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Use of TRK Inhibition in Specific Tumor Types

Insights From: David S. Hong, MD, MD Anderson Cancer Center; David Hyman, MD, Memorial Sloan Kettering Cancer Center; David Reardon, MD, Dana-Farber Cancer Institute
Published: Tuesday, Oct 29, 2019



Transcript: 

David Hyman, MD: There are an increasing number of cancers in which some form of genetic testing is required to guide prescribing behavior in a tumor specific way. And these include diseases like lung cancer, melanoma, gastrointestinal stromal tumors, colorectal cancers, and cholangiocarcinomas. And so one important paradigm in those cancers is going to be ideally, you would incorporate testing up front that can detect not only the tumor-specific biomarkers that are relevant but also incorporate TRK fusion detection. In centers, for example, where that may not be available and settings where that isn’t available, another paradigm is to screen patients for tissue-specific biomarkers. And, if they don’t have any of them, reflex those negative patients into a more focused assay like immunohistochemistry for TRK or next-generation sequencing [NGS].

So to explain this in a more granular way, if you have a papillary thyroid cancer patient, you test them for BRAF, which is standard of care, and you might look, for example, for a RET fusion. So those are the 2 most common genetic events in papillary thyroid cancer. If you didn’t find either of those, that would be the patient who is highly enriched for the presence of other actionable alterations like TRK fusions. Or, for example, if you had a patient with gastrointestinal stromal tumor [GIST] that was KIT wild-type, which is the most common alteration that’s a driver alteration in GIST tumors, that would be the patient who I would selectively rescreen for TRK fusions.

Same thing with an otherwise driver negative lung cancer. If the patient screens negative for EGFR, KRAS, ALK, and ROS, that would be a patient who you would want to secondarily screen for TRK fusions. So I think over time what we’re going to see is incorporation of assays that can detect TRK fusions along with all other alterations in one panel test. But, as we live through the evolution of the diagnostic space, I would encourage practitioners out there who are managing these patients who have done relevant tissue-specific testing and have not identified any of the common driver alterations in those cancers to consider and talk to their pathologist or local laboratories about secondary TRK screening and fusion detection in those patients.

Non–small cell lung cancer really is at the forefront of precision medicine. We now have an increasing number of genomically defined subsets of lung cancer that really guide prescribing behavior. What these data collectively show is that TRK has really joined that list of genetically defined lung cancer. Lung cancers, because they have so many genetic targets, are really now almost routinely profiled by next-generation sequencing tests. So I really think it is incumbent upon us to make sure that those next-generation sequencing tests are capable of detecting all the actionable alterations in lung cancers, including the fusions, such as ALK, ROS, and NTRK. And patients who have these NTRK fusions really ought to receive a TRK inhibitor due to the really high level of durable activity in this. And I think for those patients it really will markedly change the natural history of their disease.

David Reardon, MD: My approach for incorporating next generation sequencing for our patients with primary and secondary brain cancers is to try to make this available and do this for every patient. The TRK inhibitors are showing exciting results in the subset of patients who have these driving mutations involving the TRK genes and the infusion transcripts.

But there are other drivers that we are identifying through NGS that we are able to evaluate therapeutics capable of targeting those drivers as well. So in patients with primary and secondary brain cancers, there’s a growing appreciation and recognition of a number of different drivers and mutations that are relevant in these tumors and a growing repertoire of drugs are available to target those drivers and mutations for our brain cancer patients, analogously to what’s evolved with lung cancer and breast cancer and colorectal cancer.

Transcript Edited for Clarity
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Transcript: 

David Hyman, MD: There are an increasing number of cancers in which some form of genetic testing is required to guide prescribing behavior in a tumor specific way. And these include diseases like lung cancer, melanoma, gastrointestinal stromal tumors, colorectal cancers, and cholangiocarcinomas. And so one important paradigm in those cancers is going to be ideally, you would incorporate testing up front that can detect not only the tumor-specific biomarkers that are relevant but also incorporate TRK fusion detection. In centers, for example, where that may not be available and settings where that isn’t available, another paradigm is to screen patients for tissue-specific biomarkers. And, if they don’t have any of them, reflex those negative patients into a more focused assay like immunohistochemistry for TRK or next-generation sequencing [NGS].

So to explain this in a more granular way, if you have a papillary thyroid cancer patient, you test them for BRAF, which is standard of care, and you might look, for example, for a RET fusion. So those are the 2 most common genetic events in papillary thyroid cancer. If you didn’t find either of those, that would be the patient who is highly enriched for the presence of other actionable alterations like TRK fusions. Or, for example, if you had a patient with gastrointestinal stromal tumor [GIST] that was KIT wild-type, which is the most common alteration that’s a driver alteration in GIST tumors, that would be the patient who I would selectively rescreen for TRK fusions.

Same thing with an otherwise driver negative lung cancer. If the patient screens negative for EGFR, KRAS, ALK, and ROS, that would be a patient who you would want to secondarily screen for TRK fusions. So I think over time what we’re going to see is incorporation of assays that can detect TRK fusions along with all other alterations in one panel test. But, as we live through the evolution of the diagnostic space, I would encourage practitioners out there who are managing these patients who have done relevant tissue-specific testing and have not identified any of the common driver alterations in those cancers to consider and talk to their pathologist or local laboratories about secondary TRK screening and fusion detection in those patients.

Non–small cell lung cancer really is at the forefront of precision medicine. We now have an increasing number of genomically defined subsets of lung cancer that really guide prescribing behavior. What these data collectively show is that TRK has really joined that list of genetically defined lung cancer. Lung cancers, because they have so many genetic targets, are really now almost routinely profiled by next-generation sequencing tests. So I really think it is incumbent upon us to make sure that those next-generation sequencing tests are capable of detecting all the actionable alterations in lung cancers, including the fusions, such as ALK, ROS, and NTRK. And patients who have these NTRK fusions really ought to receive a TRK inhibitor due to the really high level of durable activity in this. And I think for those patients it really will markedly change the natural history of their disease.

David Reardon, MD: My approach for incorporating next generation sequencing for our patients with primary and secondary brain cancers is to try to make this available and do this for every patient. The TRK inhibitors are showing exciting results in the subset of patients who have these driving mutations involving the TRK genes and the infusion transcripts.

But there are other drivers that we are identifying through NGS that we are able to evaluate therapeutics capable of targeting those drivers as well. So in patients with primary and secondary brain cancers, there’s a growing appreciation and recognition of a number of different drivers and mutations that are relevant in these tumors and a growing repertoire of drugs are available to target those drivers and mutations for our brain cancer patients, analogously to what’s evolved with lung cancer and breast cancer and colorectal cancer.

Transcript Edited for Clarity
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