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ONCAlert | Upfront Therapy for mRCC

An Overview of the TRK Inhibition Landscape

Targeted Oncology
Published Online:1:42 PM, Mon February 4, 2019

Shubham Pant, MD: Dr Hong, could you tell us a little bit about these newer TRK inhibitors? Do they specifically target TRK? Do they target other tyrosine kinase, like other tyrosine kinase inhibitors?

David S. Hong, MD: So some of the new TRK inhibitors—for example, larotrectinib, or Vitrakvi—are very specific for the TRK family of receptors or fusion proteins. However, there are other TRK inhibitors such as entrectinib, which has also received breakthrough indication for NTRK cancers. And it’s less specific. It also targets, for example, ALK and ROS. And there are a number of drugs already out there, small molecules such as cabozantinib. Merestinib, I think, is another drug that is in development that seemed to be a multikinase inhibitor. They don’t just target TRK per se.

Shubham Pant, MD: So when you say a multikinase inhibitor, what does that mean?

David S. Hong, MD: That means that the actual molecule, although this primary target may be NTRK, may also fit in the ATP [adenosine triphosphate] pocket of, for example, ALK or ROS.

Shubham Pant, MD: So it may affect different pockets and inhibit different pathways, but most of the newer molecules, which are in development, exactly focus on the TRK-based pocket.

David S. Hong, MD: The newer ones, the most further in development. For example, larotrectinib is very specific for that pocket, yes.

Shubham Pant, MD: So larotrectinib recently got an FDA designation. What other molecules coming down the pike are interesting in targeting the TRK pathway?

David S. Hong, MD: So entrectinib is also interesting in the sense that it shows activity in NTRK patients. There are other drugs that are primarily in phase I development. There’s a molecule from Daiichi Sankyo and other companies that may also be drugs that eventually enter this space. One other very interesting molecule obviously developing is LOXO-195, which really was developed to target resistant mutations that arise from patients who receive larotrectinib.

Shubham Pant, MD: That’s very interesting. So the patients who got larotrectinib we can talk about later. But essentially, they had a mutation come up that you identified on tumor or in blood, and then you’re trying to target it in a different way. So tell me, in a way, what is the difference in the mechanism of action in these TRK inhibitors. Are they all the same? What is the difference when you peel aside these TRK inhibitors?

David S. Hong, MD: There’s probably not a huge difference other than the specificity of the targeting of each of the individual molecules and maybe the binding specificity or the binding sensitivity of these molecules.

Shubham Pant, MD: That means how hard it binds to the target?

David S. Hong, MD: Correct, correct. And as I shared, larotrectinib, or Vitrakvi, is probably the most specific of these drugs. There is some suggestion in the entrectinib data that it crosses the blood–brain barrier, and that is warranted by some of the data that were presented recently at ESMO [the European Society for Medical Oncology Congress]. We do think, many people who do research in this space, that larotrectinib, Vitrakvi, also can cross that blood–brain barrier.

Shubham Pant, MD: So that would be interesting for patients who have brain metastases and everything.

David S. Hong, MD: Correct.

Shubham Pant, MD: And that could be useful for them. Because we’ve seen other therapies that have come out—especially in melanoma—immunotherapies, that can cross the blood–brain barrier and cause brain metastases to shrink, not with radiation, just with their medicine.

David S. Hong, MD: Correct.

Shubham Pant, MD: Tell me this. In a way, what are the other ones? We talked a little bit about resistance mechanisms, and everything on this trial. So what kind of resistance? You said something about solvent mutations. What are the resistance mechanisms that happen with these TRK inhibitors?

David S. Hong, MD: To date all we know is that the solvent and gateway mutations do occur in these patients who receive a TRK inhibitor. We don’t know of any other specific pathways of resistance. If you look at other diseases and treatments such as EGFR inhibitors, there appear to be alternative pathways of at least inherent resistance, such as cetuximab, etc.

Shubham Pant, MD: Great.

David S. Hong, MD: But right now, there just have not been enough data to suggest there are other alternative pathways of resistance. But that is definitely something that we’re exploring, and I know my colleagues at Sloan Kettering are exploring that. We’re exploring that at our institution.

Shubham Pant, MD: So the science is going forward in this.

Transcript edited for clarity.

Shubham Pant, MD: Dr Hong, could you tell us a little bit about these newer TRK inhibitors? Do they specifically target TRK? Do they target other tyrosine kinase, like other tyrosine kinase inhibitors?

David S. Hong, MD: So some of the new TRK inhibitors—for example, larotrectinib, or Vitrakvi—are very specific for the TRK family of receptors or fusion proteins. However, there are other TRK inhibitors such as entrectinib, which has also received breakthrough indication for NTRK cancers. And it’s less specific. It also targets, for example, ALK and ROS. And there are a number of drugs already out there, small molecules such as cabozantinib. Merestinib, I think, is another drug that is in development that seemed to be a multikinase inhibitor. They don’t just target TRK per se.

Shubham Pant, MD: So when you say a multikinase inhibitor, what does that mean?

David S. Hong, MD: That means that the actual molecule, although this primary target may be NTRK, may also fit in the ATP [adenosine triphosphate] pocket of, for example, ALK or ROS.

Shubham Pant, MD: So it may affect different pockets and inhibit different pathways, but most of the newer molecules, which are in development, exactly focus on the TRK-based pocket.

David S. Hong, MD: The newer ones, the most further in development. For example, larotrectinib is very specific for that pocket, yes.

Shubham Pant, MD: So larotrectinib recently got an FDA designation. What other molecules coming down the pike are interesting in targeting the TRK pathway?

David S. Hong, MD: So entrectinib is also interesting in the sense that it shows activity in NTRK patients. There are other drugs that are primarily in phase I development. There’s a molecule from Daiichi Sankyo and other companies that may also be drugs that eventually enter this space. One other very interesting molecule obviously developing is LOXO-195, which really was developed to target resistant mutations that arise from patients who receive larotrectinib.

Shubham Pant, MD: That’s very interesting. So the patients who got larotrectinib we can talk about later. But essentially, they had a mutation come up that you identified on tumor or in blood, and then you’re trying to target it in a different way. So tell me, in a way, what is the difference in the mechanism of action in these TRK inhibitors. Are they all the same? What is the difference when you peel aside these TRK inhibitors?

David S. Hong, MD: There’s probably not a huge difference other than the specificity of the targeting of each of the individual molecules and maybe the binding specificity or the binding sensitivity of these molecules.

Shubham Pant, MD: That means how hard it binds to the target?

David S. Hong, MD: Correct, correct. And as I shared, larotrectinib, or Vitrakvi, is probably the most specific of these drugs. There is some suggestion in the entrectinib data that it crosses the blood–brain barrier, and that is warranted by some of the data that were presented recently at ESMO [the European Society for Medical Oncology Congress]. We do think, many people who do research in this space, that larotrectinib, Vitrakvi, also can cross that blood–brain barrier.

Shubham Pant, MD: So that would be interesting for patients who have brain metastases and everything.

David S. Hong, MD: Correct.

Shubham Pant, MD: And that could be useful for them. Because we’ve seen other therapies that have come out—especially in melanoma—immunotherapies, that can cross the blood–brain barrier and cause brain metastases to shrink, not with radiation, just with their medicine.

David S. Hong, MD: Correct.

Shubham Pant, MD: Tell me this. In a way, what are the other ones? We talked a little bit about resistance mechanisms, and everything on this trial. So what kind of resistance? You said something about solvent mutations. What are the resistance mechanisms that happen with these TRK inhibitors?

David S. Hong, MD: To date all we know is that the solvent and gateway mutations do occur in these patients who receive a TRK inhibitor. We don’t know of any other specific pathways of resistance. If you look at other diseases and treatments such as EGFR inhibitors, there appear to be alternative pathways of at least inherent resistance, such as cetuximab, etc.

Shubham Pant, MD: Great.

David S. Hong, MD: But right now, there just have not been enough data to suggest there are other alternative pathways of resistance. But that is definitely something that we’re exploring, and I know my colleagues at Sloan Kettering are exploring that. We’re exploring that at our institution.

Shubham Pant, MD: So the science is going forward in this.

Transcript edited for clarity.
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