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Potential Emergence of Recently Approved Fedratinib in the Myelofibrosis First-Line Treatment Landscape

Conference Correspondent

Myelofibrosis (MF) is a bone marrow cancer associated with scarring, anemia, and an enlarged spleen. Currently, the only approved first-line treatment is ruxolitinib (RUX), a JAK1/2 inhibitor. However, alternative therapeutic options are needed as a high proportion of patients with MF discontinue RUX treatment because of loss of efficacy and intolerance. Fedratinib (FEDR), a selective JAK2 inhibitor, emerged as a possible candidate after recently receiving approval in multiple countries, including the United States, Canada, European Union, and the United Kingdom, as first-line therapy for MF in patients previously treated with RUX. Although FEDR demonstrated promise in the phase 2 JAKARTA2 trial, comparative studies have not been initiated until now.

The current phase 3 trial, FREEDOM2 (current enrollment = 160), is designed to evaluate the safety and efficacy of the 400-mg/day dose of FEDR (n = 128) compared with best available treatments (n = 64), such as RUX and other JAK inhibitors, in patients diagnosed with MF who received prior RUX therapy. FREEDOM2 also investigates gastrointestinal adverse event risk mitigation strategies as well as thiamine monitoring and supplementation. FREEDOM2 is currently enrolling patients aged ≥18 years relapsed or refractory to previous treatment with RUX for a minimum of 3 months or became intolerant to RUX after a minimum of 28 days of daily therapy.

Patients must be diagnosed with primary, post-polycythemia vera, or post-essential thrombocythemia MF with Dynamic International Prognostic Scoring System intermediate-2 or high-risk disease, splenomegaly, defined as spleen volume ≥450 cm3 and palpable spleen measuring ≥5 cm below the left costal margin, Eastern Cooperative Oncology Group performance status score ≤2, and platelet count ≥50 ×109/L. The study is ongoing in the European Union, China, Russia, South Korea, and Australia, and data collection has not yet been completed. However, the primary end points of the study include spleen volume response rate (at least 35% reduction in spleen volume by the end of treatment cycle 6). The secondary end point is symptom response rate (reduction in total symptom score compared with baseline at end of treatment cycle 6). The study goals include assessment of overall survival and progression-free survival, strategies for preventing or reducing gastrointestinal events, and Wernicke’s encephalopathy, associations between FEDR efficacy and prognostic markers, and pharmacodynamics.

FREEDOM2 represents the first trial comparing FEDR with current best available therapies. Data from this trial are expected to provide meaningful insights and clarity regarding the use of FEDR as a safe and effective option in the treatment landscape for MF.

Source:
VVianelli N, Benevolo G, Vannucchi A, et al. A randomized, phase 3 trial of fedratinib versus best available therapy in patients with intermediate-2 or high-risk myelofibrosis previously treated with ruxolitinib (FREEDOM2). American Society of Hematology Annual Meeting and Exposition; December 11-14, 2021. Abstract 3643.

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