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Matching-Adjusted Indirect Comparison of Gecacitinib, Fedratinib, Pacritinib, and Momelotinib in Second-Line
Yi Zhang1,2, Hu Zhou3, Qike Zhang4
1Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Abstract:
Ruxolitinib is first-line therapy for intermediate/high-risk myelofibrosis (MF), but ∼50% of patients discontinue within 1 year due to loss of efficacy or intolerance. Four JAK inhibitors (gecacitinib, fedratinib, pacritinib, momelotinib) are approved for ruxolitinib-pretreated MF, with no head-to-head trials comparing their efficacy and safety. This study used matching-adjusted indirect comparison (MAIC) to compare these four agents, aiming to provide evidence-based insights for treatment decision-making in ruxolitinib-resistant or intolerant MF. Individual patient data (IPD) of gecacitinib (100 mg BID; ZGJAK006/ZGJAK017, n = 78) and published data of comparators (fedratinib: JAKARTA-2/FREEDOM2; pacritinib: PAC203; momelotinib: SIMPLIFY-2/MOMENTUM) were analyzed. Eight baseline characteristics were matched. Efficacy outcomes (week-24 SVR35, TSS50, transfusion independence [TI]) were reported as odds ratios (ORs); safety as risk differences (RDs). Gecacitinib showed superior SVR35 versus fedratinib (JAKARTA-2: OR = 3.96, 95% CI = 1.37-11.39, P = 0.0108), pacritinib (PAC203: OR = 6.10, 95% CI = 1.54-24.23, P = 0.0101), and momelotinib (SIMPLIFY-2: OR = 8.65, 95% CI = 1.86-40.31, P = 0.0060), and superior TSS50 versus pacritinib (OR = 7.62 95% CI = 1.84-31.51, P = 0.0050) and momelotinib (MOMENTUM: OR = 7.52, 95% CI = 1.63-34.61, P = 0.0096). Numerically, gecacitinib had better TI. It also had significantly lower incidences of diarrhea, nausea, and AE-related treatment discontinuation. Hematologic AE profiles of gecacitinib varied by comparator cohort. Gecacitinib showed favorable efficacy and tolerability signals versus several comparators, suggesting it may be a valuable second-line option.
Insights
Ruxolitinib discontinuation is common in myelofibrosis. Gecacitinib demonstrated superior efficacy and tolerability compared to fedratinib, pacritinib, and momelotinib in ruxolitinib-resistant or intolerant patients.
Area of Science:
- Hematology
- Oncology
- Pharmacology
Background:
- Ruxolitinib is a first-line treatment for intermediate/high-risk myelofibrosis (MF).
- Approximately 50% of patients discontinue ruxolitinib within one year due to loss of efficacy or intolerance.
- Four JAK inhibitors (gecacitinib, fedratinib, pacritinib, momelotinib) are approved for MF patients previously treated with ruxolitinib.
Purpose of the Study:
- To compare the efficacy and safety of four JAK inhibitors (gecacitinib, fedratinib, pacritinib, momelotinib) in patients with myelofibrosis resistant or intolerant to ruxolitinib.
- To provide evidence-based insights for treatment decision-making in the second-line setting of myelofibrosis management.
Main Methods:
- A matching-adjusted indirect comparison (MAIC) was performed using individual patient data (IPD) for gecacitinib and published data for comparator JAK inhibitors.
- Eight baseline characteristics were matched between the gecacitinib cohort and comparator cohorts.
- Efficacy outcomes (week-24 Symptomatic Response, Total Symptom Score reduction of 50% [TSS50], transfusion independence [TI]) were analyzed as odds ratios (ORs), and safety outcomes as risk differences (RDs).
Main Results:
- Gecacitinib showed significantly superior week-24 Symptomatic Response (SVR35) compared to fedratinib, pacritinib, and momelotinib.
- Gecacitinib demonstrated superior TSS50 compared to pacritinib and momelotinib.
- Gecacitinib exhibited numerically better transfusion independence (TI) and significantly lower incidences of diarrhea, nausea, and treatment discontinuation due to adverse events.
Conclusions:
- Gecacitinib presents favorable efficacy and tolerability signals when compared to fedratinib, pacritinib, and momelotinib in the second-line treatment of myelofibrosis.
- These findings suggest that gecacitinib may be a valuable therapeutic option for patients with myelofibrosis who are resistant or intolerant to ruxolitinib.
- Further head-to-head trials are warranted to confirm these comparative effectiveness findings.
