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

Nichole Tucker
Published Online:2:00 PM, Fri October 11, 2019
Andrew Kuykendall, MD
Andrew Kuykendall, MD
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.   
 
In an interview with Targeted Oncology during the 2019 SOHO Annual Meeting, Kuykendall discussed similarities and differences between fedratinib and ruxolitinib and offered advice to community oncologists who are using JAK inhibition for treating patients with MF.

TARGETED ONCOLOGY: Can you provide an overview of your presentation?

Kuykendall: I talked about a new treatment option for MF. For a long time, we've only had one FDA approved therapy which was ruxolitinib, and that's what we've relied on for the past 7 or 8 years as far as disease-related symptoms and symptoms related to an enlarged spleen. We've all been waiting to see what the next therapy would be and recently the FDA approved fedratinib for the treatment of primary and secondary MF.

TARGETED ONCOLOGY: Can you discuss the research around fedratinib that led to the FDA approval?

Kuykendall: Fedratinib has an interesting story. It's a relatively old drug that went through extensive clinical trials and was tested in many patients years ago, and it's had this resurgence. It's kind of like a rising-from-the-ashes type of story to get to where it is now. After going through phase III clinical trials and also being tested in ruxolitinib-experienced patients, there were concerns about safety, and so it was put on hold. People thought that it wasn't going anywhere and then after some of the safety signals were reanalyzed and there was a closer look done of the efficacy, it built up some steam, and now it's an approved therapy. It's very promising and exciting for us to have another agent to use to treat these patients.

TARGETED ONCOLOGY: How are you using ruxolitinib in light of the recent FDA approval of fedratinib? Which agent do you use in which setting and why? 

Kuykendall: We don't know the answer to that right now. As far as ruxolitinib, we typically use that in patients with intermediate or high-risk MF and in patients that have a significant number of disease-related symptoms as well as enlarged spleens causing symptoms. That's what ruxolitinib is good at doing. It improves disease-related symptoms and shrinks spleen size. People debate on the best time to start ruxolitinib therapy: Is there a benefit for starting it earlier rather than later.

Fedratinib being the new agent on board is indicated for the same type of patient. But it has not been compared with ruxolitinib in clinical trials. [As a result], we don't know if there's a certain patient population that would benefit more from fedratinib than ruxolitinib. We do know that the toxicity profiles differ significantly between the 2 and there are some toxicity concerns about fedratinib that we need to be aware of that may not exist with ruxolitinib. [Some of the toxicities are] nausea, diarrhea, and GI-related adverse events, which will have to be managed. I think time will tell if there are certain patients populations that we think will be more appropriate for one over the other.

TARGETED ONCOLOGY: How would explain the differences in adverse event between these 2 JAK inhibitors?

Kuykendall: The profiles are a little bit different. Every JAK inhibitor is different in the targets that it hits. Ruxolitinib is a JAK1/JAK2 inhibitor. Fedratinib is specifically for JAK2, but it also hits FLT3 as well as some other targets.

The GI toxicity profile is certainly more extensive with fedratinib as opposed to ruxolitinib. As I said, there's a lot more nausea, vomiting, and diarrhea with fedratinib as opposed to ruxolitinib. Some of these toxicities may be mitigated with prophylactic antiemetic therapy or by taking the drug with high-fat meals. That's something where we're going to have to gain some experience.

The black box warning with fedratinib is in regard to encephalopathy and this is the safety concern that was ongoing during the trials. There were 8 cases of encephalopathy and some of those were deemed to be Wernicke's encephalopathy, which was potentially due to thymine deficiencies. This has been reanalyzed and some of those concern have been mitigated but they're not completely gone and that's something that we need to be closely monitoring. Fedratinib comes with recommendations for checking thymine levels, not giving it to people who are thymine deficient, and repleting thymine levels before starting the medication. This is all part of the experience of getting more accustomed to using this medication.

TARGETED ONCOLOGY: What advice would you give to community oncologist about these 2 JAK inhibitors?

Kuykendall: I would say that it's going to be a time-will-tell situation. As I've said, we've never compared them head-to-head and what everyone is going to want to do is a head-to-head comparison and looks at response rates in one trial compared with another. Cross-trial comparison is very difficult and not appropriate in this setting.

I don't think that we should be jumping off the ruxolitinib train by any means. This is a tried-and-true medication. Community oncologists have become very adept at using it, managing it, reducing doses, increasing doses, and understanding the toxicities associated with it.

We don't know the fedratinib is better in any way compared to ruxolitinib. It is another option. I think that's were physicians like myself and others who specialize in treating myeloproliferative diseases can be a helpful resource. We can look at these patients and talk about the risks, benefits, and whether not we should be switching agents or considering other agents. This is a time in which oncologists should rely on our expertise to be able to navigate this. The MPN community is very tight-knit and we're always willing to talk to community oncologists and help to navigate these waters.

TARGETED ONCOLOGY: What challenges remain in MF treatment?

Kuykendall: Right now, the one thing we're good at doing is reducing disease-related symptoms and spleen size in patients with disease that is not extremely molecularly complex. We haven't figured out a way to impact the underlying malignant stem cell. We're not good at preventing progression to acute leukemia, or we haven't impacted the disease progression in any way.

There are a few different areas where we have strides to make. One is improving cytopenias. Patients that come in with significant anemia and thrombocytopenia are a challenge for us. Improving those blood counts [is important]. We have agents that we use but we are not particularly impressed with the results of those agents. The other area that we're not very good at is treating disease when it does progress to accelerated or blast phase. Our efforts are meek at this point, and we have to figure out how to address the disease when it becomes a full-blown acute leukemia.

TARGETED ONCOLOGY: What is the key takeaway from your presentation? 

Kuykendall: The key takeaway is that we have another agent on board. We have a second option and the data for this agent, while old, are impressive in terms of response rates, spleen responses, and impact on symptoms.

The other takeaway is that it's going to take time to figure out how to utilize this in clinical practice. Fedratinib is approved based on a phase III trial versus a placebo. Right now, we have better options than placebo for a lot of these patients.

This is a time to rely on specialists to understand how to utilize this drug going forward.
 
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).


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