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EGFR TKI Sequencing

Panelists:Benjamin P. Levy, MD, Mount Sinai Health Systems;Chandra P. Belani, MD, Penn State Cancer Institute;Marina Garassino, MD, National Cancer Institute Milan, Italy;Sarah B. Goldberg, MD, MPH, Yale Cancer Center;Ramaswamy Govindan, MD, Washington University School of Medicine;Mark G. Kris, MD, Memorial Sloan-Kettering Cancer Center
Published: Monday, Aug 29, 2016


Transcript:

Benjamin P. Levy, MD:
So, Sarah, I’ll pick on you a little bit since you brought this up. You’ve got a patient who has asymptomatic progression on an EGRF TKI, and you do a plasma test. It comes back positive for T790M. Do you just ride out the first-generation TKI, or do you just go ahead and switch to the third generation?

Sarah B. Goldberg, MD, MPH: It’s kind of what I was saying. This happens a lot, especially since T790M can be a more indolent type of progression for patients. It can have really slow progression even at just one or two sites, or even at multiple sites, but just slow, a few millimeters every couple months of growth. Asymptomatic and some patients do tolerate it very well, and they have none of these side effects, and they feel fine.

So, what do you do? And we don’t really know. It would be nice to have a trial that tells us what we should be doing. Is it better to switch early or try to get as most as you can out of the first-generation or second-generation drugs? If someone is tolerating it really well, and it’s really a minimal progression, I watch them closely because I want to switch at the first sign that there’s more than just a little bit of progression. But, I will try to get the most I can out of it. Again, assuming that they are tolerating it well and there’s no other reason to switch.

Mark G. Kris, MD: I’m with Marina on that. You know, the squeezing, I think, is the right thing to do. But, you look the patient in the eye and you say, “Is this okay with you?” And, if they tell you it’s okay, then it’s okay.

Benjamin P. Levy, MD: Yes, I agree. A shared decision making in this setting is important to elicit, to get the patient buy in, to understand how we’re thinking in terms of the treatment decision. One more question about these drugs, and, again, I think there’s a lot of confusion in the community. Chandra, you mentioned there was a response rate in the T790M-negative patients. And, there are all these questions about whether they were truly T790M-negative, or is this just tissue heterogeneity. Did they not accurately capture these patients? Any thoughts on using these drugs in T790M-negative patients? It’s certainly, not the paradigm we’re asking for, but the data are the data, at least as published in the New England Journal last year.

Chandra P. Belani, MD: But, the thing is that we also should be cognizant of the fact that they have EGFR-sensitizing mutations, in addition to the presence or absence of T790M. So, those responses may be because of that clone or EGFR-sensitizing mutations that they have rather than the T790M. As we said, if we’re doing liquid biopsies, we may miss it in 20% of those patients. And the tumor heterogeneity, that’s the third issue, that we may not be catching that area of tumor where you are able to get the DNA to look for that T790M mutation. And we also know that, as Govindan pointed out earlier, that these may actually disappear or not be present if you take another biopsy of a tissue at a separate time.

Benjamin P. Levy, MD: Let’s move forward now. We’re now approaching, and perhaps quickly, another paradigm shift using osimertinib potentially upfront. There’s been some data that were put out at ASCO last year, and in Geneva at the European Lung Conference, showing very competitive outcomes with using osimertinib first line. And we’ll also learn I guess tomorrow about some potential for it to cross the blood-brain barrier. Govindan, do you want to give us your perspective on using this drug upfront in treatment-naïve EGFR-positive patients?

Ramaswamy Govindan, MD: Chandra mentioned this before, but what is impressive is that it’s a small phase II study of 60 or more patients, osimertinib given at a couple of different doses. It’s striking that 70% had a nice partial response, 97% disease control rate, and the median progression-free survival was approaching 20 months. This looks very much like what we see now with some third-generation ALK inhibitors, and that I think is pretty impressive. And then as Mark said, it comes with very acceptable toxicity without all the rash and diarrhea, etc. So, I cannot imagine a scenario of down the line 5, 10 years from now, that we will not be using more mutant-selective inhibitors. And, I think this is the first step in that direction.

Benjamin P. Levy, MD: And how do you see EGFR TKI sequencing really happening now?

Ramaswamy Govindan, MD: Right now in the absence of data, the absence of other drugs to follow through, I think what we’re doing is reasonable. And by the time our patients begin to progress, they’ve learned to tolerate erlotinib. If they’re doing well, like Sarah said—I think we will definitely use the drug in a particular way in a sequence to the extent that they can tolerate, and then use osimertinib at the time of disease progression. But, eventually, when we see that these drugs are better in the front-line setting, they’ll probably be used in a different way.

Benjamin P. Levy, MD: Yes. It’ll be interesting to see progression on osimertinib. We’ve had some recent small case reports about this new mutation, C797S, which may predict sensitivity, oh by the way, to first-generation TKIs.

Ramaswamy Govindan, MD: Provided, it depends on the context in which these mutations happen. And, unfortunately, the C797S may be presented along with T790M, then it’s a tough thing. If that sub clone of T790M disappears, potentially using the first-generation EGFR TKI may be helpful. Again, you’ve seen a similar thing with ALK where patients who progress on alectinib may now suddenly be responsive to sunitinib, while they had received it a while ago. So, I think we will be seeing those kinds of things. Showing, once again, how dynamic the tumor evolution is, how much we force it to change in response to treatment-induced pressure.

Transcript Edited for Clarity
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Transcript:

Benjamin P. Levy, MD:
So, Sarah, I’ll pick on you a little bit since you brought this up. You’ve got a patient who has asymptomatic progression on an EGRF TKI, and you do a plasma test. It comes back positive for T790M. Do you just ride out the first-generation TKI, or do you just go ahead and switch to the third generation?

Sarah B. Goldberg, MD, MPH: It’s kind of what I was saying. This happens a lot, especially since T790M can be a more indolent type of progression for patients. It can have really slow progression even at just one or two sites, or even at multiple sites, but just slow, a few millimeters every couple months of growth. Asymptomatic and some patients do tolerate it very well, and they have none of these side effects, and they feel fine.

So, what do you do? And we don’t really know. It would be nice to have a trial that tells us what we should be doing. Is it better to switch early or try to get as most as you can out of the first-generation or second-generation drugs? If someone is tolerating it really well, and it’s really a minimal progression, I watch them closely because I want to switch at the first sign that there’s more than just a little bit of progression. But, I will try to get the most I can out of it. Again, assuming that they are tolerating it well and there’s no other reason to switch.

Mark G. Kris, MD: I’m with Marina on that. You know, the squeezing, I think, is the right thing to do. But, you look the patient in the eye and you say, “Is this okay with you?” And, if they tell you it’s okay, then it’s okay.

Benjamin P. Levy, MD: Yes, I agree. A shared decision making in this setting is important to elicit, to get the patient buy in, to understand how we’re thinking in terms of the treatment decision. One more question about these drugs, and, again, I think there’s a lot of confusion in the community. Chandra, you mentioned there was a response rate in the T790M-negative patients. And, there are all these questions about whether they were truly T790M-negative, or is this just tissue heterogeneity. Did they not accurately capture these patients? Any thoughts on using these drugs in T790M-negative patients? It’s certainly, not the paradigm we’re asking for, but the data are the data, at least as published in the New England Journal last year.

Chandra P. Belani, MD: But, the thing is that we also should be cognizant of the fact that they have EGFR-sensitizing mutations, in addition to the presence or absence of T790M. So, those responses may be because of that clone or EGFR-sensitizing mutations that they have rather than the T790M. As we said, if we’re doing liquid biopsies, we may miss it in 20% of those patients. And the tumor heterogeneity, that’s the third issue, that we may not be catching that area of tumor where you are able to get the DNA to look for that T790M mutation. And we also know that, as Govindan pointed out earlier, that these may actually disappear or not be present if you take another biopsy of a tissue at a separate time.

Benjamin P. Levy, MD: Let’s move forward now. We’re now approaching, and perhaps quickly, another paradigm shift using osimertinib potentially upfront. There’s been some data that were put out at ASCO last year, and in Geneva at the European Lung Conference, showing very competitive outcomes with using osimertinib first line. And we’ll also learn I guess tomorrow about some potential for it to cross the blood-brain barrier. Govindan, do you want to give us your perspective on using this drug upfront in treatment-naïve EGFR-positive patients?

Ramaswamy Govindan, MD: Chandra mentioned this before, but what is impressive is that it’s a small phase II study of 60 or more patients, osimertinib given at a couple of different doses. It’s striking that 70% had a nice partial response, 97% disease control rate, and the median progression-free survival was approaching 20 months. This looks very much like what we see now with some third-generation ALK inhibitors, and that I think is pretty impressive. And then as Mark said, it comes with very acceptable toxicity without all the rash and diarrhea, etc. So, I cannot imagine a scenario of down the line 5, 10 years from now, that we will not be using more mutant-selective inhibitors. And, I think this is the first step in that direction.

Benjamin P. Levy, MD: And how do you see EGFR TKI sequencing really happening now?

Ramaswamy Govindan, MD: Right now in the absence of data, the absence of other drugs to follow through, I think what we’re doing is reasonable. And by the time our patients begin to progress, they’ve learned to tolerate erlotinib. If they’re doing well, like Sarah said—I think we will definitely use the drug in a particular way in a sequence to the extent that they can tolerate, and then use osimertinib at the time of disease progression. But, eventually, when we see that these drugs are better in the front-line setting, they’ll probably be used in a different way.

Benjamin P. Levy, MD: Yes. It’ll be interesting to see progression on osimertinib. We’ve had some recent small case reports about this new mutation, C797S, which may predict sensitivity, oh by the way, to first-generation TKIs.

Ramaswamy Govindan, MD: Provided, it depends on the context in which these mutations happen. And, unfortunately, the C797S may be presented along with T790M, then it’s a tough thing. If that sub clone of T790M disappears, potentially using the first-generation EGFR TKI may be helpful. Again, you’ve seen a similar thing with ALK where patients who progress on alectinib may now suddenly be responsive to sunitinib, while they had received it a while ago. So, I think we will be seeing those kinds of things. Showing, once again, how dynamic the tumor evolution is, how much we force it to change in response to treatment-induced pressure.

Transcript Edited for Clarity
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