By Patrick Daly
December 6, 2023
Pelabresib in combination with ruxolitinib exhibited significant clinical activity and disease-modifying potential without treatment-limiting toxicities among patients with myelofibrosis (MF) in the ongoing phase II MANIFEST study, according to lead author, Raajit Rampal, MD, PhD, of the Memorial Sloan Kettering Cancer Center in New York City.
Pelabresib is an investigational oral small-molecule agent that inhibits BET-driven gene transcription that contributes to MF pathogenesis.
Following the findings of MANIFEST, Dr. Rampal and colleagues initiated the phase III MANIFEST-2 trial to further evaluate pelabresib plus ruxolitinib. Primary findings from MANIFEST-2 were presented at the 65th American Society of Hematology Annual Meeting & Exposition in San Diego, California.
The global, double-blind, active control study screened 591 patients at 138 sites, and ultimately randomized 431 Janus kinase inhibitor (JAKi)-naïve patients with primary MF, post-polycythemia vera MF, or post-essential thrombocythemia MF to either pelabresib plus ruxolitinib or placebo plus ruxolitinib.
Patients were eligible if they had a Dynamic International Prognostic Scoring System score of intermediate-1 or higher, platelet count of ≥100 × 109/L or greater, spleen volume of ≥450 cm3 or greater, two or more symptoms with an average score of three or greater on the Myeloproliferative Neoplasm Symptom Assessment Form (or a Total Symptom Score [TSS] of ≥10), peripheral blast count less than 5%, and an Eastern Cooperative Oncology Group performance status of two or less.
The primary endpoint was spleen volume reduction of ≥35% (SVR35) at week 24, and secondary endpoints included TSS changes, safety, pharmacokinetics, bone marrow fibrosis changes, progression-free survival, overall survival, and transfusion requirement and rates.
“MANIFEST-2 has completed recruitment and will provide definitive efficacy results of combination therapy in JAKi treatment-naïve pts with MF,” the authors stated, adding that “MANIFEST-2 will also provide important insights in assessing the benefits of starting treatment at an earlier stage of the disease.”
Reference
Rampal RK, Grosicki S, Chraniuk D, et al. Pelabresib in combination with ruxolitinib for Janus kinase inhibitor treatment-naïve patients with myelofibrosis: results of the MANIFEST-2 randomized, double-blind, phase 3 study. Abstract #628. Presented at the 65th ASH Annual Meeting & Exposition; December 9-12, 2023; San Diego, California.