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Emerging Agents for Advanced EGFR+ Lung Cancer

Panelists:Benjamin Levy, MD, Mount Sinai Health Systems, ; John W. Longshore, PhD, Carolinas Pathology Group; Gregory J. Riely, MD, PhD, Weill Cornell Medical College; Mark A. Socinski, MD, University of Pittsburgh; Thomas E. Stinchcombe, MD, University of North Carolina at Chapel Hill; Jared Weiss, MD, University of North Carolina School of Medicine
Published: Friday, May 06, 2016


Transcript:

Mark A. Socinski, MD:
Greg, let me ask you. This drug osimertinib is so good. Why shouldn’t we be using it first? And when it doesn’t work, why doesn’t it work?

Gregory J. Riely, MD, PhD: So, I think the why we shouldn’t use it first question is an obvious one. As oncologists, we’re used to taking the best drug and moving it into first line. We’re not content to leave a good drug as a second-line option. We want it as a first-line option, and particularly given the side-effect profile we’re talking about. It’s actually better than erlotinib in terms of side effects.

Mark A. Socinski, MD: Why is it better?

Gregory J. Riely, MD, PhD: That’s a really important question to drill down on. We call these T790M EGFR inhibitors, or third-generation EGFR inhibitors. The reason it’s better is because it targets T790M. It doesn’t target wild-type EGFR.

Mark A. Socinski, MD: But also the native mutation, too, right?

Gregory J. Riely, MD, PhD: That’s the key. So, it’s not just a T790M drug. It also hits exon 19 deletions. It hits L858Rs, these key underlying mutations. Since it hits those, we should try this in first line. We’ve seen early pilot data looking at osimertinib as a first-line agent, and at 1 year, the progression-free survival numbers are pretty impressive. It’s about 75% who are progression-free at 1 year, which is certainly better than we’d expect to see with erlotinib. But, these are very early data, selected patients. It’s hard to really know what to make of that data. But the definitive thing we need to do is a first-line trial. There’s an ongoing trial, I believe it’s called, FLAURA, comparing osimertinib to a standard EGFR inhibitor in the first-line setting. Now, this trial is a progression-free survival trial, so the primary endpoint is progression-free survival. We want it to obviously be a dramatically bit longer progression-free survival. We’re not going to say if it’s a month longer progression-free survival—when you compare osimertinib to erlotinib—that we’re going to jump into that. We want it to be months longer to really account for the fact if you started with erlotinib, you could move on to osimertinib, and stack those two therapies together.

Now, when osimertinib doesn’t work, we’re not sure why it doesn’t work. The response rates are high. They’re on the order of what we see with erlotinib as a first-line therapy, and I think one key distinguishing thing is between patients who have frank progression versus those who have modest shrinkages that are sometimes short duration, or sometimes even longer duration. The number of patients who have frank progression on osimertinib in the T790M-positive acquired resistance setting is modest. It’s really not very much at all. I think this drug is helping the majority of patients with T790M-positive–acquired resistance.

After time, these drugs do wear out, as you suggested on erlotinib. A year later, you’re thinking about resistance and, on average, a year later you’re thinking about resistance after osimertinib. It’s still very early in our understanding of what’s happening here. There have been new mutations reported, so we identified a mutation at the binding site of osimertinib. These drugs covalently link to EGFR, and, so far, we’ve seen a handful of patients who have that linkage site mutated to prevent drug binding. This is so-called C797S. That’s an important site of mutation. There has been loss of the T790M as a target, as well observed. We have a lot to learn about this. There are exciting new drugs that are just a few more years down the pipeline that are what we call, allosteric inhibitors, that are targeting EGFR. So, there’s a lot of possibility in the future.

Mark A. Socinski, MD: Is there any patient where you’ve gone from the erlotinib to osimertinib that you would go back to erlotinib at progression?

Gregory J. Riely, MD, PhD: I certainly explore that sometimes as a bridging strategy to starting chemotherapy. I sometimes give erlotinib with chemotherapy, and I will do that in that setting.

Mark A. Socinski, MD: Yes, let’s not go there.

Benjamin P. Levy, MD: I think Greg is characterizing nicely this game of whack-a-mole. Oncologists will be playing with all these changes in mutations that happen with different directed therapies.

Mark A. Socinski, MD: Jared, I’m going to ask you. We’ve heard a lot about another T790M specific drug. That’s rociletinib. Can you just give us your thoughts there?

Jared Weiss, MD: Yes. So, this is a compound that’s been in the news a lot recently because some of the unconfirmed partial responses were not ultimately confirmed. I think there’s a lot of conversation about where that came from, whether this was due to the allowance of brain metastasis in the studies of this agent, or whether it’s a difference in efficacy of the drug. But, from a simple practical perspective, it’s not currently FDA-approved, and we’re staying tuned until April’s ODAC meeting.

Transcript Edited for Clarity
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Transcript:

Mark A. Socinski, MD:
Greg, let me ask you. This drug osimertinib is so good. Why shouldn’t we be using it first? And when it doesn’t work, why doesn’t it work?

Gregory J. Riely, MD, PhD: So, I think the why we shouldn’t use it first question is an obvious one. As oncologists, we’re used to taking the best drug and moving it into first line. We’re not content to leave a good drug as a second-line option. We want it as a first-line option, and particularly given the side-effect profile we’re talking about. It’s actually better than erlotinib in terms of side effects.

Mark A. Socinski, MD: Why is it better?

Gregory J. Riely, MD, PhD: That’s a really important question to drill down on. We call these T790M EGFR inhibitors, or third-generation EGFR inhibitors. The reason it’s better is because it targets T790M. It doesn’t target wild-type EGFR.

Mark A. Socinski, MD: But also the native mutation, too, right?

Gregory J. Riely, MD, PhD: That’s the key. So, it’s not just a T790M drug. It also hits exon 19 deletions. It hits L858Rs, these key underlying mutations. Since it hits those, we should try this in first line. We’ve seen early pilot data looking at osimertinib as a first-line agent, and at 1 year, the progression-free survival numbers are pretty impressive. It’s about 75% who are progression-free at 1 year, which is certainly better than we’d expect to see with erlotinib. But, these are very early data, selected patients. It’s hard to really know what to make of that data. But the definitive thing we need to do is a first-line trial. There’s an ongoing trial, I believe it’s called, FLAURA, comparing osimertinib to a standard EGFR inhibitor in the first-line setting. Now, this trial is a progression-free survival trial, so the primary endpoint is progression-free survival. We want it to obviously be a dramatically bit longer progression-free survival. We’re not going to say if it’s a month longer progression-free survival—when you compare osimertinib to erlotinib—that we’re going to jump into that. We want it to be months longer to really account for the fact if you started with erlotinib, you could move on to osimertinib, and stack those two therapies together.

Now, when osimertinib doesn’t work, we’re not sure why it doesn’t work. The response rates are high. They’re on the order of what we see with erlotinib as a first-line therapy, and I think one key distinguishing thing is between patients who have frank progression versus those who have modest shrinkages that are sometimes short duration, or sometimes even longer duration. The number of patients who have frank progression on osimertinib in the T790M-positive acquired resistance setting is modest. It’s really not very much at all. I think this drug is helping the majority of patients with T790M-positive–acquired resistance.

After time, these drugs do wear out, as you suggested on erlotinib. A year later, you’re thinking about resistance and, on average, a year later you’re thinking about resistance after osimertinib. It’s still very early in our understanding of what’s happening here. There have been new mutations reported, so we identified a mutation at the binding site of osimertinib. These drugs covalently link to EGFR, and, so far, we’ve seen a handful of patients who have that linkage site mutated to prevent drug binding. This is so-called C797S. That’s an important site of mutation. There has been loss of the T790M as a target, as well observed. We have a lot to learn about this. There are exciting new drugs that are just a few more years down the pipeline that are what we call, allosteric inhibitors, that are targeting EGFR. So, there’s a lot of possibility in the future.

Mark A. Socinski, MD: Is there any patient where you’ve gone from the erlotinib to osimertinib that you would go back to erlotinib at progression?

Gregory J. Riely, MD, PhD: I certainly explore that sometimes as a bridging strategy to starting chemotherapy. I sometimes give erlotinib with chemotherapy, and I will do that in that setting.

Mark A. Socinski, MD: Yes, let’s not go there.

Benjamin P. Levy, MD: I think Greg is characterizing nicely this game of whack-a-mole. Oncologists will be playing with all these changes in mutations that happen with different directed therapies.

Mark A. Socinski, MD: Jared, I’m going to ask you. We’ve heard a lot about another T790M specific drug. That’s rociletinib. Can you just give us your thoughts there?

Jared Weiss, MD: Yes. So, this is a compound that’s been in the news a lot recently because some of the unconfirmed partial responses were not ultimately confirmed. I think there’s a lot of conversation about where that came from, whether this was due to the allowance of brain metastasis in the studies of this agent, or whether it’s a difference in efficacy of the drug. But, from a simple practical perspective, it’s not currently FDA-approved, and we’re staying tuned until April’s ODAC meeting.

Transcript Edited for Clarity
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