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TRK Inhibition: Ongoing Challenges

Insights From: David S. Hong, MD, MD Anderson Cancer Center; Alexander Drilon, MD, Memorial Sloan Kettering Cancer Center; David Hyman, MD, Memorial Sloan Kettering Cancer Center
Published: Friday, Jul 27, 2018



Transcript: 

David Hyman, MD: When you take a step back and look at where we are in the TRK inhibitor space and what we have been able to accomplish with larotrectinib, it’s pretty amazing to recognize that a couple of years ago, or even really at the outset of this program, most people in the oncology community would have thought that it would have been impossible to identify a sufficient number of patients to prove that this drug works. And yet this was done in under 2 years from start to finish. I think this teaches us a couple of things.

First is that the penetration of next-generation sequencing has gotten to the point now where we can be really ambitious in the targets that we pick. If we can pick targets where the biology is such that the drugs are going to work, we should not be dissuaded by the rarity of those genetic alterations because it’s helping those patients. What I’ve come to believe is that if a drug works, we can always find the patients. I think TRK inhibition is the perfect example of that.

But there’s also a cumulative effect here, which is that as we accumulate these tumor-agnostic biomarkers that drive adoption of testing platforms capable of detecting other potential tumor-agnostic biomarkers, it potentially creates a snowball effect where we’re profiling more patients, identifying patients with these rare alterations, and enrolling them in clinical trials. We actually saw that even at this year’s ASCO Annual Meeting, where within the space of 1 year, 80 patients were enrolled in a program of LOXO-292, which is a RET inhibitor that showed response rates approaching 80% in RET fusion cancers. What we’re really seeing is an acceleration of the development of these tumor-agnostic biomarkers. I hope to see that it continues. I think at this point it’s limited only by what biology can we find, how many of these mutations can we find, and whether we can build drugs that really knock these mutations out.

Alexander Drilon, MD: Regarding the ongoing challenges for tumor-agnostic drug development, obviously at the top of the list is regulatory buy-in. Thankfully, we’ve seen the approval of pembrolizumab for MSI-high cancers of any type, but that is an approval for immunotherapy. I’m very optimistic that we’ll see a similar approval for a TRK inhibitor, possibly larotrectinib first, in the NTRK fusion–positive cancer space, and that’s a big win for patients. Beyond that, once the drug is approved, the next major challenge is really getting coverage from payers for these tests in tumor types that historically have no coverage for next-generation sequencing. But once those 2 pieces are in place, I think that these programs like the NTRK fusion–positive program will have a real utility in terms of helping a wide variety of different patients with cancer and bring them therapies that they otherwise wouldn’t have previously had access to.

David S. Hong, MD: I think companion diagnostics are a complex issue, and I’m sure there are others who can comment on this much better than I, but it’s fraught with a lot beyond just approval for the specific drug. There’s a device-associated approval along with that companion diagnostic. Ultimately, I think that in the community, what’s going to be used widespread will ideally be something like a multiplatform NGS test. That would probably be the easiest way to identify, for example, NTRK-fusion patients in the future if it was used widespread. However, I think all of this is ultimately going to hinge on cost and benefit in that cost-benefit ratio.

Transcript Edited for Clarity 
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Transcript: 

David Hyman, MD: When you take a step back and look at where we are in the TRK inhibitor space and what we have been able to accomplish with larotrectinib, it’s pretty amazing to recognize that a couple of years ago, or even really at the outset of this program, most people in the oncology community would have thought that it would have been impossible to identify a sufficient number of patients to prove that this drug works. And yet this was done in under 2 years from start to finish. I think this teaches us a couple of things.

First is that the penetration of next-generation sequencing has gotten to the point now where we can be really ambitious in the targets that we pick. If we can pick targets where the biology is such that the drugs are going to work, we should not be dissuaded by the rarity of those genetic alterations because it’s helping those patients. What I’ve come to believe is that if a drug works, we can always find the patients. I think TRK inhibition is the perfect example of that.

But there’s also a cumulative effect here, which is that as we accumulate these tumor-agnostic biomarkers that drive adoption of testing platforms capable of detecting other potential tumor-agnostic biomarkers, it potentially creates a snowball effect where we’re profiling more patients, identifying patients with these rare alterations, and enrolling them in clinical trials. We actually saw that even at this year’s ASCO Annual Meeting, where within the space of 1 year, 80 patients were enrolled in a program of LOXO-292, which is a RET inhibitor that showed response rates approaching 80% in RET fusion cancers. What we’re really seeing is an acceleration of the development of these tumor-agnostic biomarkers. I hope to see that it continues. I think at this point it’s limited only by what biology can we find, how many of these mutations can we find, and whether we can build drugs that really knock these mutations out.

Alexander Drilon, MD: Regarding the ongoing challenges for tumor-agnostic drug development, obviously at the top of the list is regulatory buy-in. Thankfully, we’ve seen the approval of pembrolizumab for MSI-high cancers of any type, but that is an approval for immunotherapy. I’m very optimistic that we’ll see a similar approval for a TRK inhibitor, possibly larotrectinib first, in the NTRK fusion–positive cancer space, and that’s a big win for patients. Beyond that, once the drug is approved, the next major challenge is really getting coverage from payers for these tests in tumor types that historically have no coverage for next-generation sequencing. But once those 2 pieces are in place, I think that these programs like the NTRK fusion–positive program will have a real utility in terms of helping a wide variety of different patients with cancer and bring them therapies that they otherwise wouldn’t have previously had access to.

David S. Hong, MD: I think companion diagnostics are a complex issue, and I’m sure there are others who can comment on this much better than I, but it’s fraught with a lot beyond just approval for the specific drug. There’s a device-associated approval along with that companion diagnostic. Ultimately, I think that in the community, what’s going to be used widespread will ideally be something like a multiplatform NGS test. That would probably be the easiest way to identify, for example, NTRK-fusion patients in the future if it was used widespread. However, I think all of this is ultimately going to hinge on cost and benefit in that cost-benefit ratio.

Transcript Edited for Clarity 
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