Matching-Adjusted Indirect Comparison of Gecacitinib, Fedratinib, Pacritinib, and Momelotinib in Second-Line Myelofibrosis Therapy.
Key claim: In ruxolitinib-pretreated myelofibrosis, matching-adjusted indirect comparison found gecacitinib superior on spleen-volume and symptom responses versus fedratinib, pacritinib, and momelotinib, with lower gastrointestinal adverse-event and discontinuation rates.
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.
Why this matters
Second-line JAK inhibitor choice in ruxolitinib-failure myelofibrosis is a recurring symptom-management decision without head-to-head trials, so indirect comparisons carry disproportionate weight for spleen- and symptom-directed sequencing. This MAIC positions gecacitinib favorably on both spleen and TSS responses while flagging lower GI toxicity — the discontinuation driver that most often undermines symptom benefit in this setting. MAIC methodology limits causal inference, so the ranking is hypothesis-generating rather than definitive.