RA, et al. Long-term survival in patients treated with ruxolitinib for myelofibrosis: COMFORT-I and -II pooled analyses. J Hematol Oncol. 2017;10(1):156. DOI: 1186/s13045-017-0527-7
  3. Mesa RA, Kiladjian J, Catalano JV, et al. SIMPLIFY-1: A Phase III randomized trial of momelotinib versus ruxolitinib in janus kinase inhibitor–naïve patients with myelofibrosis. J Clin Oncol. 2017;35(34):3844-3850. DOI: 1200/JCO.2017.73.4418
  4. Harrison CN, Vannucchi AM, Platzbecker U, et al. Momelotinib versus best available therapy in patients with myelofibrosis previously treated with ruxolitinib (SIMPLIFY 2): a randomised, open-label, phase 3 trial. Lancet Haematol. 2018;5(2):e73-e81. DOI: 1016/S2352-3026(17)30237-5

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