Résumé
Background: Janus kinase inhibitors (JAKis) provide symptom improvement and spleen volume reduction in patients with primary, post-polycythemia vera, and post-essential thrombocythemia myelofibrosis (MF). There remains a substantial unmet need for therapies that alter disease trajectory, improve outcomes, and enhance survival. The COMFORT-1 and -2 studies established JAKi monotherapy as standard-of-care with spleen volume reduction of ≥35% at Week 24 (SVR 35W24) of 42% and SVR 35W48 of 29%, respectively. In combination with the JAKi ruxolitinib, navitoclax, an orally available inhibitor of antiapoptotic B-cell lymphoma 2 proteins (BCL-X L, BCL-2, BCL-W), was shown to have pronounced antitumor activity in patients with MF in the phase 2 REFINE trial (NCT03222609). TRANSFORM-1 is an ongoing, phase 3, double-blind, placebo-controlled, multicenter, international study evaluating the safety and efficacy of navitoclax plus ruxolitinib (NAV + RUX) compared with placebo plus ruxolitinib (PBO + RUX) in JAK2i-naïve adults with MF. Methods: TRANSFORM-1 (NCT04472598) enrolled adult patients with intermediate-2 or high-risk MF with measurable splenomegaly, evidence of MF-related symptoms, no prior JAK2i treatment, and ECOG Performance Score ≤2. Patients were randomized 1:1 to receive NAV (starting dose of 200 mg [platelet {PLT} >150 × 10 9/L] or 100 mg escalated to 200 mg once daily if tolerated after ≥7 days [PLT ≤150 × 10 9/L]) or PBO, plus RUX at label dose, based on stratification factors of intermediate-2 vs high-risk MF and PLT ≤200 × 10 9/L vs >200 × 10 9/L. The primary endpoint was SVR 35W24. Secondary endpoints included change in total symptom score at Week 24 (TSS W24) assessed using 7-item MFSAF v4.0 (scale 0-70), SVR 35 at any time, duration of SVR 35, anemia response (per International Working Group criteria), reduction in marrow fibrosis, overall survival, leukemia-free survival, reduction in PROMIS Fatigue scale, and improvement in EORTC QLQ-C30 physical functioning scale. Exploratory endpoints include progression-free survival. Results: At data cutoff, April 13, 2023, 252 patients were enrolled with a median (range) follow-up of 14.9 (0.0-29.5) months; 125 patients were randomized to receive NAV + RUX and 127 to receive PBO + RUX. Most patients were male (57%), median (range) age was 69 (37-87) years, and patient demographics were similar between treatment arms ( Table 1). TRANSFORM-1 met its primary endpoint, with 79 patients (63.2%) in the NAV + RUX arm achieving SVR 35W24 compared with 40 patients (31.5%) in the PBO + RUX arm ( P<0.0001). Notably, SVR 35 at any time was achieved by 96 patients (77%) with NAV + RUX compared with 53 patients (42%) with PBO + RUX. Median (range) time to SVR 35 response was 12.3 (10.1-48.3) weeks with NAV + RUX versus 12.4 (11.3-72.3) weeks with PBO + RUX. Median duration of SVR 35 was not reached (NR) in the NAV + RUX arm compared with 19.4 months (95% CI 16.8, NR) in the PBO + RUX arm. At Week 24, the mean change in TSS from baseline was -9.7 (95% CI: -11.8, -7.6) with NAV + RUX compared with -11.1 (95% CI: -13.2, -9.1) with PBO + RUX arm ( P=0.2852). Grade ≥3 adverse events (AEs) were experienced by 85% of patients with NAV + RUX and 70% with PBO + RUX. The most common AEs (>30% of patients receiving NAV; Table 2) were thrombocytopenia, anemia, diarrhea, and neutropenia. Serious AEs were experienced by 26% of patients with NAV + RUX and 32% with PBO + RUX, including anemia (NAV + RUX: n=2; PBO + RUX: n=1), thrombocytopenia (NAV + RUX: n=2), and neutropenia (NAV + RUX: n=1). With NAV + RUX, AEs led to NAV dose reduction in 101 (81%) patients and NAV interruption in 87 (70%) patients of which 83 (67%) and 65 (52%) were due to thrombocytopenia, respectively. Of all enrolled patients, 83 (33%) discontinued study treatment; most common (>5% total patients) reason for NAV/PBO discontinuation were AEs (n=32; 39% of discontinuations) and physician decision (n=14; 17% of discontinuations). In each arm, 13 (10%) patients died; 6 with NAV + RUX and 5 with PBO + RUX died ≤30 days post-final dose. Conclusions: This first randomized trial in JAKi-naïve MF with NAV + RUX combination led to an SVR 35W24 rate that was twice as high as PBO + RUX ( P<0.0001). The responses were durable; AEs of thrombocytopenia and anemia were common but manageable with dose modification without any clinically significant sequalae. Additional evaluation is ongoing.