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Next-Generation Sequencing for TRK Inhibition

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: Thursday, Jul 12, 2018



Transcript: 

Alexander Drilon, MD: Next-generation sequencing is a comprehensive molecular platform that I should underscore isn’t 1 single test: There are several different next-generation sequencing assays that can be used, and they have varying degrees of sensitivity for detecting different alterations, mutations, fusions, or copy number changes. When you’re considering the type of NGS test to use, it’s important to look at whether or not the test has been validated and how good it is at picking up on these alterations.

But in the clinic, this can be very useful because as opposed to the prior paradigm where you had a single test for a single gene, now you have a single test for potentially up to hundreds of different genes. That includes not only the alterations that I mentioned earlier but even signatures that may predict or have been associated with benefit from immune therapies, like tumor mutation burden and MSI-high disease. And so, I think there’s a wide reach in terms of the utility of next-generation sequencing, and it’s poised to really bring a variety of different matched therapies to patients in the clinic.

David Hyman, MD: One of the rapidly evolving areas of oncology these days is obviously testing paradigms, specifically the use of next-generation sequencing and how that can be best incorporated into standard of care. What we have seen is that in the academic setting, there has been an early adoption of these technologies. That makes sense because these technologies are often used to identify appropriate investigational clinical trials for patients, like TRK inhibitors.

What we have now with changes in the regulatory space in the United States is FDA approval of 2 next-generation sequencing tests and national coverage determinations that provide some access and reimbursement to these technologies. I think we’re going to see these technologies adopted more in the community setting as well. Now obviously, besides the access guaranteed by reimbursement and regulatory approval to show that these tests performed as advertised, what’s really important for patients is how this information is used and how useful it is. We’ve looked at that fairly intensively. What we could say is that not every patient’s care will be altered by the use of these tests. But we’re having an explosion of both tumor-agnostic and tumor-specific biomarkers.

Our first tumor-agnostic biomarker was microsatellite instability, and our next-generation sequencing tests are capable of detecting microsatellite instability. And now, with the data generated in TRK fusions, we have a second tumor-agnostic biomarker. It is quite rational for a physician in the community who’s treating a patient who they know will become refractory to standard therapies and have a risk of dying of their advanced cancer to sign one of these tests, at a minimum, to look for these 2 biomarkers. Of course, in the disease-specific context, there are an accumulating number of disease-specific biomarkers that can also alter therapy, and the patient may also benefit from that testing or the identification of investigational biomarkers that make clinical trial opportunities available to them.

The real benefit of next-generation sequencing is not just screening for biomarkers, which in isolation are rare, but that the ability to screen for multiple biomarkers at once means the cumulative rate of finding something that’s potentially meaningful for the patient is much higher.

This is certainly an area that we as physicians need to continue to show is creating value for patients. But when you see patients who are benefiting from larotrectinib or patients who are benefiting from pembrolizumab with MSI-high–positive cancers, as a physician you see these patients start to worry about patients whom we miss by not testing. I think that’s what it really comes down to. I think due to the tremendous efficacy of these therapies, every patient who’s dying of cancer at least deserves access to a diagnostic test that determines whether or not they could really benefit markedly from one of these approaches.

David S. Hong, MD: I am biased in that I believe that all patients should be receiving next-generation sequencing. I recognize that that is not necessarily the common or agreed-upon opinion across communities, but I’ve seen many, many drugs—targeted and precision medicine drugs—that have had benefit in patients in my population. However, NGS testing will ultimately become much more common because the cost of testing will continue to be driven down. As this technology becomes more widely used and more widely available, I think community oncologists will again order these more readily and that will lead to further economics of scale that drive down the cost of NGS.

Recently the FDA has approved the FoundationOne Medicine NGS panel and authorized the MSK-IMPACT panel. I think that’s a really great step forward in the sense that it gives credence to the value and the significance of these platforms. Whether that will lead to widespread use is not clear. Whether or not payers will eventually pay for these beyond CMS is not clear at this point. However, I think it is a good step forward.

Transcript Edited for Clarity 
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Transcript: 

Alexander Drilon, MD: Next-generation sequencing is a comprehensive molecular platform that I should underscore isn’t 1 single test: There are several different next-generation sequencing assays that can be used, and they have varying degrees of sensitivity for detecting different alterations, mutations, fusions, or copy number changes. When you’re considering the type of NGS test to use, it’s important to look at whether or not the test has been validated and how good it is at picking up on these alterations.

But in the clinic, this can be very useful because as opposed to the prior paradigm where you had a single test for a single gene, now you have a single test for potentially up to hundreds of different genes. That includes not only the alterations that I mentioned earlier but even signatures that may predict or have been associated with benefit from immune therapies, like tumor mutation burden and MSI-high disease. And so, I think there’s a wide reach in terms of the utility of next-generation sequencing, and it’s poised to really bring a variety of different matched therapies to patients in the clinic.

David Hyman, MD: One of the rapidly evolving areas of oncology these days is obviously testing paradigms, specifically the use of next-generation sequencing and how that can be best incorporated into standard of care. What we have seen is that in the academic setting, there has been an early adoption of these technologies. That makes sense because these technologies are often used to identify appropriate investigational clinical trials for patients, like TRK inhibitors.

What we have now with changes in the regulatory space in the United States is FDA approval of 2 next-generation sequencing tests and national coverage determinations that provide some access and reimbursement to these technologies. I think we’re going to see these technologies adopted more in the community setting as well. Now obviously, besides the access guaranteed by reimbursement and regulatory approval to show that these tests performed as advertised, what’s really important for patients is how this information is used and how useful it is. We’ve looked at that fairly intensively. What we could say is that not every patient’s care will be altered by the use of these tests. But we’re having an explosion of both tumor-agnostic and tumor-specific biomarkers.

Our first tumor-agnostic biomarker was microsatellite instability, and our next-generation sequencing tests are capable of detecting microsatellite instability. And now, with the data generated in TRK fusions, we have a second tumor-agnostic biomarker. It is quite rational for a physician in the community who’s treating a patient who they know will become refractory to standard therapies and have a risk of dying of their advanced cancer to sign one of these tests, at a minimum, to look for these 2 biomarkers. Of course, in the disease-specific context, there are an accumulating number of disease-specific biomarkers that can also alter therapy, and the patient may also benefit from that testing or the identification of investigational biomarkers that make clinical trial opportunities available to them.

The real benefit of next-generation sequencing is not just screening for biomarkers, which in isolation are rare, but that the ability to screen for multiple biomarkers at once means the cumulative rate of finding something that’s potentially meaningful for the patient is much higher.

This is certainly an area that we as physicians need to continue to show is creating value for patients. But when you see patients who are benefiting from larotrectinib or patients who are benefiting from pembrolizumab with MSI-high–positive cancers, as a physician you see these patients start to worry about patients whom we miss by not testing. I think that’s what it really comes down to. I think due to the tremendous efficacy of these therapies, every patient who’s dying of cancer at least deserves access to a diagnostic test that determines whether or not they could really benefit markedly from one of these approaches.

David S. Hong, MD: I am biased in that I believe that all patients should be receiving next-generation sequencing. I recognize that that is not necessarily the common or agreed-upon opinion across communities, but I’ve seen many, many drugs—targeted and precision medicine drugs—that have had benefit in patients in my population. However, NGS testing will ultimately become much more common because the cost of testing will continue to be driven down. As this technology becomes more widely used and more widely available, I think community oncologists will again order these more readily and that will lead to further economics of scale that drive down the cost of NGS.

Recently the FDA has approved the FoundationOne Medicine NGS panel and authorized the MSK-IMPACT panel. I think that’s a really great step forward in the sense that it gives credence to the value and the significance of these platforms. Whether that will lead to widespread use is not clear. Whether or not payers will eventually pay for these beyond CMS is not clear at this point. However, I think it is a good step forward.

Transcript Edited for Clarity 
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