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EGFR-Mutated NSCLC; Where We Are Now?

Panelists: Joshua Bauml, MD, University of Pennsylvania; D. Ross Camidge, MD, University of Colorado School of Medicine; Robert Doebele, MD, PhD, University of Colorado School of Medicine; Benjamin Levy, MD, Johns Hopkins Sidney Kimmel Cancer Center; Zofia Piotrowska, MD, Harvard Medical School
Published: Wednesday, Jul 31, 2019



Transcript:

Benjamin Levy, MD: We’ll start with the obvious, with EGFR-mutated lung cancer, which has been the leading edge of targeted therapies for advanced stage non–small cell lung cancer. Zofia, do you want to walk us through where we were, and where we are with current therapies for EGFR-mutated lung cancer? We’ll use that as a launching pad to discuss some of the data from today and some of the abstracts.

Zofia Piotrowska, MD: It’s 2019. EGFR mutations were discovered in 2004, so 15 years, and I think it’s remarkable how much progress we’ve made but also remarkable how much more progress we need to make for these patients. Right now, in the United States, we have 5 different EGFR inhibitors that are included for first-line use in EGFR. The first-generation EGFR inhibitors, erlotinib and gefitinib. Second-generation EGFR inhibitors, afatinib and dacomitinib, and then of course osimertinib, the third-generation EGFR inhibitor.

And really since 2004, we’ve had a long list of first randomized studies comparing the first-generation TKIs [tyrosine kinase inhibitors] and the second-generation TKIs to chemotherapy, clearly showing the superiority of the targeted therapy for our patient with EGFR. Then as we’ve gotten more and more of these drugs, we started to see some comparator studies where we started to see first comparisons of second-generation EGFR inhibitors to the first, so the LUX-Lung 7 study compared afatinib to the first-generation TKIs and really didn’t show much of a benefit.

I think it’s important in this historical perspective and in where we are to point out the ARCHER 1050 study, which was a first-line study that compared dacomitinib, another second-generation TKI to the first-generation drugs. And the DACO [dacomitinib] study was actually positive, so we did see an improvement in PFS [progression-free survival], as well as an improvement in OS [overall survival] with dacomitinib. I think the caveats to widespread adoption of the ARCHER 1050 regimen were that dacomitinib as a second-generation TKI had quite a bit of toxicity, the typical EGFR toxicities—diarrhea and rash. And about two-thirds of the patients in that study had to dose reduce dacomitinib. The other key caveat is that the ARCHER 1050 study excluded patients with brain metastases, which is a big population here.

So right around the time that the ARCHER 1050 data came out, we also had the FLAURA trial, which I think is the one that, of all the recent EGFR studies, has been the most practice-changing. FLAURA was a large randomized phase III study that compared osimertinib, the third-generation EGFR inhibitor, which at first actually had been developed for the second-line, for patients who progressed on a first- or second-generation TKI and developed T790M, the resistance mutation that we see in about half the patients who progress on a first-generation or second-generation TKI. And we had previously seen that osimertinib not only was very effective for T790M-positive disease in that setting, but also was very well tolerated and a great CNS [central nervous system] penetrant. There are a lot of favorable features about osimertinib.

In FLAURA, we compared osimertinib to erlotinib or gefitinib for newly diagnosed patients. FLAURA did include patients with brain metastases at baseline, and we saw a very nice result with PFS as the primary endpoint and a near doubling of PFS, to about 19 months with osimertinib, which was really a nice result. Now, we haven’t yet seen overall survival data from FLAURA. The early interim analyses have looked promising, but it is important to know those data are still immature and we hope to see them. But I think in addition, again we saw that osimertinib was very well tolerated, had low rates of any significant diarrhea or rash, very low rates of dose reduction. And we saw really good results in the CNS. We saw that patients benefitted whether or not they had brain metastases at baseline. And we also saw lower rates of progression in the CNS when patients were treated with osimertinib. For all of those reasons, I think that osimertinib has become the standard of care for newly diagnosed EGFR patients. And really the question becomes where do we go from here? How do we improve upon it?

Benjamin Levy, MD: Nice summary. Is there a patient for whom one of you would not consider osimertinib for an EGFR-positive patient? Is there a circumstance where osimertinib is off the table?

D. Ross Camidge, MD: You have to work really hard to think of one.

Benjamin Levy, MD: Yes.

D. Ross Camidge, MD: Technically, because it has some anti-HER2 [human epidermal growth factor receptor 2] activity and there’s some cardiac failure reported very rarely, I guess somebody with a cardiac problem you might think twice. The trouble is they’ve also got a lethal disease in their cancer, and I think you’d still probably do it.

Benjamin Levy, MD: Yes.

Zofia Piotrowska, MD: I’ve been asked this question a lot. That’s the one scenario where I, one time in my clinic, had a patient who had very severe cardiac disease and was elderly, and we were worried about any risk. With osimertinib though, the rates of cardiomyopathy are very low.

D. Ross Camidge, MD: Like 2% or so.

Zofia Piotrowska, MD: Just a few percent, yes, 2%. QTc prolongation, again occurs, but it’s low. And I think it’s important to know that for most patients who have cardiac disease, it’s important to monitor, periodic EKGs [electrocardiograms], echo [echocardiogram], but it’s not an absolute.

Benjamin Levy, MD: For patients with cardiac disease.

Zofia Piotrowska, MD: Exactly, for patients who are at increased risk of cardiac toxicities, but it’s not a contraindication really unless you really have that extreme case.

D. Ross Camidge, MD: I think technically the label says you’re supposed to do routine echoes?

Benjamin Levy, MD: Yes, who’s doing that?

D. Ross Camidge, MD: I’m voting hands down.

Zofia Piotrowska, MD: I would say for patients who have, for example, a preexisting history of CHF [congestive heart failure] or something like that, yes, but routinely, no.

Joshua Bauml, MD: Well, if they’re on it, they suddenly become short of breath, like, OK....

Zofia Piotrowska, MD: There are a lot of things that you have to look at.

Joshua Bauml, MD: Correct.

Transcript Edited for Clarity

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Transcript:

Benjamin Levy, MD: We’ll start with the obvious, with EGFR-mutated lung cancer, which has been the leading edge of targeted therapies for advanced stage non–small cell lung cancer. Zofia, do you want to walk us through where we were, and where we are with current therapies for EGFR-mutated lung cancer? We’ll use that as a launching pad to discuss some of the data from today and some of the abstracts.

Zofia Piotrowska, MD: It’s 2019. EGFR mutations were discovered in 2004, so 15 years, and I think it’s remarkable how much progress we’ve made but also remarkable how much more progress we need to make for these patients. Right now, in the United States, we have 5 different EGFR inhibitors that are included for first-line use in EGFR. The first-generation EGFR inhibitors, erlotinib and gefitinib. Second-generation EGFR inhibitors, afatinib and dacomitinib, and then of course osimertinib, the third-generation EGFR inhibitor.

And really since 2004, we’ve had a long list of first randomized studies comparing the first-generation TKIs [tyrosine kinase inhibitors] and the second-generation TKIs to chemotherapy, clearly showing the superiority of the targeted therapy for our patient with EGFR. Then as we’ve gotten more and more of these drugs, we started to see some comparator studies where we started to see first comparisons of second-generation EGFR inhibitors to the first, so the LUX-Lung 7 study compared afatinib to the first-generation TKIs and really didn’t show much of a benefit.

I think it’s important in this historical perspective and in where we are to point out the ARCHER 1050 study, which was a first-line study that compared dacomitinib, another second-generation TKI to the first-generation drugs. And the DACO [dacomitinib] study was actually positive, so we did see an improvement in PFS [progression-free survival], as well as an improvement in OS [overall survival] with dacomitinib. I think the caveats to widespread adoption of the ARCHER 1050 regimen were that dacomitinib as a second-generation TKI had quite a bit of toxicity, the typical EGFR toxicities—diarrhea and rash. And about two-thirds of the patients in that study had to dose reduce dacomitinib. The other key caveat is that the ARCHER 1050 study excluded patients with brain metastases, which is a big population here.

So right around the time that the ARCHER 1050 data came out, we also had the FLAURA trial, which I think is the one that, of all the recent EGFR studies, has been the most practice-changing. FLAURA was a large randomized phase III study that compared osimertinib, the third-generation EGFR inhibitor, which at first actually had been developed for the second-line, for patients who progressed on a first- or second-generation TKI and developed T790M, the resistance mutation that we see in about half the patients who progress on a first-generation or second-generation TKI. And we had previously seen that osimertinib not only was very effective for T790M-positive disease in that setting, but also was very well tolerated and a great CNS [central nervous system] penetrant. There are a lot of favorable features about osimertinib.

In FLAURA, we compared osimertinib to erlotinib or gefitinib for newly diagnosed patients. FLAURA did include patients with brain metastases at baseline, and we saw a very nice result with PFS as the primary endpoint and a near doubling of PFS, to about 19 months with osimertinib, which was really a nice result. Now, we haven’t yet seen overall survival data from FLAURA. The early interim analyses have looked promising, but it is important to know those data are still immature and we hope to see them. But I think in addition, again we saw that osimertinib was very well tolerated, had low rates of any significant diarrhea or rash, very low rates of dose reduction. And we saw really good results in the CNS. We saw that patients benefitted whether or not they had brain metastases at baseline. And we also saw lower rates of progression in the CNS when patients were treated with osimertinib. For all of those reasons, I think that osimertinib has become the standard of care for newly diagnosed EGFR patients. And really the question becomes where do we go from here? How do we improve upon it?

Benjamin Levy, MD: Nice summary. Is there a patient for whom one of you would not consider osimertinib for an EGFR-positive patient? Is there a circumstance where osimertinib is off the table?

D. Ross Camidge, MD: You have to work really hard to think of one.

Benjamin Levy, MD: Yes.

D. Ross Camidge, MD: Technically, because it has some anti-HER2 [human epidermal growth factor receptor 2] activity and there’s some cardiac failure reported very rarely, I guess somebody with a cardiac problem you might think twice. The trouble is they’ve also got a lethal disease in their cancer, and I think you’d still probably do it.

Benjamin Levy, MD: Yes.

Zofia Piotrowska, MD: I’ve been asked this question a lot. That’s the one scenario where I, one time in my clinic, had a patient who had very severe cardiac disease and was elderly, and we were worried about any risk. With osimertinib though, the rates of cardiomyopathy are very low.

D. Ross Camidge, MD: Like 2% or so.

Zofia Piotrowska, MD: Just a few percent, yes, 2%. QTc prolongation, again occurs, but it’s low. And I think it’s important to know that for most patients who have cardiac disease, it’s important to monitor, periodic EKGs [electrocardiograms], echo [echocardiogram], but it’s not an absolute.

Benjamin Levy, MD: For patients with cardiac disease.

Zofia Piotrowska, MD: Exactly, for patients who are at increased risk of cardiac toxicities, but it’s not a contraindication really unless you really have that extreme case.

D. Ross Camidge, MD: I think technically the label says you’re supposed to do routine echoes?

Benjamin Levy, MD: Yes, who’s doing that?

D. Ross Camidge, MD: I’m voting hands down.

Zofia Piotrowska, MD: I would say for patients who have, for example, a preexisting history of CHF [congestive heart failure] or something like that, yes, but routinely, no.

Joshua Bauml, MD: Well, if they’re on it, they suddenly become short of breath, like, OK....

Zofia Piotrowska, MD: There are a lot of things that you have to look at.

Joshua Bauml, MD: Correct.

Transcript Edited for Clarity
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