Tag Archives: fedratinib

FREEDOM2 Trial Shows Fedratinib’s Efficacy and Safety in Myelofibrosis

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By Jordyn Sava
Fact checked by Sabrina Serani

When given as a second-line JAK inhibitor option in patients with myelofibrosis, fedratinib (Inrebic) showed its effectiveness in achieving spleen volume reduction (SVR) while highlighting strategies for managing gastrointestinal adverse effects (AEs) and thiamine deficiency, according to findings from the FREEDOM2 study (NCT03952039).1

The FREEDOM2 study, a multicenter, open-label, randomized controlled trial, involved 316 patients with intermediate-2 or high-risk myelofibrosis who were either relapsed, refractory, or intolerant to ruxolitinib (Jakafi).2 The median follow-up for survival at the data cutoff on December 27, 2022, was 64.5 weeks (IQR, 37.9-104.9). The primary end point was the proportion of patients achieving an SVR of at least 35% (SVR35) at the end of cycle 6.

Results from the study demonstrated a significant difference in SVR35 between the fedratinib and best available therapy (BAT) groups, with 36% of patients in the fedratinib group achieving the primary end point compared with only 6% in the BAT group (30% difference; 95% CI 20%-39%; 1-sided P <.0001).1

“Findings from FREEDOM2 support fedratinib as a second-line Janus kinase inhibitor option to reduce spleen size after ruxolitinib failure or intolerance in patients with myelofibrosis,” wrote study authors in findings published in The Lancet Hematology.

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

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October 3, 2024

Author(s): Alexandra Gerlach, Associate Editor

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

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Bose’s Guide to Ruxolitinib, Fedratinib, Pacritinib, and Momelotinib

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By Prithviraj Bose, MD

Prithviraj Bose, MD, professor in the Department of Leukemia at MD Anderson Cancer Center, provides an overview of the different JAK inhibitors currently available for patients with myeloproliferative neoplasms.

Transcription:

0:09 | We have 4 JAK inhibitors approved for the treatment of myelofibrosis in the US. Important to note, pacritinib [Vonjo] is not approved outside the US. There is obviously a lot to say on this topic, especially, ruxolitinib [Jakafi] was approved in 2011, fedratinib [Inrebic] in 2019 and then pacritinib and momelotinib [Ojjaara], more recently, 2022 and 2023. But I think I will just hit some high points.

0:36 | So for ruxolitinib, the first thing I would say about that is that it is the JAK inhibitor with the most clearly demonstrated survival benefit in myelofibrosis. Now, is that an effect just of ruxolitinib and not of the others? We do not know that. It could be a class effect, but the data are the data and the data are that ruxolitinib is the one that has a clearly shown survival benefit. I think that needs to be considered as we use it, and it is usually the most frequently used frontline drug. Now, where you can get into trouble with ruxolitinib is with cytopenias, low blood counts, and this is a drug that you need to be able to dose well in order to get the benefit that you are seeking. The dose can get compromised by cytopenias.

1:29 | That is where I will tie that into the entry of pacritinib and momelotinib. These are easier to use in the setting of cytopenias. In fact, pacritinib has a label for platelets than 50, and momelotinib is for patients with anemia in myelofibrosis. So right there, you can see that they sort of have their place more in that cytopenic population, which could be frontline, or, more commonly, second-line, after ruxolitinib. I think those are great additions in the sense that you can give them at good doses despite low blood counts, which becomes difficult with ruxolitinib, like I just said. [They are] certainly very welcome additions to the arsenal.

2:12 | I will just say 1 last thing about fedratinib, which was the second one approved. This is a good drug, perhaps as good as ruxolitinib from an efficacy stand point, but really with no clear advantage over ruxolitinib. So, I do not use it in the frontline. I do use it, however, in post-ruxolitinib settings, where the blood counts are good. In those proliferative scenarios, as opposed to the cytopenic scenarios, in second-line and beyond, I do find fedratinib to be a useful drug. It has some toxicities that one has to pay attention to. All patients should get thiamine supplementation, stuff like that, but overall, I would say those are the kind of very high level points about the 4 drugs.

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Prospective Study to Evaluate Fedratinib Plus Nivolumab in Myelofibrosis

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Andrea S. Blevins Primeau, PhD, MBA

A single-arm, phase 2 study of fedratinib, a selective JAK2 inhibitor, plus nivolumab is planned for patients with myelofibrosis (MF) who had a suboptimal or no response to a JAK inhibitor was initiated, according to a report published in the Annals of Hematology.

“This study will provide new findings that may contribute to advancing the treatment landscape for MF patients with suboptimal responses and limited alternatives,” the researchers wrote in their report. Currently, 23 of 30 planned patients are enrolled in the study and recruitment is expected to be completed by December 2024.

The open-label FRACTION trial will treat patients with MF from 9 academic centers in Germany, who will receive 400 mg of fedratinib daily in 28-day cycles, followed by 240 mg of nivolumab every 2 weeks beginning in cycle 2. Treatment will be given until progressive disease, relapse, death, or study discontinuation.

This study will provide new findings that may contribute to advancing the treatment landscape for MF patients with suboptimal responses and limited alternatives.

The primary efficacy endpoints will be response rate within 12 treatment cycles and RCT independency. Secondary endpoints will include safety, incidence of leukemic transformation, clinical benefit, duration of response, progression-free survival, overall survival, and disease burden. Molecular analyses will also serve as exploratory endpoints for the study.

Patients with MF primary or secondary MF are eligible if they had a suboptimal or no response to a JAK inhibitor, which is defined by persistent symptoms, splenomegaly, cytopenia, or hyperproliferation. Patients who have received a prior immune checkpoint inhibitor or history of uncontrolled autoimmune disease are not eligible for the study.

Disclosures: This research was supported in part by Celgene/Bristol Myers Squibb. Please see the original reference for a full list of disclosures.

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Fedratinib and Ruxolitinib: Advice for Deciding Which Agent to Give and When

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The introduction of fedratinib (Inrebic) to the treatment landscape of myelofibrosis (MF) and the challenges that have arisen over deciding between administering fedratinib or ruxolitinib (Jakafi) means more community oncologists should consult specialists when treating these patients, said Andrew Kuykendall, MD.

Research shows that fedratinib and the earlier JAK inhibitor, ruxolitinib have similar efficacy in patients with MF. However, their toxicity profiles differ, and the potential for encephalopathy with fedratinib is an ongoing concern, resulting in a black box warning on the label. Now that the agent is FDA approved for the treatment of MF, oncologists are left with a decision of which JAK inhibitor to give to which patients and when to prescribe them.

How to continue using ruxolitinib now that fedratinib is available remains an unanswered question, said Kuykendall, assistant member, Moffitt Cancer Center; however, experts in treating myeloproliferative neoplasms (MPNs) can be a helpful resource for other oncologists.

Another resource for treatment decision-making is clinical data from the JAKARTA-2 trial, which studied fedratinib in patients with MF who were previously treated with ruxolitinib. Findings from a re-analysis of the study were presented at the 2019 ASCO Annual Meeting and showed that 46 of the 83 assessable patients achieved a spleen response (55%; 95% CI, 44%-66%), meeting the primary endpoint of the study.

The most common adverse events included diarrhea (n = 60), nausea (n = 54), vomiting (n = 40), constipation (n = 20), and others. Additionally, hematologic abnormalities including, grade 3/4 anemia (n = 96), thrombocytopenia (n = 68), and neutropenia (n = 23) were seen. Eighteen patients (19%) discontinued treatment due to adverse events.

These data suggest that fedratinib may be a second-line option for patients who are resistant or sensitive to ruxolitinib. The management of the gastrointestinal (GI)-related toxicities and checking of thymine levels to prevent encephalopathy, however, are newer management concerns that physicians must be aware of when administering fedratinib to patients with MF and is another point when consulting an MPN specialist may come in handy.

Read Targeted Oncology’s interview with Dr. Kuykendall.