Evaluation of gecacitinib vs hydroxyurea in patients with intermediate-2 or high-risk myelofibrosis: final analysis results from a randomized phase 3 study

Abstract

To compare the efficacy and safety of gecacitinib (also known as jaktinib) with hydroxyurea (HU) in treating myelofibrosis (MF) patients. In this multicenter, randomized phase 3 trial (ZGJAK016), intermediate- or high-risk primarily JAK inhibitor naïve MF patients were assigned in a 2:1 ratio to receive either gecacitinib (100 mg twice a day, BID) or HU (500 mg BID). The primary endpoint was the proportion of patients with ≥35% reduction in spleen volume (SVR35) from baseline at week 24. Secondary endpoints included the best spleen response rate, the proportion of patients with a ≥50% reduction in total symptom score (TSS50), anemia improvement, and safety profile. At 24 weeks, the SVR35 was reached by 64.8% of patients on gecacitinib (46/71), compared to 26.5% on HU (9/34), P = 0.0002. The best spleen response rates were also superior for gecacitinib at 81.7%, vs 32.4% for HU, P < 0.0001. The TSS50 rates were 62.0% for gecacitinib- and 50% for HU-treated patients. Among non-transfusion-dependent patients with baseline hemoglobin (HGB) ≤ 100 g/L, 31.0% (13/42) in the gecacitinib group showed a ≥20 g/L increase in HGB, compared to 15.0% (3/20) in HU group. The common grade ≥ 3 treatment-emergent adverse events (TEAEs), including anemia (26.8% vs 44.1%), thrombocytopenia (15.5% vs 32.4%), leukopenia (2.8% vs 20.6%), and neutropenia (1.4% vs 20.6%), were less frequent with gecacitinib than HU. Treatment discontinuation due to TEAEs was lower in gecacitinib (7.0%) compared to HU (11.8%). Gecacitinib demonstrates superior efficacy and a more favorable safety profile compared to HU, making it a promising treatment option for managing MF, particularly in patients with anemia (This trial was registered with ClinicalTrials.gov, (NCT04617028)).

Fig. 1. Patient disposition.

^*One patient who discontinued the main study period early due to a ≥25% increase in spleen volume entered the extension period and crossed over to gecacitinib. ^†As of February 15, 2023, five patients (four in the gecacitinib group and one in the HU group) completing the main study period did not yet enter the extension period. HU hydroxyurea, AE adverse event.

Fig. 2. Change in spleen volume.

A Percentage change in spleen volume compared to baseline at week 24. B Proportion of patients achieving SVR35 (≥35% reduction in spleen volume) at each visit. C Proportion of patients achieving the best spleen response. HU hydroxyurea, CMH test stratified Cochran–Mantel–Haenszel test (Note: patients without week 24 spleen volume data [8 from the gecacitinib group and 10 from the HU group] are not included on the waterfall plot).

Fig. 3. Change in MPN-SAF TSS.

A Percentage change in TSS compared to baseline at week 24. B Proportion of patients achieving TSS50 (≥50% reduction in TSS) at each visit. HU hydroxyurea (Note: patients without week 24 TSS data or with TSS 0 at baseline [9 from the gecacitinib group and 10 from the HU group] are not included on the waterfall plot).

Fig. 4. Change in hemoglobin.

A Change in hemoglobin (HGB) relative to baseline at each visit. B Mean hemoglobin levels in patients by baseline levels of <100 g/L or ≥100 g/L (main study period). GCA gecacitinib, HU hydroxyurea, BL HGB baseline hemoglobin level.

Fig. 5. Change in platelet count.

Change in platelet relative to baseline at each visit. HU hydroxyurea, BL baseline.