Symptomatic benefit of momelotinib in patients with MF

The symptomatic burden of myelofibrosis (MF) can significantly impact patient quality of life (QoL), prognosis, and overall survival. Momelotinib, a selective oral inhibitor of Janus kinase (JAK) 1, JAK2, and activin A type 1 receptor (ACVR1), is used in the treatment of MF.¹

The MPN Hub has previously reported on the phase III SIMPLIFY-1 and SIMPLIFY-2 clinical trials of momelotinib for MF. In SIMPLIFY-1, JAK inhibitor-naïve patients with MF received either momelotinib or ruxolitinib; in SIMPLIFY-2, patients previously treated with ruxolitinib received either momelotinib or best available therapy (BAT), which was ruxolitinib in the majority (88.5%) of patients. Spleen volume reduction and total symptom score (TSS) improvement were recorded in both trials.¹

In a recent publication in Cancer Medicine, Mesa et al. analyzed symptom reduction data of momelotinib in MF, using longitudinal change from baseline in TSS over the course of the SIMPLIFY trials. The MPN Hub is pleased to summarize their findings below.

Study design¹

TSS and patient reported outcomes from the SIMPLIFY trials were analyzed using a mixed-effect model repeated measure across the 24 weeks of the study. TSS was established using a modified Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF), with which patients reported on the severity of their symptom burden using a scoring system from 0–10, with 10 being the most extreme.

Symptom reduction was analyzed using two measures:

1. Comparison of TSS from baseline vs average TSS at any point, taken from the 28 previous daily scores across the 24-week trial period.
2. Comparison of individual item scores; for each symptom, a change from baseline within 1 point was classified as stable, whilst a change of 2 or more in either direction indicated improvement/decline.

Results¹

Change in TSS
In SIMPLIFY-1, the average TSS score decreased across both the overall and symptomatic population for patients receiving momelotinib and ruxolitinib. These changes exceeded the predefined non-inferiority margin of −3.38 and −8.0 for overall and symptomatic populations, respectively.

Data from SIMPLIFY-2 concurs with the momelotinib cohorts from SIMPLIFY-1, demonstrating a consistent decrease over 24 weeks. Both the overall and symptomatic groups concluded with a higher overall TSS score in the BAT arm, suggesting symptom worsening. The change in average TSS score in all cohorts from baseline to Week 24, following treatment with momelotinib or ruxolitinib in SIMPLIFY-1 and momelotinib vs BAT in SIMPLIFY-2, is outlined in Table 1.

Table 1. MMRM-based TSS change from baseline in SIMPLIFY-1 and SIMPLIFY-2*

Individual symptom score

The majority of patients experienced stability or improvement in symptom severity across all groups. In SIMPLIFY-1, the overall population experienced similar rates of symptom improvement in both the momelotinib and ruxolitinib arms. However, in SIMPLIFY-2, the overall and symptomatic populations treated with momelotinib experienced higher symptom improvement and stability rates than patients who received BAT. The frequency of improvement, decline, and stability by individual symptom for each cohort is recorded in Figure 1.

Figure 1. Percent improved, stable, or declined on MPN-SAF TSS items by treatment group in SIMPLIFY-1 A overall and B symptomatic populations, SIMPLIFY-2 C overall and D symptomatic populations* 

BAT, best available therapy; MMB, momelotinib; MPN-SAF, Myeloproliferative Neoplasm Symptom Assessment Form; RUX, ruxolitinib; TSS, total symptom score.
*Adapted from Mesa, et al.

Conclusion

Data from SIMPLIFY-1 demonstrated similar rates of symptom reduction for both momelotinib and ruxolitinib, suggesting comparable efficacy but non-superiority. The SIMPLIFY-2 data complements this, demonstrating the superiority of momelotinib compared with BAT and indicating its potential for symptom relief in MF JAK inhibitor-naïve and JAK inhibitor-exposed patients.