B03 | PELABRESIB IN COMBINATION WITH RUXOLITINIB FOR JANUS KINASE INHIBITOR-NAIVE PATIENTS WITH MYELOFIBROSIS: 72-WEEK FOLLOW-UP WITH LONG-TERM EFFICACY OUTCOMES OF THE PHASE III MANIFEST-2

Background. Pelabresib (PELA) is an investigational, oral, small molecule inhibiting BET proteins and BET-mediated expression of genes involved in Myelofibrosis (MF) pathogenesis. The Phase III MANIFEST-2 study (NCT04603495) evaluates the efficacy and safety of PELA plus ruxolitinib (RUX) in MF patients (pts). We report Week 72 results, including PFS, OS and Leukemia Free Survival (LFS). Methods. Pts with a DIPSS ≥ Intermediate-1 risk, platelet ≥100 ×109/L, spleen volume ≥450 cm3, ≥2 symptoms with average score ≥3 or total symptom score (TSS) ≥10 (MF SAF v4.0), peripheral blasts <5%, and ECOG performance status ≤2 were randomized 1:1 to PELA+RUX or placebo (PBO)+RUX. Week 72 assessments included spleen volume reduction (SVR35) ≥35% from baseline (bsl), absolute TSS change, TSS50 (≥50% TSS reduction from bsl), hemoglobin (Hb) response (≥1.5 g/dL mean Hb increase from bsl without transfusion in prior 12 weeks), bone marrow fibrosis (BMF) grade improvement, and safety. PFS (time from randomization to progression, or death from any cause), OS, and LFS were analysed (study not powered for survival outcomes). Results. As of August 30, 2024, 67.8% (145/214) of pts in PELA+RUX arm and 72.7% (157/216) in PBO+RUX remained on study (median follow-up 92 weeks). SVR35, absolute TSS change, and ≥1 grade BMF improvement favored PELA+RUX (Table I). In pts with bsl Hb <10 g/dL, Hb response was observed in 20.9% (14/67; 95% CI: 11.16–30.63) vs 16.9% (12/71; 95% CI: 8.18–25.62) for PELA+RUX vs PBO+RUX. Of 426 pts, Grade ≥3 treatment-emergent adverse events (TEAEs) occurred in 65.1% vs 65.4%, Grade ≥3 anemia in 27.4% vs 41.1%, thrombocytopenia in 17.0% vs 7.0% for PELA+RUX vs PBO+RUX. Accelerated and blast-phase progression, adjudicated independently by external experts, was reported in 6.1% (13/214) vs 4.2% (9/214), respectively. Comparing PELA+RUX vs PBO+RUX, the PFS hazard ratio (HR) was 0.874 (95% CI: 0.49–1.56), OS HR 0.932 (95% CI: 0.53–1.66), and LFS HR 0.994 (95% CI: 0.57–1.72). Conclusion. At 72 weeks, PELA+RUX showed sustained improvements in splenic response, symptoms, SVR35/TSS50 dual response, BMF, and anemia vs PBO+RUX. Grade ≥3 TEAEs were similar and consistent between arms, with decreased imbalance in leukemic transformation over time and favorable trend in survival for PELA+RUX. Overall results suggest that PELA+RUX provides meaningful clinical benefits over RUX alone and support evidence of ongoing disease modification.