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Pelabresib Plus Ruxolitinib Reduces Splenomegaly, Improves Anemia Among JAK-Inhibitor-Naive Patients With Myelofibrosis
Updated Phase 3 Results from the MANIFEST-2 Study
Updated Phase 3 Results from the MANIFEST-2 Study
According to updated phase 3 results from the MANIFEST-2 trial, pelabresib plus ruxolitinib (PELA+RUX) significantly reduced splenomegaly and improved anemia and bone marrow fibrosis (BMF) at week 24 compared with placebo plus ruxolitinib (PBO+RUX) among Janus kinase (JAK) inhibitor-treatment-naïve patients with myelofibrosis (MF). This data was presented at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, Illinois.
In this study, investigators randomized 430 patients as of Aug 31, 2023. Eligible participants in the sutdy had a Dynamic International Prognostic Scoring System (DIPSS) score ≥ INT-1, platelet count ≥100 × 109/L, spleen volume ≥450 cm3, ≥2 symptoms with an average score ≥3 or total symptom score (TSS) ≥10 (Myelofibrosis Symptom Assessment Form [MFSAF] v4.0), peripheral blast count <5%, and Eastern Cooperative Oncology Group (ECOG) PS ≤2. Patients were randomized on a 1-to-1 basis, and pelabresib or placebo was administered once a day for 14 consecutive days of 21, with ruxolitinib twice a day for 21 days (1 cycle). It was noted that the primary end point was ≥35% spleen volume reduction from baseline at week 24.
Results showed at week 24, 65.9% vs 35.2% (P <0.001) of patients had a spleen volume reduction (SVR)35 response in the PELA+RUX vs PBO+RUX arms, respectively. Additionally, SVR35 responders at any time were 80.4% vs 50%; 80% vs 63% of responders reached SVR35 at the week 12 scan; 83.7% vs 79.6% maintained response at cutoff. The mean change in absolute TSS was -15.99 (SE 1.028) vs -14.05 (SE 0.986) (P = 0.0545), and the TSS reduction 50 was 52.3% vs 46.3% (P = 0.216) at week 24.
Furthermore, there was a 2-fold difference among patients with both SVR35 and TSS50 with PELA+RUX (40.2%) vs PBO+RUX (18.5%). Hemoglobin (hb) response occurred in 10.7% vs 6% of patients, with differences in mean hemoglobin levels maintained at 48 weeks. Among patients with anemia (Hb BL <10 g/dL), hemoglobin response occurred in 16.4% vs 14.1%. A total of 30.8% vs 39.8% of required red blood cell transfusion during the first 24 weeks. It was noted that BMF improvement ≥1 grade occurred among 38.5% vs 24.2% of patients (odds ratio 2.09; P=0.019).
Out of the 426 patients who were evaluated for safety, the most common treatment-emergent adverse event (≥20%) in the PELA+RUX vs PBO+RUX arms were anemia (43.9% vs 55.6% [Grade ≥3, 23.1% vs 36.4%]), thrombocytopenia (32.1% vs 23.4% [9% vs 5.6%]), platelet count decreased (20.8% vs 15.9% [4.2% vs 0.9%]), and diarrhea (23.1% vs 18.7% [0.5% vs 1.4%]).
“Results support a potential paradigm shift to combination therapy for MF,” concluded lead author Raajit Rampal, MD, PhD, Memorial Sloan Kettering Cancer Center, New York, New York and colleagues.
“PELA+RUX significantly and durably reduced splenomegaly, with a trend toward reduced TSS, and improved anemia and BMF at [week] 24 compared with PBO+RUX in JAKi treatment-naïve pts with MF, addressing key hallmarks of MF,” they added.
Source:
Rampal R, Grosicki S, Chraniuk D, et al. Updated safety and efficacy data from the phase 3 MANIFEST-2 study of pelabresib in combination with ruxolitinib for JAK inhibitor treatment-naïve patients with myelofibrosis. Presented at the ASCO Annual Meeting. May 31-June 4, 2024; Chicago, IL. Abstract 6502
