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EGFR Testing for NSCLC

Panelists: Mark A. Socinski, MD, Florida Hospital Cancer Institute; Tracey L. Evans, MD, University of Pennsylvania; Alexander Drilon, MD, Memorial Sloan Kettering Cancer Center; Vali A. Papadimitrakopoulou, MD, The University of Texas MD Anderson Cancer Center; Jared Weiss, MD, UNC Lineberger Comprehensive Cancer Center
Published: Wednesday, Feb 22, 2017


Transcript:

Mark Socinski, MD:
Let’s turn to Vali. Vali, give us your perspective on current recommendations for EGFR testing.

Vali Papadimitrakopoulou, MD: So, the standard of care is to test all of our patients with adenocarcinoma irrespective of clinical characteristics with the approved assay. But increasingly, at academic settings, we use NGS, as Alex mentioned. The 2 most common sensitizing mutations are EGFR exon 19 deletion and the L858R, but increasingly, with next-generation sequencing, we’re also testing for rare mutations of EGFR, including exon 20 insertions. And we’re also testing for the T790M. Now, the standard of care would be to test all patients with the available cobas test. At progression from first-generation EGFR TKI (tyrosine kinase inhibitor), I cannot emphasize enough the need for a re-biopsy or plasma testing for the T790M detection, which, of course, will offer the patient the opportunity to receive the new standard of care and the best therapy, osimertinib, in this setting. So, I see increasing adoption of plasma testing.

The real recommendation should be plasma testing for patients whose tumor is not accessible for a biopsy, when the testing is not feasible for a re-biopsy, but also for cases where the patients may object to a biopsy. The sensitivity and specificity of the plasma testing depends on the assay that is used, and it ranges between 51% and 75% at the current rates that we have seen with various assays. So, for the plasma, we can also use the cobas assay that is approved for osimertinib, but we can also use NGS and other assays.

Mark Socinski, MD: You touched on this point a bit, and I’ve emphasized this a lot to our community colleagues, that there’s quite a heterogeneous group of patients when you say EGFR mutations. Now, the 2 dominant ones, the exon 19 deletion and L858R, we’re lucky they comprise 85% or so of those patients. But if you don’t have one of those mutations, it’s a mix of sensitivity versus resistance. You mentioned exon 20 insertion deletion, which we really don’t have a good strategy for. If they’re falling outside of the 2 dominant mutations, really there are lots of details in the fine print that they need to be aware of.

Vali Papadimitrakopoulou, MD: That is correct. There are investigational approaches to address some of these rarer mutations. But it is important that the practicing physician recognizes the significance of the mutation that they have detected in the tumor and doesn’t write a blank check for all the patients, because we have data suggesting that exon 20 insertions would not be responsive to first-generation EGFR TKIs. And if you don’t have any access to investigational therapy, these patients may be better served by standard-of-care therapy.

Mark Socinski, MD: Yes, that should be emphasized, because I’ve seen a few patients in my practice with exon 20 insertions that have been treated with a TKI and obviously have not benefitted from that. Tracey, in academic medicine versus community-based practitioners, what do you see from the patients you see in the community in terms of testing patterns? What are your thoughts in terms of should there be differences between the list of potentially actionable things that are looked at, at academic centers versus community colleagues?

Tracey Evans, MD: When patients come to see me from the community, what they have in the works often depends on whether or not they’ve seen a medical oncologist. A lot of places don’t have reflex testing. This means that when they diagnose a new case of lung cancer, they don’t automatically send it, even for the NCCN guideline-recommended testing—which is EGFR and ALK—and those are category 1 recommendations. And then there is a strong consideration for ROS1. So, oftentimes, there’s no testing that has been started. When I do see testing that has been done, I frequently only see the hotspot EGFR mutations—the exon 21, exon 19, and ALK. And that really misses the rare EGFR mutations. It misses insertion 20 that we don’t have a good approach for, but it also misses the exon 18, where there are data that afatinib can be beneficial for those patients. And it misses all the other ones Alex mentioned that we do have treatments for the BRAF and the MET.

The other problem of starting the tissue testing on the outside is it uses up some of the specimen, and you need enough material to get the next-generation sequencing done. So, oftentimes, if they’ve had the testing started on the outside and they’ve taken the sequential approach, you won’t have enough for the more broad-based molecular testing when they get to you. That’s one place I found the molecular testing really useful. The logistics of this testing are difficult. The turnaround time is difficult. The College of American Pathologists actually recommends that the turnaround time be 14 days from the receipt in a molecular lab. We struggle meeting that ourselves at Penn. But then when you need to get the material from an outside site to our site, that adds time. And it’s not just the sick patients who, I agree, should start on chemotherapy. Patients psychologically are tormented by having to wait to start their therapy. So, when I see a patient, I may not know the status of their molecular testing because they’re trying to track it down from an outside laboratory or I’m worried about how long that turnaround time is going to take. That’s where I sometimes send the plasma-based testing because I’m guaranteed to get a result in 2 weeks. The sensitivity is not good enough to rely only on that, but if I find an actual mutation, I could be pretty confident that that’s something I can treat the patient for.

Mark Socinski, MD: That’s a great point. I want to hear form the panel. How often is inadequacy of tissue the issue?

Alexander Drilon, MD: In that paper I mentioned earlier, where we looked at the certain piecemeal testing versus doing next-generation sequencing, there was a significant difference in biopsy load in patients where you did individual tests, where you had to go back in and get another biopsy. Whereas if you just used the initial block to do more comprehensive testing, you might have gotten everything. So, it’s something that’s often an issue.

Mark Socinski, MD: Yes, and it’s not insignificant. I think where there may be less well-defined thoracic oncology programs. I hear a lot from community doctors that some of the initial procedures that are done may not yield adequate bronch with a wash (bronchoscopy). You get a diagnosis, but you don’t get adequate tissue for these sorts of things. Plasma may help, but you never know in that particular setting.

Tracey Evans, MD: Right.

Mark Socinski, MD: So, I think the message is that community oncologists need to be talking to their pulmonologist, interventional radiologist, and surgeons to make sure that they understand it’s a different time in lung cancer. I think that’s important. Jared, any comments on that?

Jared Weiss, MD: Just that in the real world, I think there is a very high rate of nontesting. It is absolutely mandatory to get EGFR and ALK, in my opinion, and ROS1. And I agree very strongly that when there are logistic barriers to this, that liquid can help. Technique can also help a lot, and so can early communication. So, for example, not refacing the block repeatedly, not doing too many IHCs. And even in the community, tumor boards can be very helpful to promote that communication between the oncologist and the pathologist.

Mark Socinski, MD: I think the mentality that we all have to have as oncologists is as follows, and I’ve been saying this for years: there is not a woman with breast cancer in the United States that would see a medical oncologist without ER, PR, and HER2 status determined on her diagnostic material. There should not be an adenocarcinoma patient of the lung that doesn’t have some level of comprehensive testing because this is such a heterogeneous disease from a DNA point of view.

Vali Papadimitrakopoulou, MD: But Mark, I think the point that is important to make for pulmonologists and diagnosticians is, in general, that fine needle aspirates are not enough for testing of all of the above that we just discussed.

Mark Socinski, MD: We’ll come back to that because we now are in the era of immunotherapy, and our testing in immunotherapy has been largely core biopsies. So, we’ll come back and talk about this.

Jared Weiss, MD: If I could make one minor comment before moving on, we talked a little bit about the exon 20 insertions and failure of first-generation TKIs in that space. I think it’s worth just briefly mentioning that there are preclinical data and a little bit of data for the third-generation inhibitors for some of those insertions. And so, these are patients particularly important to refer to folks who will have access to those kind of trials.

Mark Socinski, MD: Great point.

Transcript Edited for Clarity
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Transcript:

Mark Socinski, MD:
Let’s turn to Vali. Vali, give us your perspective on current recommendations for EGFR testing.

Vali Papadimitrakopoulou, MD: So, the standard of care is to test all of our patients with adenocarcinoma irrespective of clinical characteristics with the approved assay. But increasingly, at academic settings, we use NGS, as Alex mentioned. The 2 most common sensitizing mutations are EGFR exon 19 deletion and the L858R, but increasingly, with next-generation sequencing, we’re also testing for rare mutations of EGFR, including exon 20 insertions. And we’re also testing for the T790M. Now, the standard of care would be to test all patients with the available cobas test. At progression from first-generation EGFR TKI (tyrosine kinase inhibitor), I cannot emphasize enough the need for a re-biopsy or plasma testing for the T790M detection, which, of course, will offer the patient the opportunity to receive the new standard of care and the best therapy, osimertinib, in this setting. So, I see increasing adoption of plasma testing.

The real recommendation should be plasma testing for patients whose tumor is not accessible for a biopsy, when the testing is not feasible for a re-biopsy, but also for cases where the patients may object to a biopsy. The sensitivity and specificity of the plasma testing depends on the assay that is used, and it ranges between 51% and 75% at the current rates that we have seen with various assays. So, for the plasma, we can also use the cobas assay that is approved for osimertinib, but we can also use NGS and other assays.

Mark Socinski, MD: You touched on this point a bit, and I’ve emphasized this a lot to our community colleagues, that there’s quite a heterogeneous group of patients when you say EGFR mutations. Now, the 2 dominant ones, the exon 19 deletion and L858R, we’re lucky they comprise 85% or so of those patients. But if you don’t have one of those mutations, it’s a mix of sensitivity versus resistance. You mentioned exon 20 insertion deletion, which we really don’t have a good strategy for. If they’re falling outside of the 2 dominant mutations, really there are lots of details in the fine print that they need to be aware of.

Vali Papadimitrakopoulou, MD: That is correct. There are investigational approaches to address some of these rarer mutations. But it is important that the practicing physician recognizes the significance of the mutation that they have detected in the tumor and doesn’t write a blank check for all the patients, because we have data suggesting that exon 20 insertions would not be responsive to first-generation EGFR TKIs. And if you don’t have any access to investigational therapy, these patients may be better served by standard-of-care therapy.

Mark Socinski, MD: Yes, that should be emphasized, because I’ve seen a few patients in my practice with exon 20 insertions that have been treated with a TKI and obviously have not benefitted from that. Tracey, in academic medicine versus community-based practitioners, what do you see from the patients you see in the community in terms of testing patterns? What are your thoughts in terms of should there be differences between the list of potentially actionable things that are looked at, at academic centers versus community colleagues?

Tracey Evans, MD: When patients come to see me from the community, what they have in the works often depends on whether or not they’ve seen a medical oncologist. A lot of places don’t have reflex testing. This means that when they diagnose a new case of lung cancer, they don’t automatically send it, even for the NCCN guideline-recommended testing—which is EGFR and ALK—and those are category 1 recommendations. And then there is a strong consideration for ROS1. So, oftentimes, there’s no testing that has been started. When I do see testing that has been done, I frequently only see the hotspot EGFR mutations—the exon 21, exon 19, and ALK. And that really misses the rare EGFR mutations. It misses insertion 20 that we don’t have a good approach for, but it also misses the exon 18, where there are data that afatinib can be beneficial for those patients. And it misses all the other ones Alex mentioned that we do have treatments for the BRAF and the MET.

The other problem of starting the tissue testing on the outside is it uses up some of the specimen, and you need enough material to get the next-generation sequencing done. So, oftentimes, if they’ve had the testing started on the outside and they’ve taken the sequential approach, you won’t have enough for the more broad-based molecular testing when they get to you. That’s one place I found the molecular testing really useful. The logistics of this testing are difficult. The turnaround time is difficult. The College of American Pathologists actually recommends that the turnaround time be 14 days from the receipt in a molecular lab. We struggle meeting that ourselves at Penn. But then when you need to get the material from an outside site to our site, that adds time. And it’s not just the sick patients who, I agree, should start on chemotherapy. Patients psychologically are tormented by having to wait to start their therapy. So, when I see a patient, I may not know the status of their molecular testing because they’re trying to track it down from an outside laboratory or I’m worried about how long that turnaround time is going to take. That’s where I sometimes send the plasma-based testing because I’m guaranteed to get a result in 2 weeks. The sensitivity is not good enough to rely only on that, but if I find an actual mutation, I could be pretty confident that that’s something I can treat the patient for.

Mark Socinski, MD: That’s a great point. I want to hear form the panel. How often is inadequacy of tissue the issue?

Alexander Drilon, MD: In that paper I mentioned earlier, where we looked at the certain piecemeal testing versus doing next-generation sequencing, there was a significant difference in biopsy load in patients where you did individual tests, where you had to go back in and get another biopsy. Whereas if you just used the initial block to do more comprehensive testing, you might have gotten everything. So, it’s something that’s often an issue.

Mark Socinski, MD: Yes, and it’s not insignificant. I think where there may be less well-defined thoracic oncology programs. I hear a lot from community doctors that some of the initial procedures that are done may not yield adequate bronch with a wash (bronchoscopy). You get a diagnosis, but you don’t get adequate tissue for these sorts of things. Plasma may help, but you never know in that particular setting.

Tracey Evans, MD: Right.

Mark Socinski, MD: So, I think the message is that community oncologists need to be talking to their pulmonologist, interventional radiologist, and surgeons to make sure that they understand it’s a different time in lung cancer. I think that’s important. Jared, any comments on that?

Jared Weiss, MD: Just that in the real world, I think there is a very high rate of nontesting. It is absolutely mandatory to get EGFR and ALK, in my opinion, and ROS1. And I agree very strongly that when there are logistic barriers to this, that liquid can help. Technique can also help a lot, and so can early communication. So, for example, not refacing the block repeatedly, not doing too many IHCs. And even in the community, tumor boards can be very helpful to promote that communication between the oncologist and the pathologist.

Mark Socinski, MD: I think the mentality that we all have to have as oncologists is as follows, and I’ve been saying this for years: there is not a woman with breast cancer in the United States that would see a medical oncologist without ER, PR, and HER2 status determined on her diagnostic material. There should not be an adenocarcinoma patient of the lung that doesn’t have some level of comprehensive testing because this is such a heterogeneous disease from a DNA point of view.

Vali Papadimitrakopoulou, MD: But Mark, I think the point that is important to make for pulmonologists and diagnosticians is, in general, that fine needle aspirates are not enough for testing of all of the above that we just discussed.

Mark Socinski, MD: We’ll come back to that because we now are in the era of immunotherapy, and our testing in immunotherapy has been largely core biopsies. So, we’ll come back and talk about this.

Jared Weiss, MD: If I could make one minor comment before moving on, we talked a little bit about the exon 20 insertions and failure of first-generation TKIs in that space. I think it’s worth just briefly mentioning that there are preclinical data and a little bit of data for the third-generation inhibitors for some of those insertions. And so, these are patients particularly important to refer to folks who will have access to those kind of trials.

Mark Socinski, MD: Great point.

Transcript Edited for Clarity
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