Study Findings Suggest Use of Fedratinib as Treatment in the Second Line for Myelofibrosis

Fedratinib (Inrebic; Bristol Myers Squibb) demonstrates safety and efficacy as a second line Janus kinase inhibitor (JAKi) option to reduce spleen size after ruxolitinib (Jakafi; Incyte Corp) failure or intolerance in patients with myelofibrosis (MF), according to results from the FREEDOM2 trial (NCT03952039). The study compared treatment with fedratinib and the best available therapy (BAT) in intermediate- or high-risk primary MF.¹

The results support the potential of fedratinib as a JAK-2 inhibitor in the second line as a therapeutic option for patients intolerant or resistance to ruxolitinib. Image Credit: © NeuroGraphix Studio - stock.adobe.com

MF is an uncommon, fatal myeloproliferative neoplasm characterized by the overproduction hematopoietic stem cells, leading to increasingly reduced red blood cell production. As a result, many patients with MF, approximately 40%, have anemia at diagnosis, of which an estimated 25% are RBC transfusion dependent (TD). In most cases, patients will develop chronic anemia and TD as the disease progresses.^2,3

Ruxolitinib is a JAKi approved by the FDA in 2011 and indicated for the treatment of patients with intermediate or high-risk myelofibrosis, including primary MF (PMF), post-polycythemia vera MF (post-PV MF) and post-essential thrombocythemia MF (post-ET MF). Despite its success for some patients, the response rate is less than 50% and survival rates after ruxolitinib discontinuation are poor. Many patients develop ruxolitinib intolerance and become relapsed or refractory.^4,5

Fedratinib is an orally available, small molecule inhibitor of JAK-2, which is often mutated in patients with MF. It was approved in 2019 by the FDA as a therapeutic option for intermediate- or high-risk primary or secondary MF and has demonstrated clinically meaningful benefits for patients. In multiple preregistration trials, fedratinib resulted in reduction spleen size and improvement in symptoms in 40% to 50% of patients, including those who were resistant or intolerant to ruxolitinib.⁶

In the multicentre, open label, randomized, controlled, phase 3 FREEDOM2 trial, researchers sought to determine the safety and efficacy of fedratinib compared with BAT in patients with high-risk PMF, post-PV MF, or post-ET MF, and previously treated with ruxolitinib. They assigned the 201 participants 2:1 to randomly receive either 400 mg per day of fedratinib (134) or BAT (67; 52 receiving ruxolitinib). The primary end point was the proportion of patients reaching spleen volume reduction (SVR) of at least 35% at end of cycle 6.⁵

At the end of cycle 6, SVR35 was observed in 36% of patients in the fedratinib treatment arm compared with 6% of patients in the BAT arm (30% difference; 95% CI 20–39; one-sided p-value <0·0001). During the first 6 cycles, treatment adverse events (AEs) occurred in 40% of patients in the fedratinib group and 12% of patients in the BAT group, of which grade 3 or greater, with anaemia (fedratinib 12 [9%] of 134; BAT 6 [9%] of 67) and thrombocytopenia (fedratinib 16 [12%] of 134; BAT 2 [3%] of 67) being the most frequent. Gastrointestinal AEs were reported more frequently in the fedratinib group compared with the BAT group, but were mostly grade 1 or 2 and occurred in early cycles.⁵

The results support the potential of fedratinib as a JAK-2 inhibitor in the second line as a therapeutic option for patients intolerant or resistance to ruxolitinib, as well as show effective strategies for managing gastrointestinal AEs and low thiamine concentrations in patients with MF.

REFERENCES

1. An efficacy and safety study of fedratinib compared to best available therapy in subjects with dipss-intermediate or high-risk primary myelofibrosis, post-polycythemia vera myelofibrosis, or post-essential thrombocythemia myelofibrosis and previously treated with ruxolitinib (freedom2). ClinicalTrials.gov Identifier: NCT03952039. Updated September 27, 2024. Accessed October 2, 2024. https://clinicaltrials.gov/study/NCT03952039

2. Study finds ruxolitinib may slow fibrosis progression in myelofibrosis. Pharmacy Times. September 24, 2024. Accessed October 2, 2024. https://www.pharmacytimes.com/view/study-finds-ruxolitinib-may-slow-fibrosis-progression-in-myelofibrosis

3. Gerlach A. Study demonstrates safety, efficacy of luspatercept for mf-related anemia. Pharmacy Times. September 19, 2024. Accessed October 2, 2024. https://www.pharmacytimes.com/view/study-demonstrates-safety-efficacy-of-luspatercept-for-mf-related-anemia

4. Ruxolitinib (oral route). Mayo Clinic. October 1, 2024. Accessed October 2, 2024. https://www.mayoclinic.org/drugs-supplements/ruxolitinib-oral-route/description/drg-20075326

5. Harrison C, Mesa R, Talpaz M, et al. Efficacy and safety of fedratinib in patients with myelofibrosis previously treated with ruxolitinib (FREEDOM2): results from a multicentre, open-label, randomised, controlled, phase 3 trial. The Lancet Haematology. September 9, 2024. doe: 10.1016/S2352-3026(24)00212-6

6. Fedratinib. National Library of Medicine. August 20, 2022. Accessed October 2, 2024. https://www.ncbi.nlm.nih.gov/books/NBK574355/