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Impressive Findings for Next-Generation EGFR Inhibitors

Panelists: Mary Jo Fidler, MD, Rush; Roy S. Herbst, MD, PhD, Yale ; Geoffrey R. Oxnard, MD, Harvard; Naiyer Rizvi, MD, Columbia; Mark A. Socinski, MD,
Published: Friday, Aug 28, 2015


Transcript:

Mark A. Socinski, MD: I always say that diagnosing an EGFR mutant patient is like the old Wide World of Sports, the thrill of victory and the agony of defeat, because nine to twelve months later we have to start dealing with resistance patterns. And we know the dominant resistance pattern is a secondary mutation, the exon 20 T790M. We have some new drugs coming out for that. And Geoff, give us your thoughts on that.

Geoffrey R. Oxnard, MD: There’s been a lot of negative trials for acquired resistance over the years. This is a target that we’ve been hammering ever since T790M was found five, ten years ago. But these new drugs, the first being rociletinib (CO-1686) and shortly thereafter AZD9291 [osimertinib], are two drugs that potently target T790M, target sensitizing mutations as well, and don’t target wild-type EGFR, so don’t lead to as much of the toxicity of rash and diarrhea.

The two reports at ASCO this year included a very nice first-line trial where they showed that AZD9291 doesn’t only cause the response rates we’ve heard about in T790M-positive resistance but also can be used first-line, 70% response rate, PFS not reached, and is actually not just a T790M inhibitor but is a great EGFR inhibitor with a different toxicity profile and less of the rash and diarrhea.

Mark A. Socinski, MD: Talk a little bit about some of the exciting data at ASCO with rociletinib, the blood-based data that we saw.

Geoffrey R. Oxnard, MD: As you mentioned before, gefitinib can now be prescribed in Europe based on a plasma EGFR mutation, and this would be very attractive for acquired resistance where you could, instead of doing a resistance biopsy, detect the resistance mutation in plasma. The data for rociletinib show that you get high response rates if they’re T790M-positive based on tissue, high response rates if they’re T790M-positive based on plasma, and you still see some responses if they’re T790M in tissue or in plasma.

One of the problems here is how we define T790M. We need to find that perfect biomarker where you can find the patients who will benefit and identify the patients who won’t benefit. My instinct is if you can find those patients who are really T790M-negative in tissue and T790M-negative in plasma, those folks have a different resistance mechanism and they’re not going to benefit from these drugs. But plasma is an emerging alternative to tumor to define which patients will benefit.

Mark A. Socinski, MD: A lot of these patients tend to progress slowly and are asymptomatic and maybe might not be the easiest patients to biopsy sometimes. Is it prime time for blood-based testing at this point? Can you do that?

Geoffrey R. Oxnard, MD: One of the problems is if the progression is really slow and sort of just starting to emerge; there’s actually not a lot of DNA floating around in the blood. I’m not sure that a liquid biopsy is necessarily going to have a very good sensitivity. As the progression becomes more clinically apparent, you can use a liquid biopsy more reliably to replace a tumor biopsy. We still have to figure out what is the right setting. But it would be great.

If you find T790M in plasma I think today you can act on it. If you don’t, you need to get a biopsy because you might have missed it.

Naiyer Rizvi, MD: But part of that question is if you have somebody who’s very slowly progressing, do you need to change therapies?

Geoffrey R. Oxnard, MD: Right or can you wait three more months and get a biopsy then or a liquid biopsy then?

Mark A. Socinski, MD: We don’t have the T790M drug option right now but we will soon, and so when we have that option that may be a more pertinent question at this point. Talk about the toxicities of the two agents. You mentioned it spares wild-type EGFR, so you typically don’t see the rash and diarrhea, but there are other toxicities that you see with it.

Geoffrey R. Oxnard, MD: For rociletinib, which was the first drug in class, there’s been a slightly newer spectrum; hyperglycemia, perhaps an effect of metabolite, also some problems with QTc, and some problems of nausea. Is that related to the hyperglycemia or is that related to the drug? There are some side effects that require some getting used to when you’re prescribing this new drug, but really no patients with rash and diarrhea.

AZD9291 has generally tolerable rash in some patients, certainly less than with the other drugs, but there’s a little bit that you see. Both drugs have occasional cases of pneumonitis which we’re still learning about and that’s been a problem for gefitinib and erlotinib in Asia. We need to figure out how to manage the 2% of patients who develop lung inflammation on these drugs.

Mark A. Socinski, MD: So, Naiyer, let me ask you, we very quickly moved to a couple of trials where these third generation drugs are being compared in phase III trials to the first generation drugs. How good does a third generation drug have to be to kind of replace our current standard of gefitinib, erlotinib, afatinib?

Naiyer Rizvi, MD: I think that’s really going to be the question. I don’t know that anyone knows what the answer is. The paradigm right now would be that if you can get 12 months out of first generation and another 12 months out of second generation, do you need to get two years out of the combination? I don’t know the answer to that.

I think, certainly, from a tolerability standpoint and quality of life standpoint, the next-generation compounds are much better tolerated. I think for the patients that we treat with first generation, not just the diarrhea but the skin toxicity, but the nail changes and the fatigue, really affect quality of life.

Historically, our preference is to try to position our best drugs first, and so it does make sense to position these next-generation compounds first, whether the data bears that out. What is the amount of difference do you need? I think that that’s unknown really.

Mark A. Socinski, MD: Because it’s not likely that the first or second generation drugs are going to work after.

Geoffrey R. Oxnard, MD: That’s a question to be asked. The resistance mechanisms might be slightly different and that’s an important dilemma. If that ends up panning out, that could be an opportunity.

Mary Jo Fidler, MD: I think one of the problems that we’re going to have is that after these trials are completed, there’s still going to be a lot of unknowns because these patients with EGFR gene mutations live longer, and progression-free survival has been the selected endpoint for these comparison trials with a third versus first generation drug. I don’t know if we’ll ever know.

I think all of us are going to wait to see what really is that progression-free survival; can you add them both together? That may be a more expensive route, especially as some drugs become generic in the first-line setting.
Transcript Edited for Clarity
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Transcript:

Mark A. Socinski, MD: I always say that diagnosing an EGFR mutant patient is like the old Wide World of Sports, the thrill of victory and the agony of defeat, because nine to twelve months later we have to start dealing with resistance patterns. And we know the dominant resistance pattern is a secondary mutation, the exon 20 T790M. We have some new drugs coming out for that. And Geoff, give us your thoughts on that.

Geoffrey R. Oxnard, MD: There’s been a lot of negative trials for acquired resistance over the years. This is a target that we’ve been hammering ever since T790M was found five, ten years ago. But these new drugs, the first being rociletinib (CO-1686) and shortly thereafter AZD9291 [osimertinib], are two drugs that potently target T790M, target sensitizing mutations as well, and don’t target wild-type EGFR, so don’t lead to as much of the toxicity of rash and diarrhea.

The two reports at ASCO this year included a very nice first-line trial where they showed that AZD9291 doesn’t only cause the response rates we’ve heard about in T790M-positive resistance but also can be used first-line, 70% response rate, PFS not reached, and is actually not just a T790M inhibitor but is a great EGFR inhibitor with a different toxicity profile and less of the rash and diarrhea.

Mark A. Socinski, MD: Talk a little bit about some of the exciting data at ASCO with rociletinib, the blood-based data that we saw.

Geoffrey R. Oxnard, MD: As you mentioned before, gefitinib can now be prescribed in Europe based on a plasma EGFR mutation, and this would be very attractive for acquired resistance where you could, instead of doing a resistance biopsy, detect the resistance mutation in plasma. The data for rociletinib show that you get high response rates if they’re T790M-positive based on tissue, high response rates if they’re T790M-positive based on plasma, and you still see some responses if they’re T790M in tissue or in plasma.

One of the problems here is how we define T790M. We need to find that perfect biomarker where you can find the patients who will benefit and identify the patients who won’t benefit. My instinct is if you can find those patients who are really T790M-negative in tissue and T790M-negative in plasma, those folks have a different resistance mechanism and they’re not going to benefit from these drugs. But plasma is an emerging alternative to tumor to define which patients will benefit.

Mark A. Socinski, MD: A lot of these patients tend to progress slowly and are asymptomatic and maybe might not be the easiest patients to biopsy sometimes. Is it prime time for blood-based testing at this point? Can you do that?

Geoffrey R. Oxnard, MD: One of the problems is if the progression is really slow and sort of just starting to emerge; there’s actually not a lot of DNA floating around in the blood. I’m not sure that a liquid biopsy is necessarily going to have a very good sensitivity. As the progression becomes more clinically apparent, you can use a liquid biopsy more reliably to replace a tumor biopsy. We still have to figure out what is the right setting. But it would be great.

If you find T790M in plasma I think today you can act on it. If you don’t, you need to get a biopsy because you might have missed it.

Naiyer Rizvi, MD: But part of that question is if you have somebody who’s very slowly progressing, do you need to change therapies?

Geoffrey R. Oxnard, MD: Right or can you wait three more months and get a biopsy then or a liquid biopsy then?

Mark A. Socinski, MD: We don’t have the T790M drug option right now but we will soon, and so when we have that option that may be a more pertinent question at this point. Talk about the toxicities of the two agents. You mentioned it spares wild-type EGFR, so you typically don’t see the rash and diarrhea, but there are other toxicities that you see with it.

Geoffrey R. Oxnard, MD: For rociletinib, which was the first drug in class, there’s been a slightly newer spectrum; hyperglycemia, perhaps an effect of metabolite, also some problems with QTc, and some problems of nausea. Is that related to the hyperglycemia or is that related to the drug? There are some side effects that require some getting used to when you’re prescribing this new drug, but really no patients with rash and diarrhea.

AZD9291 has generally tolerable rash in some patients, certainly less than with the other drugs, but there’s a little bit that you see. Both drugs have occasional cases of pneumonitis which we’re still learning about and that’s been a problem for gefitinib and erlotinib in Asia. We need to figure out how to manage the 2% of patients who develop lung inflammation on these drugs.

Mark A. Socinski, MD: So, Naiyer, let me ask you, we very quickly moved to a couple of trials where these third generation drugs are being compared in phase III trials to the first generation drugs. How good does a third generation drug have to be to kind of replace our current standard of gefitinib, erlotinib, afatinib?

Naiyer Rizvi, MD: I think that’s really going to be the question. I don’t know that anyone knows what the answer is. The paradigm right now would be that if you can get 12 months out of first generation and another 12 months out of second generation, do you need to get two years out of the combination? I don’t know the answer to that.

I think, certainly, from a tolerability standpoint and quality of life standpoint, the next-generation compounds are much better tolerated. I think for the patients that we treat with first generation, not just the diarrhea but the skin toxicity, but the nail changes and the fatigue, really affect quality of life.

Historically, our preference is to try to position our best drugs first, and so it does make sense to position these next-generation compounds first, whether the data bears that out. What is the amount of difference do you need? I think that that’s unknown really.

Mark A. Socinski, MD: Because it’s not likely that the first or second generation drugs are going to work after.

Geoffrey R. Oxnard, MD: That’s a question to be asked. The resistance mechanisms might be slightly different and that’s an important dilemma. If that ends up panning out, that could be an opportunity.

Mary Jo Fidler, MD: I think one of the problems that we’re going to have is that after these trials are completed, there’s still going to be a lot of unknowns because these patients with EGFR gene mutations live longer, and progression-free survival has been the selected endpoint for these comparison trials with a third versus first generation drug. I don’t know if we’ll ever know.

I think all of us are going to wait to see what really is that progression-free survival; can you add them both together? That may be a more expensive route, especially as some drugs become generic in the first-line setting.
Transcript Edited for Clarity
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