Addition of navitoclax to ruxolitinib improves spleen volume reduction in patients with myelofibrosis
For patients with myelofibrosis, there remains a substantial unmet need for therapies that alter disease trajectory, improve outcomes, and enhance survival. Results from the phase III TRANSFORM-1 study demonstrated that combining navitoclax with ruxolitinib produced significant reductions in spleen volume by at least 35% at week 24 (SVR35W24) compared with ruxolitinib plus placebo, but did not lead to significant changes in total symptom score.
In combination with the Janus kinase inhibitor (JAKi) ruxolitinib, navitoclax, an orally available inhibitor of anti-apoptotic B-cell lymphoma 2 proteins (BCL-XL, BCL-2, BCL-W), was shown to have pronounced antitumour activity in patients with myelofibrosis (MF) in the phase II REFINE trial. TRANSFORM-1 is an ongoing, phase III, double-blind, placebo-controlled study evaluating the safety and efficacy of navitoclax plus ruxolitinib compared with placebo plus ruxolitinib in JAK2i-naïve adults with MF.
Study design
TRANSFORM-1 enrolled adult patients with intermediate-2 or high-risk MF with measurable splenomegaly, evidence of MF-related symptoms, no prior JAK2i treatment, and an ECOG Performance Score ≤2. The trial randomised patients (1:1) to receive navitoclax (starting dose of 200 mg [platelet >150 × 109/L] or 100 mg escalated to 200 mg once daily if tolerated after ≥7 days [platelet ≤150 × 109/L]) or placebo, plus ruxolitinib at label dose, based on stratification factors of intermediate-2 vs. high-risk MF and platelet ≤200 × 109/L vs. >200 × 109/L. The primary endpoint was reductions in spleen volume by at least 35% at week 24 (SVR35W24). Secondary endpoints included change in total symptom score at week 24 (TSSW24) assessed using 7-item MFSAF v4.0 (scale 0–70), SVR35 at any time, duration of SVR35, anaemia response (per International Working Group criteria), reduction in marrow fibrosis, overall survival, leukaemia-free survival, reduction in PROMIS Fatigue scale, and improvement in EORTC QLQ-C30 physical functioning scale.
Results
In total, 125 patients were randomised to navitoclax plus ruxolitinib and 127 patients to placebo plus ruxolitinib. Most patients were male (57%), median age was 69 years and patient demographics were well balanced between both treatment arms. After a median follow-up of 14.9 months, TRANSFORM-1 met its primary endpoint, with 79 patients (63.2%) in the navitoclax plus ruxolitinib arm achieving SVR35W24 compared with 40 patients (31.5%) in the control arm (p< 0.0001). Notably, SVR35 at any time was achieved by 76.8% of patients treated with navitoclax plus ruxolitinib compared with 41.7% of patients treated with placebo and ruxolitinib. Median time to first SVR35 response was respectively 12.3 weeks and 12.4 weeks. Median duration of SVR35 was not reached in the navitoclax plus ruxolitinib arm compared with 19.4 months in the control arm. At Week 24, the mean change in TSS from baseline was -9.7 with navitoclax plus ruxolitinib compared with -11.1 with placebo and ruxolitinib (p= 0.2852).
Grade ≥3 adverse events (AEs) were reported by 85% and 70% of patients treated in the navitoclax- and control-arm, respectively. The most common AEs (>30% of patients receiving navitoclax) were thrombocytopenia, anaemia, diarrhoea, and neutropenia. Serious AEs were experienced by 26% of patients with navitoclax and ruxolitinib and 32% with placebo and ruxolitinib. In the navitoclax arm, AEs led to navitoclax dose reduction in 81% of patients and interruption in 70% patients, of which respectively 67% and 52% were due to thrombocytopenia, respectively. Of all enrolled patients, 33% discontinued study treatment. The most common primary reason in both arms was due to AEs (14% in the navitoclax-arm and 11% in the placebo-arm). Thirteen deaths (10%) were reported in each arm. Of them, 6 patients in the navitoclax arm and 5 patients in the placebo arm died within 30 days after the administration of the final dose.
Conclusion
The TRANSFORM-1 study demonstrated that the combination of navitoclax and ruxolitinib led to an SVR35W24-rate that was twice as high as with ruxolitinib plus placebo, with durable responses. Although AEs of thrombocytopenia and anaemia were common, they were manageable with dose modifications, without any clinically significant sequalae.
Reference
Pemmaraju N, et al. TRANSFORM-1: a randomized, double-blind, placebo-controlled, multicenter, international phase 3 study of navitoclax in combination with ruxolitinib versus ruxolitinib plus placebo in patients with untreated myelofibrosis. Presented at ASH 2023; Abstract 620.
