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TRK Inhibitors for Solid Tumors: Overview

Panelists: Benjamin Levy, MD, Johns Hopkins Sidney Kimmel Cancer Center, Sibley Memorial Hospitale; Mark Agulnik, MD, Northwestern University Feinberg School of Medicine; Marcia Brose, MD, PhD, University of Pennsylvania; Edward Kim, MD, Levine Cancer Institute, Atrium Health ; John Marshall, MD, Georgetown University; Philip Agop Philip, MD, PhD, FRCP, Barbara Ann Karmanos Cancer Institute
Published: Tuesday, May 07, 2019



Transcript: 

Benjamin P. Levy, MD: I promise you we’ll get to the NGS [next-generation sequencing] testing section in this panel. I knew it would evolve in every way back to testing, which is so important. Part of the base of the story here is how we test, how we identify, and whom we test. We’ll get there in due time. But first let’s talk about the data. We’ve now identified these fusions. They’re rare. They are driver mutations. We’ve had a crowded space, similar to the ALK world in lung cancer, where we’ve got all these therapies coming in. Larotrectinib was first approved by the FDA in November 2018. We have entrectinib, which is a ROS and ALK drug as well but has activity in NTRK fusions.

And then a host of other drugs—LOXO-195, cabozantinib, crizotinib. Just a quick question before we talk about the data: Do these drugs all work the same? Are they just as active in TRK fusions as another one, or are there differences here?

Edward S. Kim, MD: We have lung cancer experience [that] says not all the TKIs [tyrosine kinase inhibitors] are the same, whether you’re talking about EGFR or ALK. We can site our own I-O [immuno-oncology] experience, in which the main I-Os don’t seem to be behaving the same way in exactly the same situation. So I would assume that they’re going to be different regardless of how sterically, chemically they look with the figures. But they seem to have differences.

Marcia S. Brose, MD, PhD: I would just say that there are sort of 2 groups here, of the drugs you were just talking about. There are these sort of second-generation ones that, for the most part, are much more narrowly targeted; versus ones like cabozantinib and other ones, regorafenib, that had VEGFR2, as well as multiple other things. It’s important, when we get into toxicity profiling, that you consider those 2 things. Sort of making it into 2 classes is probably the best way to start. We have the ultraspecific ones versus the ones that are hitting multiple…

Edward S. Kim, MD: Of course. That’s exactly how ALK and crizotinib came about, right?

Marcia S. Brose, MD, PhD: Exactly.

Edward S. Kim, MD: With crizotinib, the first target was not ALK in the IC50s [half maximal inhibitory concentrations], etc. It was MET and RON, and it was dirty enough that it hit ALK. And so it worked.

Marcia S. Brose, MD, PhD: Right.

Edward S. Kim, MD: So yes, I think it’s a very similar example of how we’ve looked at it.

John L. Marshall, MD: I’ve just been very impressed with the drug development in these rare spaces. I watched the GIST [gastrointestinal stromal tumors] world. We discovered GIST on the backs of a drug, and I thought, “Why would we ever need another one?” because that was the best one. And now we have lines of therapy in GIST. That’s a relatively common disease compared with these fusion abnormalities, yet we’re already seeing who’s got a better product. Are there different subtypes of these? Will there be resistance that emerges, just like you lung people taught us in the EGFR space? So I’m fascinated that, when we get 1 of these things by the tail, we don’t let it go until we really optimize the therapy.

Philip Agop Philip, MD, PhD, FRCP: The other issue is the toxicity. If you have off-target effect, which you’re going to have more of and with the dirtier of the drug, that may well be 1 of the differentiators of the drug.

Benjamin P. Levy, MD: Mark?

Mark Agulnik, MD: You mentioned GIST—and I do treat GIST, and this is not dissimilar to what happened with GIST. We don’t say anymore that someone has a GIST. Now you actually figure out what their mutation is, and then you specifically go to the axon. You’re figuring out what part, and you really break it down further. What drugs work for which ones? I think that will evolve with this as well, and we’ll start to see NTRK1, NTRK2, NTRK3. We’ll see which is better. So the model just keeps applying from disease to disease, it just keeps breaking it down, and the therapies get more effective as we break it down. It’s fascinating.

Marcia S. Brose, MD, PhD: I was also going to say some of the off-target effects can also be therapeutic. In thyroid cancer, we’ve really enjoyed things like cabozantinib in medullary thyroid cancer because it had RET activity, but it also was a VEGFR inhibitor. It was great for people who had RET mutations, but it was also great for people who didn’t. And so, sometimes it’s sort of a love-hate relationship with those more broadly targeted therapies.

Benjamin P. Levy, MD: Yeah. I’ve been impressed, as John mentioned, how many drugs have come into the space but also the difference between the drugs. As the newer generations come out from the ALK and the EGFR world, to see the next-generation drug outperform the old generation has been impressive. It’s been an impressive story.

Transcript Edited for Clarity

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Transcript: 

Benjamin P. Levy, MD: I promise you we’ll get to the NGS [next-generation sequencing] testing section in this panel. I knew it would evolve in every way back to testing, which is so important. Part of the base of the story here is how we test, how we identify, and whom we test. We’ll get there in due time. But first let’s talk about the data. We’ve now identified these fusions. They’re rare. They are driver mutations. We’ve had a crowded space, similar to the ALK world in lung cancer, where we’ve got all these therapies coming in. Larotrectinib was first approved by the FDA in November 2018. We have entrectinib, which is a ROS and ALK drug as well but has activity in NTRK fusions.

And then a host of other drugs—LOXO-195, cabozantinib, crizotinib. Just a quick question before we talk about the data: Do these drugs all work the same? Are they just as active in TRK fusions as another one, or are there differences here?

Edward S. Kim, MD: We have lung cancer experience [that] says not all the TKIs [tyrosine kinase inhibitors] are the same, whether you’re talking about EGFR or ALK. We can site our own I-O [immuno-oncology] experience, in which the main I-Os don’t seem to be behaving the same way in exactly the same situation. So I would assume that they’re going to be different regardless of how sterically, chemically they look with the figures. But they seem to have differences.

Marcia S. Brose, MD, PhD: I would just say that there are sort of 2 groups here, of the drugs you were just talking about. There are these sort of second-generation ones that, for the most part, are much more narrowly targeted; versus ones like cabozantinib and other ones, regorafenib, that had VEGFR2, as well as multiple other things. It’s important, when we get into toxicity profiling, that you consider those 2 things. Sort of making it into 2 classes is probably the best way to start. We have the ultraspecific ones versus the ones that are hitting multiple…

Edward S. Kim, MD: Of course. That’s exactly how ALK and crizotinib came about, right?

Marcia S. Brose, MD, PhD: Exactly.

Edward S. Kim, MD: With crizotinib, the first target was not ALK in the IC50s [half maximal inhibitory concentrations], etc. It was MET and RON, and it was dirty enough that it hit ALK. And so it worked.

Marcia S. Brose, MD, PhD: Right.

Edward S. Kim, MD: So yes, I think it’s a very similar example of how we’ve looked at it.

John L. Marshall, MD: I’ve just been very impressed with the drug development in these rare spaces. I watched the GIST [gastrointestinal stromal tumors] world. We discovered GIST on the backs of a drug, and I thought, “Why would we ever need another one?” because that was the best one. And now we have lines of therapy in GIST. That’s a relatively common disease compared with these fusion abnormalities, yet we’re already seeing who’s got a better product. Are there different subtypes of these? Will there be resistance that emerges, just like you lung people taught us in the EGFR space? So I’m fascinated that, when we get 1 of these things by the tail, we don’t let it go until we really optimize the therapy.

Philip Agop Philip, MD, PhD, FRCP: The other issue is the toxicity. If you have off-target effect, which you’re going to have more of and with the dirtier of the drug, that may well be 1 of the differentiators of the drug.

Benjamin P. Levy, MD: Mark?

Mark Agulnik, MD: You mentioned GIST—and I do treat GIST, and this is not dissimilar to what happened with GIST. We don’t say anymore that someone has a GIST. Now you actually figure out what their mutation is, and then you specifically go to the axon. You’re figuring out what part, and you really break it down further. What drugs work for which ones? I think that will evolve with this as well, and we’ll start to see NTRK1, NTRK2, NTRK3. We’ll see which is better. So the model just keeps applying from disease to disease, it just keeps breaking it down, and the therapies get more effective as we break it down. It’s fascinating.

Marcia S. Brose, MD, PhD: I was also going to say some of the off-target effects can also be therapeutic. In thyroid cancer, we’ve really enjoyed things like cabozantinib in medullary thyroid cancer because it had RET activity, but it also was a VEGFR inhibitor. It was great for people who had RET mutations, but it was also great for people who didn’t. And so, sometimes it’s sort of a love-hate relationship with those more broadly targeted therapies.

Benjamin P. Levy, MD: Yeah. I’ve been impressed, as John mentioned, how many drugs have come into the space but also the difference between the drugs. As the newer generations come out from the ALK and the EGFR world, to see the next-generation drug outperform the old generation has been impressive. It’s been an impressive story.

Transcript Edited for Clarity
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