New Myelofibrosis Therapies and Potential Future Treatment Strategies

Expert Roundtable Part 4

In this expert roundtable series, Firas El Chaer, MD, University of Virginia Comprehensive Cancer Center, Charlottesville, Virginia, leads a roundtable panel discussion on updates in myelofibrosis with Raajit K Rampal, MD, Memorial Sloan Kettering, New York, New York, and Lindsay A M Rein, MD, Duke University Medical Center, Durham, North Carolina.

In part 4 of the roundtable, the experts discuss innovative myelofibrosis treatments and exciting new data on future therapies.

Transcript:

Dr El Chaer: In the last few minutes of our discussion tonight, we want to focus on few newer therapies in this space, whether is combination of the single agent, whether targets myelofibrosis itself, anemia, or any other associated symptom.

I can start, I think we're soon going to learn about the INDEPENDENCE trial that's testing luspatercept, a TGF beta superfamily-targeting agent. Of course it's approved in MDS. This is going to be interesting, so far the study has been showing positive outcomes, once it is approved for this disease, I think we're going to see a wider adoption of combining it with many other JAK inhibitors that can cause anemia.

This is one of the things that I'm excited about. Lindsay, what's another thing you're excited about in this space?

Dr Rein: I'll highlight some data that you had the opportunity, as our esteemed moderator, to present this year at ASH of the Pim-1 kinase inhibitor, that's exciting data. We're seeing with nuvisertib, or TP-3654, some interesting data that's starting to come out of these phase 1 studies looking at symptom improvement or symptom benefit and a relapsed/refractory patient population for MF.

It's interesting, again, going along with the idea of combination strategies and which JAK along the lines of the question, which JAK inhibitor do we use? A lot of the combination trials now are using ruxolitinib as frontline. Is there an opportunity to combine alternative JAK inhibitors? Now with this particular Pim-1 kinase inhibitor, we're seeing the combination with both ruxolitinib and momelotinib. That'll be really interesting to see how some of that data matures.

Dr El Chaer: I agree with that assessment. I presented the data. Raajit, your turn.

Dr Rampal: There's so much to talk about here in terms of new drugs. This is cool, this is what we've been waiting for. Things continue to evolve in terms of the trials that are ongoing, but things that have been reported, so one example is pelabresib, the BET inhibitor, where the top line data was presented last year and this year at ASH there was an update on the week 48 data, which very encouragingly shows that it seems that the loss of response occurs much to a greater extent with ruxolitinib only versus ruxolitinib and pelabresib and there was also a deepening of symptom response. Over time we are seeing that that combination is showing persistent benefit over ruxolitinib alone.

That's actually important data for all of these drugs that we're developing because our readouts are at 6 months, 6 months is 6 months right and this is a long disease. We've got to see really what they do in a longer period of time. Hopefully all of the drugs that we're talking about here, we will see more and more mature data over time. Pelabresib remains an interesting drug under development.

Dr El Chaer: Since we’re focusing on myelofibrosis, I’ll focus on anemia. Imetelstat, it's a telomerase inhibitor, that of course now it's approved for MDS. It's making its way in the myelofibrosis space, it's going to be interesting, it's called IMbark and it's a phase 2 study, and one of the side effects of it that we see in the MDS space is neutropenia and thrombocytopenia. It's going to be interesting how that drug is going to be used in the myelofibrosis space with its associated cytopenias that can of course happen, but I'm excited to see how it's going to affect symptom reduction as clear response, as well as potentially anemia response, in that patient population. Lindsay next.

Dr Rein: We saw some really interesting data that was presented this year at ASH looking at the MDM2 inhibitors. Navtemadlin is what was presented at ASH. I thought it was particularly interesting that there was some really nice correlative data that was presented within the context of the BOREAS study, there were 2 abstracts and 2 presentations by Dr Mascarenhas.

This brings to light 2 important points. Number 1, a novel therapeutic agent that works with a really interesting and different mechanism and we're seeing more trials, the POIESIS study, which is ongoing and more data reading out. It also brings up a big point within the MF community, which is what are we looking at in terms of biomarkers? How are we monitoring myelofibrosis in patients when we're starting not only JAK inhibitors, but now when we're starting combinations and these novel agents.

For me, this is really exciting because again, novel therapy, but also really going down the line of questioning of what biomarkers do we need? What should we be looking at? How do we monitor these diseases? Do we look at molecular type data? Are we looking at spleen volume, which we've talked about symptoms. How do we assess how things are working and how do we define disease modification?

Dr Rampal: Something that wasn't presented at the meeting per se, but the calreticulin story, right? There are now 2 drugs in phase 1 trials that target calreticulin both for myelofibrosis and for ET. Preclinical data looks really strong in that there's a specific effect on CALR mutant cells and really not on JAK mutant cells or non CALR-expressing cells, I think that's interesting. It's going to be exciting to see what comes of these studies, which are enrolling really robustly right now. That could make a big change in how we think about this.

Could these drugs be like our Rituxan? We would love a Rituxan for our disease. That would be cool. We'll have to see what happens.

Dr El Chaer: Absolutely. The next family that's exciting in this space is the anti-hemojuvelin monoclonal antibodies. One of them is presented at ASH this year, the DISC-0974 and it's still early. It's phase 1b-2a study, but it's interesting that it can have a lot of effect on transfusion dependency, improvement of anemia. Potentially you can look at it as an add on to a JAK inhibitor or something like that, especially as it inhibits the signaling pathway of the hepcidin that we've seen. It is making its way now to the MPN space. Lindsay, you want to take maybe one more round?

Dr Rein: Let's go with LSD1 [lysine-specific demethylase 1] inhibition and let's specifically within MF, think a little bit about bomedemstat. This has been presented previously, I find this fascinating, really the natural history of these diseases. Again, really lovely data coming out of the Malawi lab and in various labs looking at how these diseases progress over time on a spectrum. bomedemstat and LSD1 inhibition is interesting because it's being utilized not only in MF, but we're also seeing it now in trials for ET, essential thrombocytosis and polycythemia vera. This particular group of agents has potential across the spectrum of MPNs, which I think brings out a whole other interesting line of thought as we think about how we approach patients earlier versus later. When do we intervene? How do we make that work? 

Dr Rampal: The new JAK inhibitors, now we've got a type 2 JAK inhibitors in clinical trials and we also have a selective JAK inhibitor from Incyte inside that actually, supposedly, selectively goes after the V617F mutation. This is really cool. These are drugs that might change the therapeutic index and maybe give us less in the way of off-target effects, we'll have to see. We don't know anything at this point, but at least we have these as options and they are enrolling currently.

Dr El Chaer: I have last 2 abstracts or posters that were interesting to me. Of course, selinexor and that drug making, its comeback in the myelofibrosis world. Of course it's approved for multiple myeloma now and it blocks the XP01 and restores tumor suppressive function. It's still early in the phases and it's being combined with other drugs, but what we've seen so far, the combination has really shown spleen response. It's quite impressive and symptom reduction. 

The last one that I want to think about is the elritercept, which is again similar to luspatercept, which is the TGF beta superfamily, which enhances erythropoiesis, again, focusing on anemia in this disease space. Those are what comes to mind.

I want to just open the space, a last comment from Lindsay and Raajit before we close this session tonight. Lindsay, do you want to give last thoughts something that we did not discuss or something that you want to bring up?

Dr Rein: What I think we need to start thinking about is, we've created so many novel therapeutics, we've come up with combinations, and as a field, what we really need to work on now is figuring out what our endpoints are and what we're hoping to achieve as a field. That's really the huge question that we need to address. I think the endpoints that we use when we're looking at monotherapies, JAK inhibitor monotherapy, are not going to be the same as the endpoints and the biomarkers that we need to utilize for some of these combinations or perhaps novel agents.

What's really exciting and interesting is just the amount of growth that we've already seen, but also just sitting here thinking about the amount of growth that we really need to continue to have. Lots of work done, but also lots that still needs to be done.

Dr Rampal: There's a lot going on and if we get some of these drugs to approval, then the question is for who are these drugs? Is everything for every patient, we've got to think about the potential toxicities including financial toxicity, right? Because its going to cost more. We've got to begin to think about as we move, hopefully some of these drugs towards the finish line, who are we treating and for what benefit? That's going to take some time to figure out.

Dr El Chaer: Well, I want to thank you both so much for taking the time to be with us tonight, and I want to thank our audience who listened to us. And I want to thank Oncology Learning Network for organizing this discussion and we'll see you soon. Thank you.

Dr Rein: Thank you. 

Dr Rampal: Thank you.