Momelotinib vs fedratinib safety in MF: Indirect treatment comparison

Janus kinase inhibitors (JAKi) represent a mainstay of myelofibrosis (MF) treatment.¹ The JAKi momelotinib demonstrated a consistent benefit in improving anemia, symptom burden, and spleen volume in patients with MF across three phase III trials previously covered by the MPN Hub; MOMENTUM (NCT04173494), SIMPLIFY 1 (NCT01969838), and SIMPLIFY 2 (NCT02101268).

JAKi safety profiles vary, and some approved JAKi are associated with hematologic toxicity. The phase III SIMPLIFY 1 trial (NCT01969838) directly compared momelotinib with ruxolitinib and demonstrated that momelotinib offered a more favorable hematologic toxicity profile. However, there are limited data comparing momelotinib with other JAKi such as fedratinib, which is currently licensed for the treatment of MF.

To address this, Masarova and colleagues performed an indirect treatment comparison of safety outcomes between momelotinib and fedratinib in patients with MF.¹ We are pleased to summarize the findings presented by Masarova at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting.

Study design

• A matching-adjusted indirect comparison was used to compare the safety outcomes of momelotinib and fedratinib from phase II/III trials.

• After adjustment, effective momelotinib sample sizes were 151.1 JAKi-naïve and 79.4 JAKi-experienced patients (Table 1).

• Patient demographics and characteristics were well balanced across treatment and exposure categories.
• Treatment-emergent adverse events that occurred in ≥10% of patients in any treatment arm over 24 weeks were evaluated.
  • For fedratinib, evaluable outcomes were those reported in regulatory documents and peer-reviewed manuscripts.
  • Primary outcomes were Grade 3/4 anemia and thrombocytopenia.
  • Other outcomes occurring in ≥10% of patients were considered secondary outcomes.

Table 1. Patient populations for the indirect safety comparison*

ESS, effective sample size; JAKi, Janus kinase inhibitor. *Adapted from Masarova.1
Prior JAKi exposure			JAKi naïve
Before adjustment		After adjustment	Before adjustment		After adjustment
Fedratinib	Momelotinib	Momelotinib	Fedratinib	Momelotinib	Momelotinib
JAKARTA2; n = 97	SIMPLIFY-2 and MOMENTUM; n = 215	ESS = 79.4	JAKARTA; n = 97	SIMPLIFY-1; n = 212	ESS = 151.1

Results

• Risk of any grade or Grade 3/4 anemia, diarrhea, nausea, and serious adverse events leading to dose reductions were statistically less likely with momelotinib versus fedratinib in both JAKi naïve and JAKi experienced populations (Table 2).
• Any grade or Grade 3/4 thrombocytopenia was also less likely with momelotinib versus fedratinib; significantly so in JAKi-naive patients (Table 2).
• Odds/risk of other outcomes assessed varied in significance (Table 2).
• No identified outcomes were statistically less likely with fedratinib (Table 2).

Table 2. Risk differences in safety outcomes with momelotinib versus fedratinib in patients with MF*

AE, adverse event; JAKi, Janus kinase inhibitor; TEAE, treatment-emergent AE. *Adapted from Masarova.1 †All grades.
Risk difference	JAKi-experienced patients	JAKi-naïve patients
Anemia
All grades	−34.14	−36.98
Grade 3/4	−41.85	−85.34
Thrombocytopenia
All grades	−5.44	−8.23
Grade 3/4	−4.63	−42.70
Diarrhea†	−29.65	−48.16
Headache†	0.01	4.21
Dizziness†	2.61	—
Abdominal pain†	1.05	−4.41
Nausea†	−40.22	−49.25
Fatigue†	−1.23	0.42
All AEs (Grade 3/4)	−10.00	−34.22
Serious AEs	3.45	−13.89
TEAEs (discontinuation)	−8.79	−1.46
TEAEs (dose reduction)	−35.33	−30.23

Conclusion

Momelotinib demonstrated a favorable safety profile compared with fedratinib in both JAKi-naive and -experienced patients, including a significantly lower risk of key hematologic adverse events, diarrhea, and nausea over 24 weeks. These data support the use of momelotinib for the treatment of patients with MF, regardless of prior JAKi exposure.