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iwMDS 2022 | How can we improve the efficiency of drug approval in MDS?

In this exclusive discussion chaired by Hetty Carraway, MD, Cleveland Clinic, Cleveland, OH, Justin Taylor, MD, Sylvester Comprehensive Cancer Center, Miami, FL, Andrew Brunner, MD, Massachusetts General Hospital, Boston, MA, and Olatoyosi Odenike, MD, UChicago Medicine, Chicago, IL, share some insights into improving the efficiency of drug approval in myelodysplastic syndromes (MDS). Topics covered in this discussion include the challenges of treating patients with TP53 mutation and high-risk disease, the biology behind XPO1 inhibition, and an overview of the MDS MyeloMATCH efforts. This discussion took place at the 1st International Workshop on Myelodysplastic Syndromes (iwMDS) 2022 held in Miami, FL.

Transcript (edited for clarity)

Hetty Carraway:

All right. Well, that was a fantastic session that we just had at the iwMDS 2022 first inaugural meeting. What a delight to be here. My name is Dr Hetty Carraway. I work currently at the Cleveland Clinic as the leukemia director there. And I’m very excited to be here with my colleagues who also were part of the symposium today and part of this amazing session. So I’ll let each of you introduce yourself and we’ll talk briefly about each of the talks that you each gave independently...

Hetty Carraway:

All right. Well, that was a fantastic session that we just had at the iwMDS 2022 first inaugural meeting. What a delight to be here. My name is Dr Hetty Carraway. I work currently at the Cleveland Clinic as the leukemia director there. And I’m very excited to be here with my colleagues who also were part of the symposium today and part of this amazing session. So I’ll let each of you introduce yourself and we’ll talk briefly about each of the talks that you each gave independently. So let’s begin.

Olatoyosi Odenike:

Hi, I’m Toyosi Odenike and I am at the University of Chicago. I also serve as the director of the leukemia program there, and it was very great, very exciting to be at this meeting.

Andrew Brunner:

Hi, I’m Andrew Brunner. I’m at Massachusetts General Hospital Cancer Center and there, I run our MDS clinical trial portfolio. And yeah, I think this meeting was excellent. I had the opportunity to talk about how p53-mutated disease, especially in higher-risk MDS, represents a big challenge for us and some of the recent clinical trial efforts to treat it.

Hetty Carraway:

Fantastic.

Justin Taylor:

And I’m Justin Taylor, I’m at the Sylvester Comprehensive Cancer Center at the University of Miami, here in Miami. And I’m a physician scientist, so I got to talk a little bit about the science behind XPO1 inhibition and a little bit about the clinical trials that have been done so far and where we’re going from there.

Hetty Carraway:

Yeah. This has been a fantastic session and I think for many of us, just a delight to be together, to talk about what’s needed in the MDS space and where we go from here. And hopefully year on year, we’ll continue to have further discussion. Toyosi, you really focused on the MyeloMATCH. So tell us a little bit about the efforts there and both the short term and the long term vision for that.

Olatoyosi Odenike:

Thank you so much for the opportunity. So one significant challenge with myelodysplastic syndromes in general is the heterogeneity. We are treating most of our patients the same way, whereas we know that both biologically and also from a physical perspective, that they are very different. And so the purpose of the MyeloMATCH is to use a precision medicine approach or lens to be able to rapidly screen our patients for the mutations underlying their disease, and then based on that, allocate them to clinical trials that have been developed to match their spectrum of mutations. It is our hope that that will bring us closer to finding the best therapy for the right patient, sort of at the right time and more to come in the years coming forward.

Hetty Carraway:

What a huge effort. And you talked a lot about the NCI- and you talked a lot about the cooperative groups with that. Can you teach us a little bit about how people get involved in kind of the infrastructure?

Olatoyosi Odenike:

Sure. So it’s been a very collaborative, extensive effort between the National Cancer Institute and cooperative groups. So these are the groups that are charged with developing clinical trials all across the country. And so a number of academic investigators are involved in that regard. There’s also a laboratory component to it. And then there are these individual working group baskets. I am privileged to chair the MDS working group basket and investigators across the country who are interested in MDS and in solving that problem, at least with regards to finding therapies for our patients can join us. We meet monthly.

Hetty Carraway:

Herculean effort as you described in your beautiful talk. And with that, I’ll transition to two investigators that are really leading the effort with some of the most challenging patient populations. So whether it’s the relapsed/refractory MDS setting or with novel therapies, one such population harboring TP53 mutations. You spoke about, Dr Brunner, about those patients exposed to APR-246 and kind of the current data that is, or is not out there floating. And we’re eagerly awaiting and kind of lessons learned and how do we move forward and your thoughts on that. So share with us some of the lessons that you taught us in today’s discussion.

Andrew Brunner:

And I think that segues well with the idea of being able to try to match people with a targeted treatment that really is focused on their disease. p53-mutated MDS, higher-risk MDS is a real challenge. I think all of us in the clinic when faced with patients who have this disease really struggle for how to provide them the best therapy. And there are some treatments that work for too few patients and responses are not long enough.

Andrew Brunner:

So really, it’s an area of immediate need that I’m glad is being explored and APR-246, or eprenetapopt, is one such way that we can learn a lot. This is a very large cohort of patients with p53-mutated disease, randomized between either azacitidine or azacitidine plus eprenetapopt in the Phase III study, and also reflecting a lot of early phase data, Phase I/II studies that have shown how we can think about this disease.

Andrew Brunner:

I think we’re all waiting for the final Phase III data, and it will be really important to learn from. A resounding echoing message from this meeting is just how much we can learn from our experiences in these Phase III trials. Regardless of the endpoint, we learn about the biology of the disease, we learn about who has some meaningful benefits. And we learn about how to design better trials for our patients in the future in efforts such as MyeloMATCH or other efforts, how do we refine those. So we really are doing well for our patients.

Andrew Brunner:

I think that there are a lot of lessons that we can take directly into the clinic, particularly around how we deal with novel biomarkers, the heterogeneity of this disease, MDS, even within one gene mutation has so much heterogeneity. It’s really challenging. And also, how do we think about transplant and more definitive therapies or phases of treatment. And so while we’re still waiting on some of the final results with APR-246, no matter what, I think it will push the field forward, which I’m excited about.

Hetty Carraway:

Well, thank you so much for your thoughts on all of that. It was not an easy task. I think you probably had one of the more challenging topics to address. So I was not envious of that, but you did a fantastic job. And then Justin, please share with us some of your thoughts and your work, your translational work in this area with XPO.

Justin Taylor:

Yeah. I think it’s a great lead in to this talk because we heard about how we could be targeting different mutations. And also we heard in this meeting about how the classifications have recently changed and p53 single or double mutation being different classifications. And we hear about drugs targeting them. And so, it still remains though that azacitidine or decitabine, these so-called hypomethylating agents, are the mainstay or backbone of treatment for high-risk MDS. And we also heard in this session, some exciting trials for low-risk MDS. But really, what I was talking about was focusing on high-risk MDS patients that have been treated with hypomethylating agent, and the therapy has failed them. They haven’t failed the therapy, but the therapy has failed to adequately give them a response and that happens in about 50 to 60% of patients so it’s a big need. And particularly we’re focusing on one target, but there’s many. And so one thing that I study in my lab is this protein XPO1, which exports proteins out of the nucleus, and that has been shown to be a good target in other cancers and it’s led to FDA approval of a drug called selinexor. And so I reviewed some of the data on selinexor and MDS. There were a lot of toxicities with that drug in these patients who already have low blood counts and decreasing those blood counts further is not necessarily helpful. And we had great discussions about endpoints in trials.

And so luckily, there’s a second generation drug called eltanexor, which seems to be a little more tolerable, but both of these were early phase studies, so, not to be rushed into the clinic. I think they just show that there was some activity and they are expanding the study to enroll more patients. We now know the safe dose to do that with eltanexor. So the next steps will be enrolling more patients to see, is it really promising enough to take forward to a larger study? And I thought that was another good thing that came out of this session, was how do we identify the most promising drugs and how do we really think through the trials before we go enrolling a large number of patients and find out the study didn’t work as we had hoped.

Hetty Carraway:

Yeah. Some really important comments from Rich Little, right? Really kind of highlighting the fact and the importance of the biomarkers and validating them, and/or using them in earlier phase studies so that we kind of make earlier decisions about whether or not we’re truly hitting the target or not, challenging us to think more creatively in that space rather than just embarking on these large studies. So I definitely took that message home too. And hopefully, as we move forward with novel agents in this space we’ll be able to have an impact there.

Hetty Carraway:

And I think some of the larger questions was really around how do we accelerate approval or get these novel agents to the patients in need sooner. And so much of the effort over the last couple of days was really focused on conversations around that. One of the presentations that I had the honor of doing today was really focusing on patients that have over-expression of RARA, and for those patients, they may in fact benefit from an agent called SY-1425 and early data using that agent in combination with a backbone of azacitidine for patients with AML that were unfit for intensive chemotherapy, did appear to have improvement in their CR rates, overall response rates, that were promising as well as transfusion independence.

Hetty Carraway:

And with that data, it’s now moved forward with the SELECT-1 in the AML study and the SELECT-1 MDS study. So with regard to that, I think really exciting next steps with a drug that is fairly, has a pretty good toxicity profile and is well tolerated. And I think that kind of dovetails nicely with some of the other agents that we’ve been talking about and the challenges in the MDS space, where we really have issues with tolerability in keeping patients on drug. And then having challenges in the Phase III space and specifically where patients on monotherapy stay on drugs longer than patients on combination therapy. So, any thoughts on that issue from anybody here?

Olatoyosi Odenike:

I would say, I know we’re all working very hard in trying to be thoughtful and innovative and creative about clinical trial design, but I also think we have to interject some patients early on to make sure that in fact, we’re doing very careful dose finding and sequence finding trials, and really not brushing those toxicities under the carpet. Like, “It’ll be okay. It was just a…”

Hetty Carraway:

“Just move forward.”

Olatoyosi Odenike:

Yeah, “Just move forward.” It seems kind of exciting, right? Yeah. So I think investing a little more time upfront early can yield huge dividends later. Just hitting that maximum tolerated dose, that’s probably not what we should be aiming for, right, because our patients have to stay on it. We want them to stay on it long enough to be able to get a benefit.

Hetty Carraway:

I think we’re getting those messages from the FDA too, where they’re talking about dose de-escalation rather than dose escalation. So thank you for that comment. Any other thoughts?

Andrew Brunner:

Actually, it parallels really nicely, the session earlier talking about frailty and we have an older patient population and this idea of really goal-directed therapy, in some ways, for patients. Some patients, you might want to go with intensive therapy and your strategy is going to be very different than patients where maybe choosing an optimal,  gentler approach or starting and ramping up to their tolerance may be a much more appropriate strategy. And can we get into different phases of therapy based on goals with our patients? I think that that is increasingly a message rather than just treating everyone with a blanket regimen.

Hetty Carraway:

And dose modifying, but not telling anybody. Or, I mean, some of the data that was presented was the number of cycles that was reported in clinical trials versus the real-world data of what our patients are actually able to tolerate.

Justin Taylor:

Yeah. I was just going to mention that the azacitidine and venetoclax studies were also presented at this meeting. The speakers were virtual, this was a nice hybrid meeting, but I thought they hit on some of those points about how the dose used is not the same as an AML and it’s a shorter duration. And if they had to reduce the doses, they were trying to reduce the azacitidine dose first. I learned lots of interesting things from that.

Hetty Carraway:

Yeah.  Well, thank you to each of you for the work that you did today and the work that you do every day to treat patients with myelodysplastic syndromes. I’m looking forward to many future meetings together with each of you, and thank you for coming today and doing this brief.

 

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