ONCAlert | Upfront Therapy for mRCC

NGS Testing to Detect TRK Fusions

Targeted Oncology
Published Online:12:00 PM, Mon August 19, 2019

Marcia Brose, MD, PhD: At what point in a patient’s disease are you going to be testing the patient? I mean, we talked about when we would give the drug, but what about the testing?

David Hong, MD: I think testing is incredibly key in all this. Again, larotrectinib and entrectinib work [only] in patients who have either NTRK fusion or ROS or ALK-ROS, so you need to test. NTRK fusion is a complicated molecular alteration to identify. I would say next-generation sequencing [NGS] is really the gold standard here, because there are so many different partners, so many different 1, 2, 3, and all different multiple partners, you can’t really do just FISH [fluorescence in situ hybridization]. IHC [immunohistochemistry] right now is still kind of in development, but we really need NGS.

What’s interesting is that for NTRK1, NTRK2, and NTRK3, particularly NTRK3, the fusions are very long, there [are] long introns, and so forth. You really need what’s called RNA sequencing or RNA-based NGS in order to capture some of that. For example, the FoundationOne CDx [companion diagnostic], which many community oncologists send for, covers NTRK1, NTRK2, NTRK3, and only ETV6 NTRK3, but they may be missing 30% to 40% of NTRK3 patients, if not more.

Marcia Brose, MD, PhD: And given how common those are, that’s a significant number of the patients, right?

David Hong, MD: Yes. I recommend ordering FoundationOne Heme, which is kind of confusing. That’s an RNA-sequencing panel that FoundationOne will actually allow solid tumors to be screened for. That would be my recommendation. There are other vendors—Caris has an ArcherDX FusionPlex assay, which also covers all the NTRK fusions at this point.

Marcia Brose, MD, PhD: Are you going to be recommending that everybody who gets diagnosed with cancer then get this panel? Or would you wait until the time of progression? What would be the point that you would want to get testing done?

David Hong, MD: What I recommend and what is commercially feasible is a different question, right? I’m a big believer that there are definitely patients who will benefit from this drug, and it’s really upon us to identify these patients. Understandably, there are a lot of religious obeyers. I don’t think all payers will pay for NGS testing, but I think definitely patients who have metastatic cancer, who at least fail standard chemotherapy—certain subsets of patients who may not have alterations that we would typically target, such as in lung or other tumor types, like in thyroid. I think those are patients who are clearly worth testing for NTRK fusion.

Corey Langer, MD: The next generation of sequencing is really the key component of managing these patients. NTRK is not an abnormality that we typically order as one-off. It’s a part of a much larger panel, and it’s a bit complicated. It’s a very large intron. Not all panels will necessarily detect every member of the NTRK family. So it’s important for individual clinicians to talk to their pathologists, or to talk to molecular pathologists if they’re on staff. And if the tissue is sent out to a commercial outfit, it’s important to talk to the vendor that’s actually providing the assay and doing the screening, regardless of whether NTRK is properly covered, whether they have DNA or RNA based assays.

I feel it’s crucial in any patient with advanced non–small cell cancer that ideally the next-generation sequencing be done early in their diagnosis, preferably at the time of diagnosis, certainly in any individual with adenocarcinoma, regardless of smoking history—any never smoker, remote former smoker—regardless of histology. I suspect we’re on the brink of an era where we’ll be testing anyone with non–small cell, regardless of histology, regardless of smoking history.

If an individual has gone through a number of treatments—had high PD-L1 [programmed death-ligand 1], initially responded to pembrolizumab, or were on some clinical trial to which they responded and then pembrolizumab stopped working and they went on to chemotherapy—if that patient has not undergone next-generation sequencing, then they need to. Either it should be done on the original tumor specimen—the original biopsy or, if necessary, the patient should be rebiopsied. It opens the door to a number of different potential actionable, molecular abnormalities. Not just NTRK but other—in some cases equally obscure—mutations and rearrangements, for which there are now an emerging field of targeted agents that work specifically on oncogenic drivers. In some cases, patients who had been told that they had only months to live—because we were running out of treatment—have enjoyed sustained survival because of that diagnostic intervention.

Marcia Brose, MD, PhD: I’d wonder what your thoughts are then about any patient who’s going to get systemic therapy. Because of course, in the metastatic setting, I can see obviously you’re going to want to give larotrectinib if it’s available, or RET [rearranged during transfection] inhibitors, or whatever else you might find. On the other end of that spectrum, on a patient who’s going to be cured because they have a stage I breast cancer, I can’t imagine running a panel like this if they’re going to be cured. What about patients who might be looking at primary surgery that is a little more difficult? And you’re wondering if a systemic agent could help at first progression or earlier on in the stages than we would normally think. When would you be testing? Because even if it won’t affect them immediately, wouldn’t you want to know? Or is there a place that you would say no?

David Hong, MD: I think going back to that question about the neoadjuvant setting, I think there are certain diseases worth exploring. But right now I think it’s too early for us to kind of just make that call. I mean, the indication specifically is for patients who have metastatic NTRK fusion histology.

Marcia Brose, MD, PhD: It will be interesting to see the algorithms that will be generated in the next few months to years because I think it’s really going to be interesting to see where this might starting to have impact beyond what we would normally think. We talked a little bit about which NGS test you would order, and we pointed out that the CDx FoundationOne is missing many. Are you going to send it to FoundationOne, to ask for the Heme panel? It seems like they’re just growing. My list that used to be on 1 table is now 2 or 3 pages long at this time.

David Hong, MD: You’re right, there are now many different vendors out there that are ordering these things. I think the important point is that you need to know what you’re ordering. You can’t just assume that it’s going to have NTRK fusion or all the partners, etc. I think it’s important just to ask your representative who’s involved if you need that information. Or the website, know exactly what you’re ordering or what tests are being ordered on that. Right now, my understanding is that—and I’m not a molecular pathologist— most community hospitals don’t have their own NGS testing in house. Much of this is too complicated—the bioinformatics. So many of these patients’ samples are being sent to FoundationOne and Caris and other places, but again, I think the most important thing is to know what you are ordering and what you are testing for.

Marcia Brose, MD, PhD: Which is so important because it might say TRK but it doesn’t say anything about the granularity that you’d need to know.

Transcript edited for clarity.

Marcia Brose, MD, PhD: At what point in a patient’s disease are you going to be testing the patient? I mean, we talked about when we would give the drug, but what about the testing?

David Hong, MD: I think testing is incredibly key in all this. Again, larotrectinib and entrectinib work [only] in patients who have either NTRK fusion or ROS or ALK-ROS, so you need to test. NTRK fusion is a complicated molecular alteration to identify. I would say next-generation sequencing [NGS] is really the gold standard here, because there are so many different partners, so many different 1, 2, 3, and all different multiple partners, you can’t really do just FISH [fluorescence in situ hybridization]. IHC [immunohistochemistry] right now is still kind of in development, but we really need NGS.

What’s interesting is that for NTRK1, NTRK2, and NTRK3, particularly NTRK3, the fusions are very long, there [are] long introns, and so forth. You really need what’s called RNA sequencing or RNA-based NGS in order to capture some of that. For example, the FoundationOne CDx [companion diagnostic], which many community oncologists send for, covers NTRK1, NTRK2, NTRK3, and only ETV6 NTRK3, but they may be missing 30% to 40% of NTRK3 patients, if not more.

Marcia Brose, MD, PhD: And given how common those are, that’s a significant number of the patients, right?

David Hong, MD: Yes. I recommend ordering FoundationOne Heme, which is kind of confusing. That’s an RNA-sequencing panel that FoundationOne will actually allow solid tumors to be screened for. That would be my recommendation. There are other vendors—Caris has an ArcherDX FusionPlex assay, which also covers all the NTRK fusions at this point.

Marcia Brose, MD, PhD: Are you going to be recommending that everybody who gets diagnosed with cancer then get this panel? Or would you wait until the time of progression? What would be the point that you would want to get testing done?

David Hong, MD: What I recommend and what is commercially feasible is a different question, right? I’m a big believer that there are definitely patients who will benefit from this drug, and it’s really upon us to identify these patients. Understandably, there are a lot of religious obeyers. I don’t think all payers will pay for NGS testing, but I think definitely patients who have metastatic cancer, who at least fail standard chemotherapy—certain subsets of patients who may not have alterations that we would typically target, such as in lung or other tumor types, like in thyroid. I think those are patients who are clearly worth testing for NTRK fusion.

Corey Langer, MD: The next generation of sequencing is really the key component of managing these patients. NTRK is not an abnormality that we typically order as one-off. It’s a part of a much larger panel, and it’s a bit complicated. It’s a very large intron. Not all panels will necessarily detect every member of the NTRK family. So it’s important for individual clinicians to talk to their pathologists, or to talk to molecular pathologists if they’re on staff. And if the tissue is sent out to a commercial outfit, it’s important to talk to the vendor that’s actually providing the assay and doing the screening, regardless of whether NTRK is properly covered, whether they have DNA or RNA based assays.

I feel it’s crucial in any patient with advanced non–small cell cancer that ideally the next-generation sequencing be done early in their diagnosis, preferably at the time of diagnosis, certainly in any individual with adenocarcinoma, regardless of smoking history—any never smoker, remote former smoker—regardless of histology. I suspect we’re on the brink of an era where we’ll be testing anyone with non–small cell, regardless of histology, regardless of smoking history.

If an individual has gone through a number of treatments—had high PD-L1 [programmed death-ligand 1], initially responded to pembrolizumab, or were on some clinical trial to which they responded and then pembrolizumab stopped working and they went on to chemotherapy—if that patient has not undergone next-generation sequencing, then they need to. Either it should be done on the original tumor specimen—the original biopsy or, if necessary, the patient should be rebiopsied. It opens the door to a number of different potential actionable, molecular abnormalities. Not just NTRK but other—in some cases equally obscure—mutations and rearrangements, for which there are now an emerging field of targeted agents that work specifically on oncogenic drivers. In some cases, patients who had been told that they had only months to live—because we were running out of treatment—have enjoyed sustained survival because of that diagnostic intervention.

Marcia Brose, MD, PhD: I’d wonder what your thoughts are then about any patient who’s going to get systemic therapy. Because of course, in the metastatic setting, I can see obviously you’re going to want to give larotrectinib if it’s available, or RET [rearranged during transfection] inhibitors, or whatever else you might find. On the other end of that spectrum, on a patient who’s going to be cured because they have a stage I breast cancer, I can’t imagine running a panel like this if they’re going to be cured. What about patients who might be looking at primary surgery that is a little more difficult? And you’re wondering if a systemic agent could help at first progression or earlier on in the stages than we would normally think. When would you be testing? Because even if it won’t affect them immediately, wouldn’t you want to know? Or is there a place that you would say no?

David Hong, MD: I think going back to that question about the neoadjuvant setting, I think there are certain diseases worth exploring. But right now I think it’s too early for us to kind of just make that call. I mean, the indication specifically is for patients who have metastatic NTRK fusion histology.

Marcia Brose, MD, PhD: It will be interesting to see the algorithms that will be generated in the next few months to years because I think it’s really going to be interesting to see where this might starting to have impact beyond what we would normally think. We talked a little bit about which NGS test you would order, and we pointed out that the CDx FoundationOne is missing many. Are you going to send it to FoundationOne, to ask for the Heme panel? It seems like they’re just growing. My list that used to be on 1 table is now 2 or 3 pages long at this time.

David Hong, MD: You’re right, there are now many different vendors out there that are ordering these things. I think the important point is that you need to know what you’re ordering. You can’t just assume that it’s going to have NTRK fusion or all the partners, etc. I think it’s important just to ask your representative who’s involved if you need that information. Or the website, know exactly what you’re ordering or what tests are being ordered on that. Right now, my understanding is that—and I’m not a molecular pathologist— most community hospitals don’t have their own NGS testing in house. Much of this is too complicated—the bioinformatics. So many of these patients’ samples are being sent to FoundationOne and Caris and other places, but again, I think the most important thing is to know what you are ordering and what you are testing for.

Marcia Brose, MD, PhD: Which is so important because it might say TRK but it doesn’t say anything about the granularity that you’d need to know.

Transcript edited for clarity.
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