Post Hoc Analysis of Phase III Gecacitinib Clinical Trial Outcomes: Enhanced Understanding and Implications

Background: Myelofibrosis clinical manifestations typically include significant splenomegaly, high symptom burden and severe anemia. A phase III study (ZGJAK016) of gecacitinib (also known as jaktinib) met its primary endpoint, demonstrating 64.8% patients with a spleen volume reduction of ≥35% from baseline at week 24, along with favorable benefits in symptoms and anemia (presented at the European Hematology Association Hybrid Congress 2024). Herein, we present additional efficacy data that complement the positive findings from the ZGJAK016 study. Methods: A total of 105 myelofibrosis patients were included in the study (71 patients were randomized to gecacitinib and 34 to hydroxyurea). Key endpoints included changes in spleen length assessed by palpation, individual symptom score improvements, and transfusion independence rate. Transfusion independence was defined as not requiring red blood cell transfusion (except in cases of clinically overt bleeding) for ≥12 weeks, with hemoglobin ≥80 g/L. Results: Baseline characteristics were similar between treatment groups. The median spleen lengths were 15.0 cm and 13.3 cm in the gecacitinib and hydroxyurea groups. The median total symptom scores were 20.0 points and 19.0 points, respectively. A total of 77 (73.3%) symptomatic patients had a baseline total symptom score of ≥10 points (50 [70.4%] in the gecacitinib group and 27 [79.4%] in the hydroxyurea group). A lower proportion of patients in the gecacitinib group were transfusion-independent at baseline compared to hydroxyurea (70.4% vs. 76.5%). At Week 2, mean percentage changes from baseline in spleen length were -25.1% and -6.4% in the gecacitinib and hydroxyurea groups, with a higher proportion of patients achieving in a ≥50% decrease in palpable spleen length in the gecacitinib than in the hydroxyurea group (17.4% vs. 0, respectively). 84.5% for gecacitinib and 61.8% for hydroxyurea achieved a ≥50% total symptom score reduction from baseline at any time (p = 0.0109). At Week 24, significant symptom improvement was observed in the gecacitinib group for each individual item, with mean percentage changes from baseline exceeding 50% in almost all cases (fatigue: -52.5%; early satiety: -59.7%; abdominal discomfort: -62%; inactivity: -39.6%; problems with concentration: -44.7%; night sweats: -87.7%; fever: -59.8%; weight loss: -87.6%; itching: -65.1%; and bone pain: -50.6%). In the symptomatic population, patients treated with gecacitinib showed higher rates of symptom improvement-defined as a decrease of at least 2 points-compared to those who received hydroxyurea in most individual items. This was particularly notable in night sweats (69.4% vs. 38.5%). Transfusion independence rates at Week 24 were achieved by 60.6% of 71 patients in the gecacitinib group and 38.2% of 34 in the hydroxyurea group, with a rate difference of 22.8% (95% CI, 3.1% to 42.5%; p = 0.0288). A steady increase in mean hemoglobin levels over time has been observed in patients with a baseline level of less than 100 g/L. Conclusions: The findings indicate that gecacitinib not only reaffirms its high efficacy in splenic size reduction but also demonstrates a rapid onset of action. In terms of symptom improvement, it significantly alleviated a range of symptoms, particularly in symptomatic patients. Regarding anemia, gecacitinib enhanced transfusion independence as evidenced by a higher transfusion independence rate at Week 24 compared to hydroxyurea, with comparable baseline characteristics. The ZGJAK016 study validates the critical role of gecacitinib in addressing the core treatment needs of myelofibrosis patients.