JAK Inhibitors Enter Treatment Landscape for Patients With Early Myelofibrosis

Ruben Mesa, MD

The treatment landscape for myeloproliferative neoplasms (MPNs) has been enriched by the introduction of JAK inhibitors, such as the FDA’s first approval of ruxolitinib (Jakafi) for the treatment of intermediate-2 and high-risk myelofibrosis (MF), but these agents are now showing promise as well in early-stage MF.

Fedratinib (Inrebic) also received FDA approval for the treatment of patients with MF and may be a promising agent in earlier stage disease as well. Other JAK inhibitors in this space include momelotinib and pacritinib, but these agents are not yet FDA-approved. Both momelotinib and pacritinib appear promising for the treatment of patients with MF, but the most encouraging options for early-stage disease remain ruxolitinib and fedratinib.

During the first annual Texas Virtual MPN Workshop and Meeting, Ruben Mesa, MD, introduced the evidence for use of JAK inhibitors in early MF. According to Mesa, there is a robust amount of data supporting the use of JAK inhibitors in MF, and as these agents continue to develop, treatment of patients with MF can become more individualized. As research continues to evaluate these agents, better markers of response, as well, will emerge to improve treatment outcomes for patients with select disease characteristics that might make them more responsive to 1 JAK inhibitor over another.

In an interview with Targeted Oncology, Mesa, director, Mays Cancer Center at The University of Texas Health San Antonio, MD Anderson Cancer Center San Antonio, TX, discussed the role of JAK inhibitors in early MF and other promising treatment options coming down the pipeline.

TARGETED ONCOLOGY: Could you provide an overview of your presentation on JAK inhibitors in early MF?

Mesa: When we first had the JAK inhibitors approved, first ruxolitinib, it was in intermediate-2 and high-risk MF, and in large part, that was because of the phase 3 trial we did as an extension of the experience that we had in the phase 1 study. Before we tested JAK inhibitors, the discussion with the FDA was to use it in the sickest patients because we don't know the safety, and we don't know the efficacy. After approval, it became pretty clear that it was a safe drug and a pretty effective drug, as the other JAK inhibitors have been as well. With that, there has been a growing experience of use in earlier disease.

Early MF can include a variety of different things. Does that mean people that have lower risk but have symptoms and splenomegaly? Sure. Does that mean individuals that are more recent to the time of diagnosis? It certainly can, so we recognize JAK inhibitors can help individuals with splenomegaly, symptoms, and MF disease features, somewhat independent of the issue of their risk. Risk is a marker of survival, and it can be related to a whole variety of different variables. It might be independent of whether or not they benefit from JAK inhibition.

TARGETED ONCOLOGY: Where do each of the JAK inhibitors stand currently in the treatment landscape for early MF?

Mesa: We have 2 that are commercially available, so we have ruxolitinib, and now in the NCCN guidelines, there's clearly data both in real-world evidence and expanded access data about the safety in earlier MF. It certainly is a recommended consideration in symptomatic lower-risk MF, as well as intermediate-1 MF with splenomegaly and/or symptoms

We have fedratinib, which I believe will be the same situation. Now we have less data in this population because when fedratinib was approved, it had a period of time where it had been on a clinical hold, so what we did not have with fedratinib was the expanded access trials that might include lower-risk symptomatic or intermediate-1 risk patients. The current NCCN guidelines don't include that group for fedratinib, but I do expect over time, we will gain more experience and have no reason to think that it wouldn't benefit those patients the same. There's just less data.

We have momelotinib that is very helpful for splenomegaly and symptoms. It might be superior in terms of anemia, so it similarly might be helpful for earlier folks. It's not FDA-approved yet so people are able to access it through the MOMENTUM study. That study, by definition, includes individuals that have failed MF and have anemia, so it will tend to be a more advanced group of patients. I suspect that group will look at more downstream after hopefully an approval.

Finally, we have pacritinib. Similarly, it is likely beneficial in that group, but it too is on the final stages of hopefully getting approved now with the PACIFICA study, and its main niche is individuals with marked thrombocytopenia. That group, by definition, is not early MF, so I think the momelotinib and pacritinib, perhaps in the future, [could be evaluated earlier], but fedratinib is much more real time. For example, if there were a patient tomorrow that my colleague treated with a low-risk MF but had splenomegaly and symptoms, and they took ruxolitinib and didn't respond, I would consider for fedratinib. If they took it and had an allergy to ruxolitinib or didn't tolerate it, then absolutely, I think that would be fair game.

TARGETED ONCOLOGY: What data have we seen so far to support the JAK inhibitors’ roles in early MF?

Mesa: The best data that we have is from shortly after the approval of ruxolitinib with specifically the expanded access data from the JUMP trial, where we saw response rates that mirrored the response rates that we're seeing in the COMFORT studies with more responses and splenomegaly of a greater than 35% volume reduction, as well as over 30% symptomatic improvement or higher. Like the COMFORT studies, most people benefited, but 30% to 40% reached that threshold, that is a fairly high threshold, in terms of response. Similarly, there has been real-world evidence that's been presented from several different countries that similarly show that efficacy and safety. Finally, there was data from the United Kingdom that had been presented not that long after the approval of ruxolitinib, where they also included intermediate-1 risk patients with MF and saw very similar safety and efficacy.

Those are the data that are being cited by the NCCN for including that in the recommendations. As I mentioned for fedratinib, we don't have data like that yet, but I suspect we will aggregate that data over time from real-world experiences.

TARGETED ONCOLOGY: What are the challenges that still remain and treating this patient population?

Mesa: I think there are several as it relates to earlier disease. First, we don't have very good surrogate markers regarding progression. In many ways, we are trying to both alleviate the burden of the disease that patients have at that time, like spleen, symptoms, anemia, etc, but we really do care about decreasing the risk of progression and creating progression-free survival. Part of our difficulty is we don't necessarily know why patients progress. We have not been able to clearly show that there is a specific molecular marker, but undoubtedly, there is some interim step. That'll be crucial for us to know if we are using a JAK inhibitor and it is helping to delay disease progression, [because] that augments its value in terms of caring for the patient, both in terms of health economics, as well as value to the patient. That will help to answer if there is a benefit to any form of combination.

Another therapy that has been active in early MF is interferon, or long-acting interferons, again, with potentially theoretical benefit of helping to delay disease progression. However, to quantify that is difficult to do. At the current time, it involves treating people and waiting years to see whether they progress or not. It's not a very practical way of measuring that, and there tends to be a whole variety of other variables that might impact how they are doing and things of that nature.

I do think 1 of the biggest gaps we have in MPNs, overall, is a lack of understanding. What is the pathophysiology of disease progression? And then if we're using therapy to try to interrupt that, whether that's interferon in polycythemia vera, whether that's JAK inhibition in early MF, are we achieving that? Do we need to adjust the dose of a particular medicine to achieve that? That’s a whole other issue as well. We do see response around splenomegaly and symptoms, but we don't know whether a higher dose might be necessary to achieve further progression-free survival.

We have a variety of drugs that were discussed in the meeting that might potentially be used in combination therapy and more advanced disease, but might they have a role earlier on in combination, and knowing whether we were achieving progression-free survival would be very important for us to know. We just don't have a good way to measure that yet.

TARGETED ONCOLOGY: Could you elaborate on these combinations?

Mesa: I think for these combinations, clearly, their trials are geared toward more advanced disease. That’s logical early on in the testing of drugs, so they tend to have eligibility of people that have been on ruxolitinib and failed ruxolitinib, but I think they fall into a couple different categories. I am very excited about them. First is the model of they’re on ruxolitinib, but they have a suboptimal response, and then you add a second drug on top, like the venetoclax (Venclexta) study, or the BET inhibitor. With both of those, they've shown that you can have people who are at a steady state and achieve in a nice response in terms of splenomegaly and symptoms potentially anemia and fibrosis.

Those are exciting, and then there are drugs that are being used as single-agents post-ruxolitinib failure. There's a trial that we're involved in with the LSD1 inhibitor, AMG7289. They too have seen a nice response, splenomegaly, and symptoms, different mechanism of action, and post-ruxolitinib.

Imetelstat has been looked at post-ruxolitinib, potentially with even impacting survival in people with more advanced disease. We have a phase 1 trial with AVID200 being looked at in patients who failed the ruxolitinib through the MPN Research Consortium. There is the MM2 inhibitor that is being looked at in that setting, as well.

There's quite a robust pipeline, heavily focused on this post-ruxolitinib group, so that does tend to make it a more challenging pool of patients to treat it as they tend to have more advanced disease, so I think it's a good place to start. I always have a bit of concern when we're treating patients who are in the most advanced phases that we might miss the activity of a drug that would have been active in an earlier setting, so it's a good place to begin, but again, another example of if we had a good surrogate marker progression-free survival, we will probably learn more about what impact we're having with these novel therapies.

TARGETED ONCOLOGY: Are there any other treatments that are looking promising in the landscape for MF?

Mesa: I think it's a very exciting time. I think that constitutes a lot of the current pipeline, but other important things coming up in parallel are the anemia-focused drugs such as luspatercept (Reblozyl), which is approved now in MDS and in hemoglobinopathies. It might become part of the equation. There are also other JAK inhibitors and epigenetic modifiers. Longer-term, we certainly hope that there are some things on the horizon such as vaccines trying to target the CALR mutation. Those aren't ready for primetime yet, but will they be active and CALR-mutated disease? There has been interest in checkpoint inhibitors that have been transformational in solid tumors. They have not shown a lot of activity yet in this group, but with the whole issue of PD-1/PD-L1 immunotherapy, we're hopeful there are many that are studying aspects of all those pathways to see how they might be more applicable in myeloid diseases, and hopeful that those will also round out our options in the future.

TARGETED ONCOLOGY: What is the key take home message from your presentation?

Mesa: My key takeaway is to be incredibly hopeful for having such a robust set of therapies in development, many of which are active, credible, and we might have, 2 years from now, multiple approved agents that might have a variety of different pathways that might be individualized. If you've got marked thrombocytopenia, you get pacritinib. If you're transfusion-dependent, maybe you get momelotinib upfront or maybe you get ruxolitinib and luspatercept or fedratinib and luspatercept. If you've got a certain high-risk situation, maybe you start with a JAK inhibitor and the BET inhibitor. Maybe you get treated with ruxolitinib for 3 months and have a suboptimal response, so you then also get end up getting venetoclax.

I think it will become much more nuanced, much more individualized, and I think that the period of time you're on a therapy before an evaluation will change. With more options, before we put people on ruxolitinib, and they pretty much stayed on ruxolitinib indefinitely unless somebody had access to a clinical trial. I think increasingly we will have much more concrete markers, so if you don't achieve a response in 3 months or 6 months, you can try 1 of the other therapies.