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NGS Across Tumor Types 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 19, 2018



Transcript: 

David S. Hong, MD: To date, the data have suggested that in some instances, actionable mutations occur in maybe 10% to 20% of cases, in which patients may actually benefit from precision medicine for actionable alterations like NTRK fusions or BRAF mutations. I think that’s just the beginning. We’re just at the beginning of this era of defining cancer other than just by histology. I anticipate, and I think many of us in the community anticipate, that in the next several years, we’re going to see more and more of that, so that actual number of patients who may benefit from precision medicine or precision immuno-oncology may actually grow.

Alexander Drilon, MD: Because the activity of TRK inhibition has been tissue agnostic—meaning we’re seeing responses in any TRK fusion–positive cancer regardless of the origin or etiology of that cancer—I think that our testing practices shouldn’t be biased toward certain disease types. Obviously, there are rarer tumors that are highly enriched in NTRK fusions like secretory breast carcinoma, congenital fibrosarcoma, and mammary analog secretory carcinoma. In those cases, we should be keen about testing patients. But I think for the other cases, we’ve hopefully come to a point where physicians have the ability to order testing across a variety of different cancers to look for these rare events. Certainly, when you find one of these TRK fusions, it can be highly meaningful for a patient when you have these therapies that can result in very brisk and durable benefit.

David Hyman, MD: In reference to TRK fusions specifically, we really see 2 patterns in patients. There are certain rare cancer types, which are almost defined by the presence of a TRK fusion and are, therefore, found universally. Those pertain to certain types of sarcomas or their adult equivalents, tumors like infantile fibrosarcoma and other related cancers that we see in children, such as congenital nephromas. The adult equivalent of these conditions is called mammary analog secretory gland cancer, which is a salivary gland cancer, or secretory breast cancer.

These are rare cancer types that I now think are going to be universally tested for the presence of TRK fusions in patients who have advanced disease, or potentially even locally advanced disease, where these drugs might be used to actually down-stage patients and allow more minimal surgeries.

Then we have more common cancers, the names of which we all know—breast, colon, lung, pancreas, and melanoma—that harbor TRK fusions much more rarely, typically in the order of 1% to even less than 0.5%. In those cancers, it becomes a more challenging proposition to use a test to specifically and only look for TRK fusions as opposed to a broader next-generation sequencing test that could identify a much broader array of tumor-agnostic and tumor-specific biomarkers. I think that’s how we’ll capture the majority of TRK fusions in these more common cancer types, where the fusion is a rare event.

David S. Hong, MD: In general, what’s interesting is we’ve observed in the phase I, the phase II, and the pediatric population that even in the adult population, for example, patients who seem to harbor these NTRK fusions are younger. They tend to not have other alterations or driver mutations.

For example, with a patient with lung cancer who does not have BRAF, ALK, ROS, or EGFR and who’s young and not a smoker, there’s a chance that they may actually have NTRK fusions. And so those are some of the considerations that I’ve suggested to other physicians outside MD Anderson to look for in those situations. We have a patient with papillary thyroid cancer who is young and had no alterations. They did not have your typical RET or BRAF alteration, but when we got the NGS results, the patient had a clear NTRK3 fusion alteration, has benefited from larotrectinib, and has been on the study for almost 2 and a half years.

Transcript Edited for Clarity 
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Transcript: 

David S. Hong, MD: To date, the data have suggested that in some instances, actionable mutations occur in maybe 10% to 20% of cases, in which patients may actually benefit from precision medicine for actionable alterations like NTRK fusions or BRAF mutations. I think that’s just the beginning. We’re just at the beginning of this era of defining cancer other than just by histology. I anticipate, and I think many of us in the community anticipate, that in the next several years, we’re going to see more and more of that, so that actual number of patients who may benefit from precision medicine or precision immuno-oncology may actually grow.

Alexander Drilon, MD: Because the activity of TRK inhibition has been tissue agnostic—meaning we’re seeing responses in any TRK fusion–positive cancer regardless of the origin or etiology of that cancer—I think that our testing practices shouldn’t be biased toward certain disease types. Obviously, there are rarer tumors that are highly enriched in NTRK fusions like secretory breast carcinoma, congenital fibrosarcoma, and mammary analog secretory carcinoma. In those cases, we should be keen about testing patients. But I think for the other cases, we’ve hopefully come to a point where physicians have the ability to order testing across a variety of different cancers to look for these rare events. Certainly, when you find one of these TRK fusions, it can be highly meaningful for a patient when you have these therapies that can result in very brisk and durable benefit.

David Hyman, MD: In reference to TRK fusions specifically, we really see 2 patterns in patients. There are certain rare cancer types, which are almost defined by the presence of a TRK fusion and are, therefore, found universally. Those pertain to certain types of sarcomas or their adult equivalents, tumors like infantile fibrosarcoma and other related cancers that we see in children, such as congenital nephromas. The adult equivalent of these conditions is called mammary analog secretory gland cancer, which is a salivary gland cancer, or secretory breast cancer.

These are rare cancer types that I now think are going to be universally tested for the presence of TRK fusions in patients who have advanced disease, or potentially even locally advanced disease, where these drugs might be used to actually down-stage patients and allow more minimal surgeries.

Then we have more common cancers, the names of which we all know—breast, colon, lung, pancreas, and melanoma—that harbor TRK fusions much more rarely, typically in the order of 1% to even less than 0.5%. In those cancers, it becomes a more challenging proposition to use a test to specifically and only look for TRK fusions as opposed to a broader next-generation sequencing test that could identify a much broader array of tumor-agnostic and tumor-specific biomarkers. I think that’s how we’ll capture the majority of TRK fusions in these more common cancer types, where the fusion is a rare event.

David S. Hong, MD: In general, what’s interesting is we’ve observed in the phase I, the phase II, and the pediatric population that even in the adult population, for example, patients who seem to harbor these NTRK fusions are younger. They tend to not have other alterations or driver mutations.

For example, with a patient with lung cancer who does not have BRAF, ALK, ROS, or EGFR and who’s young and not a smoker, there’s a chance that they may actually have NTRK fusions. And so those are some of the considerations that I’ve suggested to other physicians outside MD Anderson to look for in those situations. We have a patient with papillary thyroid cancer who is young and had no alterations. They did not have your typical RET or BRAF alteration, but when we got the NGS results, the patient had a clear NTRK3 fusion alteration, has benefited from larotrectinib, and has been on the study for almost 2 and a half years.

Transcript Edited for Clarity 
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