Effect of Fedratinib Versus Best Available Therapy on Patient-Reported Outcomes in Patients with Myelofibrosis Who Were Previously Treated with Ruxolitinib: Results from the Phase 3 FREEDOM2 Trial

Introduction: Fedratinib (FEDR) is a Janus kinase 2 inhibitor approved in the United States for the treatment of intermediate-2 or high-risk primary or secondary myelofibrosis (MF). In the phase 3, open-label, randomized FREEDOM2 trial (NCT03952039), FEDR significantly improved rates of spleen volume reduction and symptom response when compared with best available therapy (BAT) among patients with MF and prior treatment with ruxolitinib (RUX). This post hoc analysis compared treatment effects of FEDR versus BAT on patient-reported outcomes (PROs) in FREEDOM2 (data cutoff Dec 27, 2022).

Methods: FREEDOM2 enrolled adults with intermediate-2 or high-risk primary, post-polycythemia vera, or post-essential thrombocythemia MF who were relapsed/refractory or intolerant to RUX. Patients were randomized 2:1 to receive FEDR 400 mg/day or BAT in 28-day cycles until intolerance or lack of efficacy. Crossover from BAT to FEDR was allowed for disease progression or after the end of cycle (EOC) 6 response assessment. PRO assessments (secondary endpoints) included the Myelofibrosis Symptom Assessment Form (MFSAF) version 4.0, the European Organisation for Research and Treatment of Cancer Quality-of-Life Core 30 Questionnaire (EORTC QLQ-C30), and the EuroQol EQ-5D-5L at day 1 of each treatment cycle and the end of treatment. MFSAF was also administered at screening and during response assessment at the EOC 3, 6, 12, 18, and 24 visits. Analyses were performed on the PRO-evaluable populations, defined as all randomized patients with an evaluable assessment of the respective measure at baseline and ≥1 post-baseline time point. Prespecified primary domains of interest were MFSAF total symptom score (TSS); QLQ-C30 global health status/quality of life, physical functioning, fatigue, and pain; and the EQ-5D-5L visual analog scale (EQ-VAS). Comparison of PROs included least-squares (LS) mean changes from baseline at EOC 6 (for MFSAF) or at cycle 7 day 1 (C7D1; for the other PROs), analyzed using a constrained longitudinal data analysis model. Time to sustained response was analyzed for achievement of clinically meaningful changes from baseline that were sustained through EOC 6/C7D1 using Cox proportional hazards models. Meaningful changes from baseline were based on prespecified published thresholds for each measure. PRO scores were evaluated descriptively alongside published population norms. All analyses were performed according to the International Council for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use E9(R1) estimand framework for the handling of relevant intercurrent events. Adjustment for multiplicity was not performed.

Results: Of 201 randomized patients, the PRO-evaluable population included 183 (91%) patients for the MFSAF (FEDR, n=121; BAT, n=62), and 155 (77%) for both the QLQ-C30 (FEDR, n=105; BAT, n=50) and the EQ-5D-5L (FEDR, n=103; BAT, n=52). Most baseline demographics, disease characteristics, and PRO scores were generally comparable between treatment arms in the PRO-evaluable populations. Mean baseline PRO scores for both treatment arms were numerically worse than the general population norms for almost all QLQ-C30 and EQ-5D-5L domains. PRO completion rates through EOC 6/C7D1 were generally high (>80% at most assessment visits). Differences in LS mean (95% CI) changes from baseline at EOC 6/C7D1 consistently favored FEDR versus BAT in all primary domains of interest, with significant differences (P<0.05) observed for MFSAF TSS (−4.3 [−8.2 to −0.3]); QLQ-C30 fatigue (−10.2 [−20.2 to −0.2]) and pain (−9.5 [−17.3 to −1.6]); and EQ-VAS (9.1 [1.8 to 16.4]). Time to sustained response through EOC 6/C7D1 also consistently favored FEDR versus BAT across all primary domains of interest, with significantly (P<0.05) higher rates observed for MFSAF TSS (hazard ratio [95% CI]: 2.28 [1.00 to 5.22]) and QLQ-C30 physical functioning (2.27 [1.04 to 4.96]).

Conclusions: FEDR demonstrated more favorable effects versus BAT on patient-reported MF-related symptoms and health-related quality of life. These findings further support the use of FEDR as a second-line option after RUX failure/intolerance for patients with intermediate-2 or high-risk MF.

Harrison:Sobi: Consultancy; CTI: Ended employment in the past 24 months; AOP: Consultancy, Honoraria, Speakers Bureau; Geron: Consultancy; BMS: Consultancy, Honoraria, Speakers Bureau; GSK: Consultancy, Honoraria, Other: Teaching and speaking; Research: PI, Research Funding, Speakers Bureau; MorphoSys/Constellation: Consultancy, Honoraria, Other: Research: PI, Research Funding, Speakers Bureau; Keros: Consultancy, Honoraria, Speakers Bureau; Galecto: Consultancy; IMAGO: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy; MSD: Consultancy, Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria, Other: Teaching and Speaking; Research: PI, Speakers Bureau; AbbVie: Consultancy, Honoraria, Other: Teaching and speaking; Research: PI, Speakers Bureau; Novartis: Consultancy, Honoraria, Other: Teaching and speaking; Research: PI, Research Funding, Speakers Bureau; MPN voice: Other: Leadership role. Lord-Bessen:Bristol Myers Squibb: Current equity holder in publicly-traded company. Shi:Evidera: Current Employment. Guo:Bristol Myers Squibb: Research Funding; Evidera Inc., a part of Thermo Fisher Scientific.: Current Employment, Other: Evidera, a consulting company, received fees for consultancy from BMS to carry out this work.. Yucel:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Zissler:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Jones:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Slaff:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company.