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Mutation Testing in NSCLC

Panelists: Luis E. Raez, MD, FACP, FCCP, Memorial Cancer Institute; Benjamin P. Levy, MD, Johns Hopkins Kimmel Cancer Center
Published: Monday, Apr 24, 2017


Transcript:

Luis Raez, MD:
Nowadays, it’s very interesting. We have changed the standard of care for molecular testing. There was no molecular testing 4 or 5 years ago. Now, every new patient with lung cancer, especially nonsquamous non–small cell lung cancer, needs next-generation sequencing testing, generally from the tissue. And there is a lot of options. Most of the industry vendors offer you panels that can go from 60 genes to 600 genes. And in our practice, because we do a lot of research, we collaborate with some vendors who do 500 to 600 genes in each patient. But I have to emphasize that is not standard of care because the number of drugs approved is limited to a small number of genes. And probably for the community oncologist, there is no need to do so many genes, unless they have clinical trials as an option for the other genetic aberrations where there is no FDA-approved drug.

Ben Levy, MD: Every patient with at least a stage 4 adenocarcinoma of the lung needs to be tested for EGFR. Now I think EGFR should be a part of a comprehensive genomic panel, and if you’re instituting a comprehensive genomic panel, which is next-generation sequencing, you’re going to be able to test for every type of EGFR mutation. The ones that are most commonly identified that are most important to drive decisions are the exon19 deletions, the point mutations, the L858R, and exon21. Those are the most common, those are the ones that we need. If you have those mutations or patients have them, then they should be eligible for targeted therapies with a TKI.

A little nuance here, and this is somewhat controversial, is, should stage 3 or earlier stage patients be tested as well? Should our stage 1 or 2 resected lung adenocarcinomas be tested? Should our stage 3 lung cancers be tested, adenocarcinomas? I think that there’s no hard recommendation that they should, but I think there should be a significant consideration to doing testing in earlier stages. And the reason for that is there are clinical trials out there looking at the role of adjuvant TKIs for patients with resected adenocarcinomas. And then, in the stage 3 setting, there’s a high likelihood despite good intent—and the goal is cure there—that these patients will relapse, and you need that information anyway. So, my message is, really, EGFR testing in the context of a comprehensive genomic profiling panel, next-generation panel, which would be able to pick up not only on the exon19s and the exon21s, but all the mutations that are relevant for EGFR.

Tissue is the issue, even with the new plasma diagnostic platforms coming down. I think it’s so important, before a biopsy decision is made, that physicians critically think about tissue procurement. These days, we need tissue not only for genetic testing or molecular profiling, but for PD-L1 testing as well. So, I think that while it’s not a hard recommendation, core biopsies should be considered for patients with suspected lung cancer. That can’t be the case for everyone. Obviously, lesions may be located in areas that are more amenable to bronchoscopy or EBUS approaches where FNA is done. I think that’s reasonable as well. If that’s done, there just needs to be multiple passes done to get as much tissue as possible.

We’ve learned lessons, recently actually, that even under the best of circumstances, tissue may not yield all the molecular results we need. There have been some data that looked at patients at a large academic institution in which they were going to be biopsied with core needles—100 patients to match the genetic interrogation off the tissue with a plasma test. And while the results are not important to this discussion, one of the interesting nuances that came out of that data is that only 50 patients out of the 100 had enough tissue for molecular testing. So, I think it’s really important that there’s a critical assessment of how to best procure the tissue to get as much as possible so that we can get all the relevant information we need, including PD-L1 and the genetic testing so we can tailor our treatment decisions.

Based on the KEYNOTE-024 data, which showed a survival advantage with pembrolizumab versus chemotherapy in those patients with a tumor proportion score greater than 50%, every stage 4, advanced stage, adenocarcinoma, and squamous needs to have PD-L1 testing done. And, again, if the PD-L1 tumor proportion score is greater than 50%, these patients, if eligible for immunotherapy, should be offered single-agent pembrolizumab every 3 weeks. And I think that has completely rocked the lung cancer world. These data were positive and changed the diagnostic algorithm based on the overall survival advantage. So, patients with PD-L1-positive disease, greater than 50%, should get immunotherapy. The question really comes to, what happens if you have a patient who has a PD-L1 tumor proportion score greater than 50% who also has an EGFR mutation? I will tell you that this is rare, but I have seen it. And I think we don’t really know yet what to do with these patients. The current recommendation is to do or deliver a TKI, not immunotherapy. And I think we’ll learn more and more as more data comes out.

I think what we know about patients who are EGFR-mutated is that they do better with chemotherapy than they do with immunotherapy. And even for those patients who are EGFR-mutated and who have a high tumor proportion score, they have about a 50% less response, less chance of responding to pembrolizumab than those patients with a high PD-L1 who aren’t EGFR-mutated. So, if a patient in that rare circumstance has both an EGFR mutation and a PD-L1 tumor proportion score greater than 50%, I would consider doing a TKI.

I think the question then dovetails into, what if you have a tumor proportion score greater than 50% and you don’t have the EGFR test back yet? This is a challenge. If it’s a never-smoker—which, in a lot of cases, won’t have a tumor proportion score greater than 50%—and you are clinically suspicious that this patient may have an EGFR mutation, it may be best to wait before you decide what therapy to give them. I don’t think it’s wrong for a patient with a tumor proportion score greater than 50% to start pembrolizumab while you’re waiting for the molecular interrogation. But keep in mind that if that molecular interrogation comes back EGFR-positive, you need to consider a therapeutic switch to a TKI.

Transcript Edited for Clarity
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Transcript:

Luis Raez, MD:
Nowadays, it’s very interesting. We have changed the standard of care for molecular testing. There was no molecular testing 4 or 5 years ago. Now, every new patient with lung cancer, especially nonsquamous non–small cell lung cancer, needs next-generation sequencing testing, generally from the tissue. And there is a lot of options. Most of the industry vendors offer you panels that can go from 60 genes to 600 genes. And in our practice, because we do a lot of research, we collaborate with some vendors who do 500 to 600 genes in each patient. But I have to emphasize that is not standard of care because the number of drugs approved is limited to a small number of genes. And probably for the community oncologist, there is no need to do so many genes, unless they have clinical trials as an option for the other genetic aberrations where there is no FDA-approved drug.

Ben Levy, MD: Every patient with at least a stage 4 adenocarcinoma of the lung needs to be tested for EGFR. Now I think EGFR should be a part of a comprehensive genomic panel, and if you’re instituting a comprehensive genomic panel, which is next-generation sequencing, you’re going to be able to test for every type of EGFR mutation. The ones that are most commonly identified that are most important to drive decisions are the exon19 deletions, the point mutations, the L858R, and exon21. Those are the most common, those are the ones that we need. If you have those mutations or patients have them, then they should be eligible for targeted therapies with a TKI.

A little nuance here, and this is somewhat controversial, is, should stage 3 or earlier stage patients be tested as well? Should our stage 1 or 2 resected lung adenocarcinomas be tested? Should our stage 3 lung cancers be tested, adenocarcinomas? I think that there’s no hard recommendation that they should, but I think there should be a significant consideration to doing testing in earlier stages. And the reason for that is there are clinical trials out there looking at the role of adjuvant TKIs for patients with resected adenocarcinomas. And then, in the stage 3 setting, there’s a high likelihood despite good intent—and the goal is cure there—that these patients will relapse, and you need that information anyway. So, my message is, really, EGFR testing in the context of a comprehensive genomic profiling panel, next-generation panel, which would be able to pick up not only on the exon19s and the exon21s, but all the mutations that are relevant for EGFR.

Tissue is the issue, even with the new plasma diagnostic platforms coming down. I think it’s so important, before a biopsy decision is made, that physicians critically think about tissue procurement. These days, we need tissue not only for genetic testing or molecular profiling, but for PD-L1 testing as well. So, I think that while it’s not a hard recommendation, core biopsies should be considered for patients with suspected lung cancer. That can’t be the case for everyone. Obviously, lesions may be located in areas that are more amenable to bronchoscopy or EBUS approaches where FNA is done. I think that’s reasonable as well. If that’s done, there just needs to be multiple passes done to get as much tissue as possible.

We’ve learned lessons, recently actually, that even under the best of circumstances, tissue may not yield all the molecular results we need. There have been some data that looked at patients at a large academic institution in which they were going to be biopsied with core needles—100 patients to match the genetic interrogation off the tissue with a plasma test. And while the results are not important to this discussion, one of the interesting nuances that came out of that data is that only 50 patients out of the 100 had enough tissue for molecular testing. So, I think it’s really important that there’s a critical assessment of how to best procure the tissue to get as much as possible so that we can get all the relevant information we need, including PD-L1 and the genetic testing so we can tailor our treatment decisions.

Based on the KEYNOTE-024 data, which showed a survival advantage with pembrolizumab versus chemotherapy in those patients with a tumor proportion score greater than 50%, every stage 4, advanced stage, adenocarcinoma, and squamous needs to have PD-L1 testing done. And, again, if the PD-L1 tumor proportion score is greater than 50%, these patients, if eligible for immunotherapy, should be offered single-agent pembrolizumab every 3 weeks. And I think that has completely rocked the lung cancer world. These data were positive and changed the diagnostic algorithm based on the overall survival advantage. So, patients with PD-L1-positive disease, greater than 50%, should get immunotherapy. The question really comes to, what happens if you have a patient who has a PD-L1 tumor proportion score greater than 50% who also has an EGFR mutation? I will tell you that this is rare, but I have seen it. And I think we don’t really know yet what to do with these patients. The current recommendation is to do or deliver a TKI, not immunotherapy. And I think we’ll learn more and more as more data comes out.

I think what we know about patients who are EGFR-mutated is that they do better with chemotherapy than they do with immunotherapy. And even for those patients who are EGFR-mutated and who have a high tumor proportion score, they have about a 50% less response, less chance of responding to pembrolizumab than those patients with a high PD-L1 who aren’t EGFR-mutated. So, if a patient in that rare circumstance has both an EGFR mutation and a PD-L1 tumor proportion score greater than 50%, I would consider doing a TKI.

I think the question then dovetails into, what if you have a tumor proportion score greater than 50% and you don’t have the EGFR test back yet? This is a challenge. If it’s a never-smoker—which, in a lot of cases, won’t have a tumor proportion score greater than 50%—and you are clinically suspicious that this patient may have an EGFR mutation, it may be best to wait before you decide what therapy to give them. I don’t think it’s wrong for a patient with a tumor proportion score greater than 50% to start pembrolizumab while you’re waiting for the molecular interrogation. But keep in mind that if that molecular interrogation comes back EGFR-positive, you need to consider a therapeutic switch to a TKI.

Transcript Edited for Clarity
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