Fedratinib Demonstrates Promising Efficacy for Second-Line Treatment of Myelofibrosis

Phase 3 Results from the FREEDOM2 Trial

According to phase 3 results from the FREEDOM2 trial, patients with myelofibrosis (MF) previously treated with ruxolitinib demonstrated superior spleen volume reduction (SVR) and symptom response when treated with fedratinib as a second-line Janus kinase (JAK) inhibitor compared with best available therapy, predominantly ruxolitinib.

“Most patients with myelofibrosis develop ruxolitinib intolerance or disease that is relapsed or refractory, and survival rates after ruxolitinib discontinuation are poor,” stated first study author Claire Harrison, MD, Guy's and St Thomas' NHS Foundation Trust, London, UK, and colleagues.

This multicenter, open label, randomized, controlled trial to assess the safety and efficacy of fedratinib among patients with myelofibrosis previously treated with ruxolitinib was conducted at 86 clinics in 16 countries. Investigators included 201 patients aged at least 18 years with intermediate-2 or high-risk MF that was relapsed or refractory (R/R) or intolerant to ruxolitinib with Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2.

Patients were stratified by spleen size by palpation, platelet count, and previous ruxolitinib treatment, and randomly assigned on a 2-to-1 basis by interactive response technology to receive fedratinib 400 mg per day (4 × 100 mg capsules orally once daily, open-label) or best available therapy. They received prophylactic antiemetics and thiamine supplementation, and symptomatic antidiarrheals as required. The measured primary end point was the proportion of patients reaching SVR of at least 35% (SVR35) at end of cycle 6 in the intention-to-treat population.

Between September 9, 2019, and June 24, 2022, trial participants were randomly assigned and treated; 134 to fedratinib, 67 to best available therapy [including 52 receiving ruxolitinib]). It was noted that 46 patients from the best available therapy group crossed over to fedratinib. 

Results demonstrated at the data cutoff of Dec 27, 2022, the median survival follow-up was 64.5 weeks ([Interquartile Range] IQR 37.9 to 104.9). Additionally, SVR35 at the end of cycle 6 was seen in 48 (36%) of 134 patients receiving fedratinib versus 4 (6%) of 67 patients receiving best available treatment (30% difference; 95% [confidence interval] CI 20 to 39; one-sided P <0.0001).

During the first 6 treatment cycles, 53 (40%) of 134 patients in the fedratinib group and 8 (12%) of 67 patients in the best available treatment group had grade 3 or greater treatment-related adverse events, such as anemia (fedratinib 12 [9%] of 134; best available therapy 6 [9%] of 67) and thrombocytopenia (fedratinib 16 [12%] of 134; best available therapy 2 [3%] of 67). Study authors noted 1 patient in the fedratinib group died from acute kidney injury, which was suspected to be related to study drug, however there were no recorded treatment-related deaths in the best available therapy cohort.

Furthermore, gastrointestinal adverse events occurred more frequently in the fedratinib arm compared with the best available therapy group, but were mostly grade 1 to 2 in severity and more frequent in early cycles and were less frequent than in prior clinical trials. It was recorded that a total of 28 (21%) of 134 patients in the fedratinib group and 3 (4%) of 67 patients in the best available therapy arm had thiamine levels below the lower limit of normal per central laboratory assessment, with only 1 case of low thiamine in the fedratinib arm after the introduction of prophylactic thiamine supplementation. 

“The safety profile of fedratinib was consistent with previous trials, and mitigation measures effectively managed known adverse events. Overall, the results indicate that fedratinib is a promising option for second-line JAK inhibitor treatment of [MF],” concluded Dr Harrison and coauthors.

Investigators noted that follow-up data for this trial is ongoing.

Source:

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 multicenter, open-label, randomized, controlled, phase 3 trial. Lancet Haem. Published online September 9, 2024. doi: 10.1016/S2352-3026(24)00212-6