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Comprehensive NGS and Screening for TRK Gene Fusion

Insights From: Alexander Drilon, MD, Memorial Sloan Kettering Cancer Center
Published: Monday, Jan 14, 2019



Transcript: 

Alexander Drilon, MD: Fortunately, my background as an early drug development trialist really comes from the lung cancer field where we’ve known about these gene signatures, or drivers in lung cancer, for a while now, beginning with EGFR, subsequently ALK and ROS1. And so in my little corner of the world, we’re used to doing comprehensive sequencing to detect these gene signatures across lung cancer, especially those that are stage IV when they present at diagnosis. But now, given the approval of larotrectinib for track fusions regardless of cancer type, we’re also considering the approval of pembrolizumab for MSI [microsatellite instability]–high cancers of any type. I think now we have to think carefully about testing other tumor types for these gene signatures.

And you know that’s a bit of a complicated thing to consider. There’s the element of seeing that insurers or payers cover a next-generation sequencing test. And I think that with the recent FDA approval of the FoundationOne platform, for example, and the authorization of the MSK-IMPACT next generation sequencing platform, that may become easier over time. But the preference, of course, is the environments where there’s no barrier to doing a comprehensive next-generation sequencing test that detects a track fusion. Then I would advocate that that be done for patients with an advanced cancer. And an important piece here is that we’ve really moved away from the earlier paradigm several years ago of doing 1 test for 1 particular gene. So when you order this next-generation sequencing test, you’re not only looking for track fusion, you’re looking for other relevant drivers that might be harbored within the cancer of interest. So, for example, if you have a melanoma and in the series of larotrectinib there were a few melanoma cases that harbored track fusions, when you do next-generation sequencing for a patient with a melanoma, you’re not only looking for a track fusion, you’re also looking at whether or not they might have a BRAF V600E aberration or other gene signatures that may pop up in this cancer type.

So in addition to that, these sequencing platforms, the turnaround time is starting to decrease compared to before, and hopefully they get cheaper over time. With that being said, I think that when you have the opportunity to do this testing, I would recommend DNA-based, comprehensive, hopefully broad hybrid capture next-generation sequencing up front, and knowing that these fusions, you increase the chances of detecting them when there’s an RNA pass. If you have the opportunity to use a next-generation sequencing assay that also has an RNA component, that would maximize the likelihood of your picking up a track fusion.

Now, not all environments are the same in terms of resources. And there are some areas that might not have direct access to next-generation sequencing assay or there may be situations where a payer might not cover it. Now because of that there is an immunohistochemical test, that’s a VENTANA pan TRK antibody, that is able to help you screen your patients’ cancers for a TRK fusion. And this is an IHC [immunohistochemistry] test similar to the ALK D5F3IHC antibody, for example. And the way I would recommend using that is if you have access to the antibody, especially for cancers that may be highly enriched for a TRK fusion, like some rare salivary, or breast cancers, if you have a positive result on the IHC, I would still recommend trying to confirm that on a DNA/RNA-based test post hoc, just to make sure you’re really dealing not just with overexpression of the TRK protein, but also you’re dealing with a cancer that truly harbors a TRK fusion.

Transcript Edited for Clarity
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Transcript: 

Alexander Drilon, MD: Fortunately, my background as an early drug development trialist really comes from the lung cancer field where we’ve known about these gene signatures, or drivers in lung cancer, for a while now, beginning with EGFR, subsequently ALK and ROS1. And so in my little corner of the world, we’re used to doing comprehensive sequencing to detect these gene signatures across lung cancer, especially those that are stage IV when they present at diagnosis. But now, given the approval of larotrectinib for track fusions regardless of cancer type, we’re also considering the approval of pembrolizumab for MSI [microsatellite instability]–high cancers of any type. I think now we have to think carefully about testing other tumor types for these gene signatures.

And you know that’s a bit of a complicated thing to consider. There’s the element of seeing that insurers or payers cover a next-generation sequencing test. And I think that with the recent FDA approval of the FoundationOne platform, for example, and the authorization of the MSK-IMPACT next generation sequencing platform, that may become easier over time. But the preference, of course, is the environments where there’s no barrier to doing a comprehensive next-generation sequencing test that detects a track fusion. Then I would advocate that that be done for patients with an advanced cancer. And an important piece here is that we’ve really moved away from the earlier paradigm several years ago of doing 1 test for 1 particular gene. So when you order this next-generation sequencing test, you’re not only looking for track fusion, you’re looking for other relevant drivers that might be harbored within the cancer of interest. So, for example, if you have a melanoma and in the series of larotrectinib there were a few melanoma cases that harbored track fusions, when you do next-generation sequencing for a patient with a melanoma, you’re not only looking for a track fusion, you’re also looking at whether or not they might have a BRAF V600E aberration or other gene signatures that may pop up in this cancer type.

So in addition to that, these sequencing platforms, the turnaround time is starting to decrease compared to before, and hopefully they get cheaper over time. With that being said, I think that when you have the opportunity to do this testing, I would recommend DNA-based, comprehensive, hopefully broad hybrid capture next-generation sequencing up front, and knowing that these fusions, you increase the chances of detecting them when there’s an RNA pass. If you have the opportunity to use a next-generation sequencing assay that also has an RNA component, that would maximize the likelihood of your picking up a track fusion.

Now, not all environments are the same in terms of resources. And there are some areas that might not have direct access to next-generation sequencing assay or there may be situations where a payer might not cover it. Now because of that there is an immunohistochemical test, that’s a VENTANA pan TRK antibody, that is able to help you screen your patients’ cancers for a TRK fusion. And this is an IHC [immunohistochemistry] test similar to the ALK D5F3IHC antibody, for example. And the way I would recommend using that is if you have access to the antibody, especially for cancers that may be highly enriched for a TRK fusion, like some rare salivary, or breast cancers, if you have a positive result on the IHC, I would still recommend trying to confirm that on a DNA/RNA-based test post hoc, just to make sure you’re really dealing not just with overexpression of the TRK protein, but also you’re dealing with a cancer that truly harbors a TRK fusion.

Transcript Edited for Clarity
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