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FL: Potential for SYK/JAK Inhibitors or Azacitidine

Panelists: Ian W. Flinn, MD, PhD, Sarah Cannon Research Institute; Peter Martin, MD, MS, Weill Cornell Medicine; Loretta J. Nastoupil, MD, University of Texas MD Anderson Cancer Center; Grzegorz S. Nowakowski, MD, Mayo Clinic; Anas Younes, MD, Memorial Sloan Kettering Cancer Center
Published: Thursday, Feb 08, 2018



Transcript: 

Ian W. Flinn, MD, PhD: The SYK inhibitors have been around for a while and have been fairly disappointing. I guess that is the best way to say it. There’s cerdulatinib, which is a combined pathway SYK and JAK inhibitor. You have some experience with this drug. Is that what we need to be doing from now on, looking at dual-pathway inhibitors?

Anas Younes, MD: It’s an interesting question. In the old days, we had these multikinase inhibitors—they used to be called multikinase inhibitors—and they had some activities. Then, the precision medicine came and it was very fashionable. Everybody wants to use a more precise approach. So, some of these multikinase inhibitors overnight switched to an SYK inhibitor or BCL2 inhibitor and so forth. Although they are still multikinase inhibitors, they go by the lowest IC50 that produces inhibition and then they label the drug differently.

I think what I’m trying to say is that the field is moving forward with combinations. If you have a drug that hits multikinases, it is probably better than just a single kinase if the disease is not known to be driven by a single genetic alteration. This is not a CML. Screwing up a couple of kinases is probably better than just 1, and if you can do it with 1 drug, that’s probably better than 2 drugs or 3 drugs. It simplifies drug development. You don’t need to do a drug–drug combination. Here’s a drug that hits both.

Let’s look at this now in a different way, and it’s okay to not be too selective. It’s okay to have more than 1 kinase. You’re going to be guided by activity. I agree with you that SYK inhibitors, the selective ones or the multikinase inhibitors that include SYK, have been disappointing, but BTK inhibitors have been disappointing for follicular lymphoma, too. It’s going to be combinations in the future.

Ian W. Flinn, MD, PhD: That’s an interesting point that Anas brought up from a drug development standpoint of having a combination in 1 pill. It simplifies the drug development. Yet that’s probably not all that realistic, right? For most things, we’re probably going to want different amounts of drug A that’s inhibiting pathway A versus drug B that’s inhibiting pathway B, and then that brings up all the issues of working with 2 novel agents from different pharmaceutical companies. It’s a challenge.

Peter Martin, MD, MS: Yes.

Ian W. Flinn, MD, PhD: Have you got that figured out? Did you figure out how to do it?

Anas Younes, MD: Let me go back to this one. I think, probably 10 years ago, it was very challenging to work with more than 1 company, as all of us know. I think right now, sponsors are realizing that it’s going to be a win-win situation if there is an opponent’s drug, even though it’s outside their pipeline. If it can reasonably enhance the activity of their own agent, they’re willing to do that. And we’re seeing this more frequently happening today. I’d like to see it even more, but I think it’s happening more frequently today than 10 years ago. At the end of the day, I think response and the response duration will guide drug therapy regardless of whether it’s from your pipeline or not.

Grzegorz S. Nowakowski, MD: I think further adoption of molecular testing will help as well, because it is done more commonly, even in the smaller practices. If they, for example, see a patient with EZH2 mutations, they can actually refer that patient to a tertiary center that has a trial. It may not be cost-effective to open this particular trial if the center received few follicular lymphoma patients. But if they do see mutations, then they’ll be more likely to refer this patient. So, I think the adoption of follicular testing could help us move forward.

Ian W. Flinn, MD, PhD: What about beyond the molecular subsets? In the solid tumor world, it seems like these mutations are much more important in terms of the next generation of therapies. But we have some tools that are available to us today in the clinic, such as hypomethylating agents in combination with chemotherapy. There are some data with R-CHOP in that.

Peter Martin, MD, MS: Yes. Many lymphomas, follicular lymphoma included, are largely driven by epigenetic changes, and they change 1 gene and that has an impact on thousands of genes downstream. EZH2 is a perfect example of that. How do you change it? Azacitidine has been around for a long time in myelodysplastic syndromes. We’re currently studying it in diffuse large B-cell lymphoma in combination with chemotherapy, but we do think that it has some rationale, potentially, in indolent lymphomas as well. One of the challenges is that those hypomethylating agents theoretically have to be incorporated in the DNA of proliferating tumors, and if the proliferation rate is very low, maybe it won’t work. But there may be other ways by which they work, including incorporation into RNA or mitochondrial DNA, so I think we’ll see. I think that it’s definitely a field that’s ripe for more research.

Transcript Edited for Clarity 

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Transcript: 

Ian W. Flinn, MD, PhD: The SYK inhibitors have been around for a while and have been fairly disappointing. I guess that is the best way to say it. There’s cerdulatinib, which is a combined pathway SYK and JAK inhibitor. You have some experience with this drug. Is that what we need to be doing from now on, looking at dual-pathway inhibitors?

Anas Younes, MD: It’s an interesting question. In the old days, we had these multikinase inhibitors—they used to be called multikinase inhibitors—and they had some activities. Then, the precision medicine came and it was very fashionable. Everybody wants to use a more precise approach. So, some of these multikinase inhibitors overnight switched to an SYK inhibitor or BCL2 inhibitor and so forth. Although they are still multikinase inhibitors, they go by the lowest IC50 that produces inhibition and then they label the drug differently.

I think what I’m trying to say is that the field is moving forward with combinations. If you have a drug that hits multikinases, it is probably better than just a single kinase if the disease is not known to be driven by a single genetic alteration. This is not a CML. Screwing up a couple of kinases is probably better than just 1, and if you can do it with 1 drug, that’s probably better than 2 drugs or 3 drugs. It simplifies drug development. You don’t need to do a drug–drug combination. Here’s a drug that hits both.

Let’s look at this now in a different way, and it’s okay to not be too selective. It’s okay to have more than 1 kinase. You’re going to be guided by activity. I agree with you that SYK inhibitors, the selective ones or the multikinase inhibitors that include SYK, have been disappointing, but BTK inhibitors have been disappointing for follicular lymphoma, too. It’s going to be combinations in the future.

Ian W. Flinn, MD, PhD: That’s an interesting point that Anas brought up from a drug development standpoint of having a combination in 1 pill. It simplifies the drug development. Yet that’s probably not all that realistic, right? For most things, we’re probably going to want different amounts of drug A that’s inhibiting pathway A versus drug B that’s inhibiting pathway B, and then that brings up all the issues of working with 2 novel agents from different pharmaceutical companies. It’s a challenge.

Peter Martin, MD, MS: Yes.

Ian W. Flinn, MD, PhD: Have you got that figured out? Did you figure out how to do it?

Anas Younes, MD: Let me go back to this one. I think, probably 10 years ago, it was very challenging to work with more than 1 company, as all of us know. I think right now, sponsors are realizing that it’s going to be a win-win situation if there is an opponent’s drug, even though it’s outside their pipeline. If it can reasonably enhance the activity of their own agent, they’re willing to do that. And we’re seeing this more frequently happening today. I’d like to see it even more, but I think it’s happening more frequently today than 10 years ago. At the end of the day, I think response and the response duration will guide drug therapy regardless of whether it’s from your pipeline or not.

Grzegorz S. Nowakowski, MD: I think further adoption of molecular testing will help as well, because it is done more commonly, even in the smaller practices. If they, for example, see a patient with EZH2 mutations, they can actually refer that patient to a tertiary center that has a trial. It may not be cost-effective to open this particular trial if the center received few follicular lymphoma patients. But if they do see mutations, then they’ll be more likely to refer this patient. So, I think the adoption of follicular testing could help us move forward.

Ian W. Flinn, MD, PhD: What about beyond the molecular subsets? In the solid tumor world, it seems like these mutations are much more important in terms of the next generation of therapies. But we have some tools that are available to us today in the clinic, such as hypomethylating agents in combination with chemotherapy. There are some data with R-CHOP in that.

Peter Martin, MD, MS: Yes. Many lymphomas, follicular lymphoma included, are largely driven by epigenetic changes, and they change 1 gene and that has an impact on thousands of genes downstream. EZH2 is a perfect example of that. How do you change it? Azacitidine has been around for a long time in myelodysplastic syndromes. We’re currently studying it in diffuse large B-cell lymphoma in combination with chemotherapy, but we do think that it has some rationale, potentially, in indolent lymphomas as well. One of the challenges is that those hypomethylating agents theoretically have to be incorporated in the DNA of proliferating tumors, and if the proliferation rate is very low, maybe it won’t work. But there may be other ways by which they work, including incorporation into RNA or mitochondrial DNA, so I think we’ll see. I think that it’s definitely a field that’s ripe for more research.

Transcript Edited for Clarity 
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