Expert Highlights Data that Led to the Approval of Fedratinib in Myelofibrosis

Ruben Mesa, MD

Ruben Mesa, MD

Fedratinib (Inrebic) wasapproved by the FDA on August 16, 2019, for the treatment of adult patients with intermediate-2 or high-risk primary or secondary myelofibrosis (MF), based on findings from the JAKARTA and JAKARTA-2 trials. Findings from a stricter reanalysis of the JAKARTA-2 trial were presented at the 2019 ASCO Annual Meeting and helped to further define the benefit of fedratinib.

In the initial JAKARTA-2 trial, 97 patients with MF who were resistant or intolerant to ruxolitinib (Jakafi) were treated with fedratinib. This trial demonstrated a 35% or greater reduction in spleen volume. However, the reanalysis was conducted to investigate the drug under more stringent criteria for ruxolitinib failure.

Patients in the reanalysis had to have received ruxolitinib for at least 3 months and demonstrate growth in spleen size and/or other symptoms to be included in the reanalysis. Patients also had to have received fedratinib for at least 6 months. Overall, 79 patients from the initial study met these criteria.

Based on the reanalysis of this patient population, fedratinib led to clinically meaningful reductions in splenomegaly and symptoms. The spleen volume response rate was 30% and the symptom response rate was 27%.

Based on initial findings from the JAKARTA-2 study, the most common grade 3/4 adverse events (AEs) included anemia and thrombocytopenia. The label for the approval of fedratinib also includes a warning of the risk of Wernicke’s encephalopathy..

The phase IIIb FREEDOM trial is enrolling patients who are resistant to or intolerant of ruxolitinib based on a stringent definition of ruxolitinib failure (NCT03755518). Investigators are evaluating risk mitigation strategies for gastrointestinal AEs and Wernicke’s encephalopathy. This trial will further validate the role of fedratinib in patients with MF who have failed or become intolerant to ruxolitinib.

“We have been very grateful for all of the activity and benefit of ruxolitinib, but…now having a second agent approved is a great advantage for patients,” said Ruben Mesa, MD. “This is a great [time] for patients with myeloproliferative neoplasms; more options are always better patients.”

In an interview withTargeted Oncology, Mesa, the director of the Mays Cancer Center, UT Health San Antonio MD Anderson Cancer Center, discussed the results from the reanalysis of the JAKARTA-2 trial that led to the approval of fedratinib in patients with MF. He also highlighted the role of the FREEDOM study that is currently enrolling patients with MF for treatment with fedratinib.

TARGETED ONCOLOGY: What was the rationale for conducting a reanalysis of the JAKARTA-2 study?

Mesa:At this year’s ASCO meeting, we presented the results of a reanalysis of the JAKARTA-2 study. The JAKARTA-2 study was conducted several years ago in patients that had failed ruxolitinib. However, in that study, it was a heterogenous group of criteria [to define] the patients that had failed ruxolitinib. At the time, it wasn’t overly rigorous.

It had been shortly after ruxolitinib had been approved, and there were patients that had a brief duration of therapy with ruxolitinib ahead of time. We didn’t feel that the criteria for entry fully captured the activity of fedratinib.

TARGETED ONCOLOGY: What came out of this reanalysis of patients with MF who failed ruxolitinib?

Mesa:We did a reanalysis where we defined ruxolitinib intolerance or resistance in a more modern way, now with more than 8 years of hind sight with ruxolitinib. [In this analysis, patients] had at least 3 months of therapy and a certain amount of regrowth of the spleen, symptoms, cytopenias, etc. Secondly, we looked to evaluate the efficacy of fedratinib in individuals that had at least 6 months of therapy.

In looking at that group, we were able to look at the larger JAKARTA-2 group, and weed that down to a cohort of just under 70 patients that failed both criteria, clearly failed ruxolitinib through a rigorous set of criteria and had an adequate try of fedratinib. With that, we see an over 30% response rate for reduction of splenomegaly and improvement in symptoms in individuals that had been significantly pretreated with ruxolitinib and had fedratinib therapy. We thought that was very encouraging, particularly in light of the further development of fedratinib now held by Celgene.

TARGETED ONCOLOGY: Prior to its approval, fedratinib was put on a clinical hold. How did the JAKARTA-2 trial overcome that?

Mesa:Fedratinib had been previously run by Sanofi, then had been on hold, in limbo. Interestingly, it resurfaced because of the significant activities from the JAKARTA study that had been a placebo-controlled study that showed that it was an effective drug. There has been a question around a low rate of neurologic toxicities that caused this hold that didn’t get resolved. Now it has been taken over by Celgene; the hold has been lifted and [we are]looking forward to amplifying with some additional prospective data to go along with the prior data from earlier studies.

TARGETED ONCOLOGY: Where does the FREEDOM trial fit into this?

Mesa:This study of fedratinib is a follow-up to this reanalysis of the JAKARTA-2 study. The FREEDOM study is the prospective version of that, where we have individuals that have been resistant or intolerant to ruxolitinib through a relatively rigorous set of criteria, including over 3 months of therapy, a certain amount of lack of responses, regrowth in the spleen, or worsening of symptoms in these patients. Those patients then received fedratinib.

First, there was an efficacy piece in terms of that prospective study, which is now enrolling. Second, [there is] a further validation of the safety endpoint. Fedratinib had been put on a clinical hold because of a less than 1% rate of neurologic events that had initially been thought to be Wernicke’s encephalopathy. It turns out, in the prior studies, there was probably only 1 patient that had Wernicke’s encephalopathy. It may have been preexisting prior the trial entry for that patient.

TARGETED ONCOLOGY: How is this trial investigating the risk of Wernicke’s encephalopathy?

Mesa:This study is monitoring the development of Wernicke’s encephalopathy. It is trying to prevent it through thiamine supplementation and monitoring of thiamine levels. We are hopeful that we will not have any patients develop Wernicke’s encephalopathy, but if there is an impact on thiamine, we will be able to be recognize it and if there is a risk, [we hope]that it is able to be mitigated.

We’re highly confident that it shouldn’t be a barrier, but at least we will understand that part to a much better degree because we had not had prospective data after that issue had been identified when the drug was put on hold.

Reference:

Harrison CN, Schaap N, Vannucchi AM, et al. Fedratinib (FEDR) in myelofibrosis (MF) patients previously treated with ruxolitinib (RUX): A reanalysis of the JAKARTA-2 study.J Clin Oncol.2019;37(suppl; abstr 7057).