Safety and Efficacy of Fedratinib in Patients with Primary (P), Post-Polycythemia Vera (Post-PV), and Post-Essential Thrombocythemia (Post-ET) Myelofibrosis (MF) Previously Treated with Ruxolitinib: Primary Analysis of the FREEDOM Trial

Introduction: Fedratinib is an oral selective Janus kinase (JAK) 2 inhibitor approved for treatment (tx) of patients (pts) with MF, including those previously treated with ruxolitinib (RUX). In the single-arm phase 2 JAKARTA2 trial (NCT01523171), fedratinib 400 mg once daily improved spleen volume and MF symptom burden in pts with MF resistant/intolerant to prior RUX (Harrison et al. Am J Hematol 2020). Long-term data are lacking due to early termination. The ongoing, single-arm, phase 3b FREEDOM trial (NCT03755518) further evaluates the safety and efficacy of fedratinib in pts with MF previously treated with RUX and includes proactive strategies to mitigate gastrointestinal (GI) adverse events (AEs), thiamine level decreases, and potential encephalopathy (including Wernicke's encephalopathy [WE]).

Methods: Eligible pts aged ≥ 18 years with PMF, post-PV MF, or post-ET MF with ≥ 3 months prior tx with RUX were enrolled in the study. Pts were required to have Dynamic International Prognostic Scoring System (DIPSS) intermediate- or high-risk MF, Eastern Cooperative Oncology Group performance status ≤ 2 and baseline platelet count ≥ 50 x 10⁹/L. Pts were treated with fedratinib 400 mg once daily in continuous 28-day cycles until lack of efficacy, intolerance, or disease progression, and followed for 12 months after end of tx (EOT). AE mitigation strategies included prophylactic use of antiemetics and symptomatic use of antidiarrheals, thiamine supplementation, surveillance for encephalopathy, and adjusting preferred time of day for fedratinib administration.

Results: Thirty-eight pts were enrolled and treated. Due to accrual challenges during the COVID-19 pandemic, the study was capped early, and data lost statistical power due to reduced sample size. At the database cutoff (November 29, 2021), median tx duration was 38 weeks, 13 pts had tx ongoing, and 25 pts had discontinued tx. At baseline, median age was 68.5 years, 23 (60.5%) pts had a diagnosis of PMF, 9 (23.7%) post-PV MF, and 6 (15.8%) post-ET MF, with DIPSS assessment of intermediate-1 risk in 13 (34.2%) pts, intermediate-2 risk in 18 (47.4%) pts, and high risk in 7 (18.4%) pts. Baseline median spleen volume was 1831.6 mL. A total of 9/35 (25.7%) evaluable pts met the primary endpoint of ≥ 35% spleen volume reduction (SVR) by magnetic resonance imaging/computed tomography at end of cycle (EOC) 6; 13 (37.1%) pts had ≥ 35% SVR when missing EOC6 assessments were imputed with last observation carried forward (LOCF) method (Table). In addition, 9 (25.7%) pts achieved a ≥ 35% SVR before or after EOC6, for a best overall response of ≥ 35% SVR in 22 (62.9%) pts up to end of tx. With a ≥ 25% SVR threshold, 24 (68.6%) pts had a response with LOCF at EOC6. Of ≥ 35% SVR responders, 19/22 (86.4%) maintained durable response at data cutoff (Figure). In secondary endpoints, 21/36 (58.3%) and 16/36 (44.4%) evaluable pts showed ≥ 50% reduction in total symptom score (TSS) at EOC3 and EOC6, respectively. A total of 34/38 (89.5%) pts had 1 tx-emergent AE related to study medication; 3 (7.9%) were serious AEs. Anemia and thrombocytopenia were reported in 23 (60.5%) and 13 (34.2%) pts, respectively. GI AEs were reported in 34 (89.5%) pts, with nausea, vomiting, and diarrhea reported in 15 (39.5%), 7 (18.4%), and 15 (39.5%) pts, respectively. Most GI AEs were grade 1/2 and occurred during cycle 1, and decreased in the subsequent cycles. Grade 1/2 decreases in thiamine levels were reported in 6 pts after initial tx; all instances were treated and resolved at next assessment. No pts required tx discontinuation due to low thiamine levels. There were no cases of WE reported. There were 2 deaths during tx and 7 during follow-up; none were related to study medication.

Conclusions: Clinically relevant and durable spleen and symptom responses were observed in FREEDOM study participants, with a majority of responders showing durable SVR at data cutoff. This supports the use of fedratinib in pts with MF previously treated with RUX. One limitation of the study was small pt sample size. In this first fedratinib study proactively assessing a GI mitigation strategy and thiamine monitoring, results showed GI AEs were easily mitigated and no WE was reported.

Study support: This study was supported by Bristol Myers Squibb.

Gupta:BMS Celgene: Consultancy, Honoraria, Other: Participation on a Data Safety or Advisory board; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Other: Participation on a Data Safety or Advisory board; Roche: Other: Participation on a Data Safety or Advisory board; Sierra Oncology: Consultancy; AbbVie: Consultancy, Other: Participation on a Data Safety or Advisory board; Constellation Pharmaceuticals, Inc., a MorphoSys Company: Consultancy, Honoraria. Yacoub:Stemline Therapeutics: Research Funding; Servier: Consultancy; Acceleron Pharma: Consultancy; Agios: Consultancy; AbbVie: Consultancy; Apellis: Consultancy; Gilead: Consultancy; Notable Labs: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; PharmaEssentia: Consultancy; CTI Pharma: Consultancy; Incyte: Consultancy, Speakers Bureau. Verstovsek:Protagonist Therapeutics: Research Funding; CTI BioPharma Corp.: Research Funding; PharmaEssentia: Research Funding; ItalPharma: Research Funding; Promedior: Research Funding; Incyte: Consultancy, Research Funding; Gilead: Research Funding; Novartis: Consultancy, Research Funding; NS Pharma: Research Funding; Genentech: Research Funding; Roche: Research Funding; Sierra Oncology: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Blueprints Medicines Corp.: Research Funding; AstraZeneca: Research Funding; Constellation Pharmaceuticals: Consultancy; Pragmatist: Consultancy. Mesa:Roche: Consultancy; Samus: Consultancy, Research Funding; Constellation Pharmaceuticals, Inc., a MorphoSys Company: Consultancy, Research Funding; Celgene: Research Funding; Gilead: Research Funding; LaJolla Pharmaceutical: Consultancy; Bristol Myers Squibb: Consultancy; Blueprint: Consultancy; Genotech: Research Funding; Promedior: Research Funding; CTI: Research Funding; AOP: Consultancy; AbbVie: Research Funding; Geron: Consultancy; Incyte: Consultancy, Research Funding; Sierra Oncology: Consultancy, Research Funding; Novartis: Consultancy; Imago: Research Funding. Harrison:Shire: Membership on an entity's Board of Directors or advisory committees; Sierra: Honoraria; EHA: Other: Leadership role; Keros: Consultancy; AOP Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings, Research Funding; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees; MPN voice: Other: Leadership role; Incyte: Speakers Bureau; Galecto: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Galacteo: Membership on an entity's Board of Directors or advisory committees; Constellation Pharmaceuticals, Inc., a MorphoSys Company: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Geron: Membership on an entity's Board of Directors or advisory committees; Promedior: Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees. Vannucchi:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AOP Orphans Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Blueprint: Membership on an entity's Board of Directors or advisory committees, Other: Lectures; GSK: Membership on an entity's Board of Directors or advisory committees, Other: Lectures; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Lectures. Deeg:CSL/Behring: Other: Advisory Board. Fazal:Sanofi: Honoraria; GlaxoSmithKline: Consultancy, Honoraria; AbbVie: Consultancy; Pharmaessentia: Honoraria; Janssen: Honoraria; Incyte: Consultancy, Honoraria; Takeda: Honoraria; Blueprint: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Novartis: Honoraria; Jazz: Consultancy, Honoraria; Amgen: Honoraria; CTI Biopharma: Consultancy, Honoraria; Stemline: Honoraria; Karyopharm: Honoraria; Gilead: Honoraria; Servier: Honoraria; Taiho Pharmaceuticals: Honoraria; Pfizer: Honoraria. Foltz:Amgen: Current Employment, Current equity holder in publicly-traded company; Bristol Myers Squibb: Honoraria, Research Funding; Constellation: Research Funding; CTI Biopharma: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria; Paladin Labs: Membership on an entity's Board of Directors or advisory committees; Sierra: Research Funding. Miller:Bristol Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; CTI: Consultancy, Honoraria, Research Funding, Speakers Bureau; Incyte: Consultancy, Honoraria, Research Funding, Speakers Bureau. Martin-Regueira:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Hernandez:Bristol Myers Squibb: Current Employment. Wang:Bristol Myers Squibb: Current Employment. Talpaz:Bristol Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy; Sumitomo: Consultancy; Kirin: Consultancy; Theravance: Other: Data Safety Monitoring Board.