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Upfront EGFR-Targeted Therapy

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: Wednesday, Apr 27, 2016


Transcript:

Mark A. Socinski, MD:
Let’s move into the arena of targeted therapies and start with a discussion of the issues in the most common actionable mutation that we diagnose, which is EGFR mutations. We now have, in terms of first-line treatment, 3 EGFR TKIs: gefitinib, erlotinib, and afatinib—not necessarily in that order. Greg, walk us through your thought process with these 3 agents and just how you view them in the clinic.

Gregory J. Riely, MD, PhD: Absolutely. I think we’ve talked about molecular subtypes of lung cancer like they’re a separate disease for a while. But with just the last year, we now have first-line and second-line options for EGFR-mutant lung cancer, so it really becomes a separate disease with a whole different treatment paradigm.

Mark A. Socinski, MD: Yes, I couldn’t agree more.

Gregory J. Riely, MD, PhD: It’s a very exciting time. We sometimes have disappointment around the patient who doesn’t have an oncogenic driver. The contrast is when you identify the patient with an EGFR mutation. It’s the excitement around that. So, when I’m picking first-line EGFR inhibitors, I have to say that I tend to use one rather than all three of them. The three available drugs—gefitinib, erlotinib, and afatinib—they’re all in the clinic together, and the differences among them are a bit challenging to sort out. We have some prospective data comparing drugs. We’ll talk about that in a second. But I think for the most part, these drugs work very much in the same way. They have the same mechanism of action. They have the same side effect profile, and they have all been compared head-to-head to chemotherapy, demonstrating improved outcomes compared to chemotherapy. If we line them up together, I think there’s a modest difference in the side-effect profile at the FDA-approved dose.

When you put this out there, you see that gefitinib, at its FDA-approved dose, has a pretty reasonable side-effect profile with little bit lower rates of rash and diarrhea. Erlotinib at its FDA-approved dose of 150 mg has a bit more of those, and afatinib, probably the most. And I think there has been an effort to look at outcomes based upon individual mutation subtypes, particularly comparing patients to the two most common types, EGFR L858R and EGFR exon 19 deletion. Importantly, a large analysis of multiple trials demonstrated that patients who had exon 19 deletions and got afatinib had a better overall survival compared to chemotherapy. And while a number of trials have demonstrated clear improvements in PFS, this is the first analysis to demonstrate a benefit in terms of overall survival. Now, whether that’s an afatinib-specific effect is a little unclear. We don’t have the same quality and amount of data for some of the other EGFR inhibitors, so it’s a bit hard to say that that effect wasn’t seen. But we haven’t seen that result put together. So, I think it’s certainly rational to say that for EGFR exon 19 deletions, afatinib is your choice. I have to admit, I haven’t made that leap in my clinical practice day-to-day. I think gefitinib, erlotinib, and afatinib are about the same at their doses.

Now, that’s been my take on things. One little twist on that, and what always gets in the way of things, is actual data. We can have our opinions as long as we like, but now we have some actual data looking at this. And so, at a small meeting at the end of 2015, there was presentation of a trial that randomized patients to either afatinib or gefitinib.

Mark A. Socinski, MD: LUX-Lung 7.

Gregory J. Riely, MD, PhD: That’s right, LUX-Lung 7. And this trial was a very small trial, a few hundred patients, and used a primary endpoint of progression-free survival (PFS). And there was a statistically and clinically significant difference in the progression-free survival for patients who got afatinib compared with gefitinib. As was suggested from earlier trials, there was more toxicity in the afatinib arm as well. Interestingly, the differences in these two trials didn’t really come until toward the end of the curves. If you look at the first 6 months or thereabouts, they’re right next to each other. I’m not sure what’s driving that, and I notice it is a relatively small trial, and that kind of does serve as a little bit of caveat, in my idea, that all these drugs are the same.

Mark A. Socinski, MD: But also response rates were higher for the afatinib.

Gregory J. Riely, MD, PhD: That’s right. Response rate, progression-free survival were both higher. We don’t have overall survival data. That’s very immature data. Given that with these patients now, we can expect to have median overall survivals on the order of 3 years.

Mark A. Socinski, MD: So, in a patient, let’s say you go back to your practice tomorrow, a new exon 19 walks in and says, “Doctor, I want the best treatment for my mutation.” I mean, given the data we have from the LUX-Lung 3 and 6 combined analysis, the LUX-Lung-7, wouldn’t you have to say afatinib?

Gregory J. Riely, MD, PhD: So, if I’m thinking about my patient with an EGFR exon 19 deletion that has the best therapy, I might offer them erlotinib plus bevacizumab as the optimal choice, given the prospective data from Japan demonstrating clear, long progression-free survival when you combine erlotinib plus bevacizumab. Now, we have to confirm this data in a larger trial. We have an ongoing cooperative group trial here in the United States, and I think that’s a really important question to ask.

Mark A. Socinski, MD: That really changes the playing field, right?

Gregory J. Riely, MD, PhD: Truly, truly.

Mark A. Socinski, MD: From giving IV bevacizumab?

Gregory J. Riely, MD, PhD: To go from handing a patient a prescription for one pill to committing them to an every-3-week IV treatment is a dramatic change. But I have to say I’m impressed by the preliminary data we’ve seen.

Mark A. Socinski, MD: Do others feel like that should be an option for patients? Tom, you’re heading up the phase III trial, right?

Thomas E. Stinchcombe, MD: Yes, phase III. It’s very similar to the Japanese trial in design, looking at erlotinib and erlotinib/bevacizumab. And I think if you look at the combination, the Japanese trial had a median progression-free survival of 16 months.

Mark A. Socinski, MD: Very impressive.

Thomas E. Stinchcombe, MD: The Swiss trial was 14.4 months, so these numbers are a little bit higher with the hazards across trial comparison. In the US trial, we enrolled 74 of 86 patients, so I’m hoping to complete enrollment in the next couple months so that, hopefully, that will be confirmatory to the very promising data from Japan. I wouldn’t use it off of a trial right now. It’s still not an FDA-approved combination, and there is an incremental risk of the bevacizumab, albeit small, in the trial.

Mark A. Socinski, MD: Jared, your perspective on the choice of TKI in the first-line setting: any differing opinions?

Jared Weiss, MD: Well, I think you’ve brought up before the priorities of the patient, and this is a case where that really drives it. With gefitinib, I think we have, at least at the standard FDA-approved doses, we have perhaps the best toxicity profile. I think we have the greatest comfort with erlotinib if we want to be in the box and what we’re comfortable with.

Mark A. Socinski, MD: And the best data with afatinib.

Jared Weiss, MD: Yes, and then you get into the question of erlotinib/bevacizumab, where you’re medicalizing the life of a patient that you would have liked to de-medicalize, but with a hope of a real PFS improvement. This is classic territory where you have to ask open-ended questions and then listen.

Benjamin P. Levy, MD: And I think there are competing standards. I think afatinib does have a compelling story to tell with the deletion 19 story and the head-to-head comparison. But we have to put the efficacy in the context of tolerability, and afatinib does have, at least in my patient population, a little higher AE events. Interestingly, that deletion 19 story seemed to be shaken a little bit from the subset analysis from the LUX-Lung-7, showing no differences between the two TKIs and deletion 19. I think the data is there, but we always have to make decisions based on both efficacy and toxicity.

Mark A. Socinski, MD: I do think the deletion 19s are more sensitive no matter what you use.

Benjamin P. Levy, MD: No matter what you do. And there’s data on first-generation TKIs showing that, retrospectively, deletion 19 tends to be a more sensitive mutation no matter what TKI you give.

Transcript Edited for Clarity
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Transcript:

Mark A. Socinski, MD:
Let’s move into the arena of targeted therapies and start with a discussion of the issues in the most common actionable mutation that we diagnose, which is EGFR mutations. We now have, in terms of first-line treatment, 3 EGFR TKIs: gefitinib, erlotinib, and afatinib—not necessarily in that order. Greg, walk us through your thought process with these 3 agents and just how you view them in the clinic.

Gregory J. Riely, MD, PhD: Absolutely. I think we’ve talked about molecular subtypes of lung cancer like they’re a separate disease for a while. But with just the last year, we now have first-line and second-line options for EGFR-mutant lung cancer, so it really becomes a separate disease with a whole different treatment paradigm.

Mark A. Socinski, MD: Yes, I couldn’t agree more.

Gregory J. Riely, MD, PhD: It’s a very exciting time. We sometimes have disappointment around the patient who doesn’t have an oncogenic driver. The contrast is when you identify the patient with an EGFR mutation. It’s the excitement around that. So, when I’m picking first-line EGFR inhibitors, I have to say that I tend to use one rather than all three of them. The three available drugs—gefitinib, erlotinib, and afatinib—they’re all in the clinic together, and the differences among them are a bit challenging to sort out. We have some prospective data comparing drugs. We’ll talk about that in a second. But I think for the most part, these drugs work very much in the same way. They have the same mechanism of action. They have the same side effect profile, and they have all been compared head-to-head to chemotherapy, demonstrating improved outcomes compared to chemotherapy. If we line them up together, I think there’s a modest difference in the side-effect profile at the FDA-approved dose.

When you put this out there, you see that gefitinib, at its FDA-approved dose, has a pretty reasonable side-effect profile with little bit lower rates of rash and diarrhea. Erlotinib at its FDA-approved dose of 150 mg has a bit more of those, and afatinib, probably the most. And I think there has been an effort to look at outcomes based upon individual mutation subtypes, particularly comparing patients to the two most common types, EGFR L858R and EGFR exon 19 deletion. Importantly, a large analysis of multiple trials demonstrated that patients who had exon 19 deletions and got afatinib had a better overall survival compared to chemotherapy. And while a number of trials have demonstrated clear improvements in PFS, this is the first analysis to demonstrate a benefit in terms of overall survival. Now, whether that’s an afatinib-specific effect is a little unclear. We don’t have the same quality and amount of data for some of the other EGFR inhibitors, so it’s a bit hard to say that that effect wasn’t seen. But we haven’t seen that result put together. So, I think it’s certainly rational to say that for EGFR exon 19 deletions, afatinib is your choice. I have to admit, I haven’t made that leap in my clinical practice day-to-day. I think gefitinib, erlotinib, and afatinib are about the same at their doses.

Now, that’s been my take on things. One little twist on that, and what always gets in the way of things, is actual data. We can have our opinions as long as we like, but now we have some actual data looking at this. And so, at a small meeting at the end of 2015, there was presentation of a trial that randomized patients to either afatinib or gefitinib.

Mark A. Socinski, MD: LUX-Lung 7.

Gregory J. Riely, MD, PhD: That’s right, LUX-Lung 7. And this trial was a very small trial, a few hundred patients, and used a primary endpoint of progression-free survival (PFS). And there was a statistically and clinically significant difference in the progression-free survival for patients who got afatinib compared with gefitinib. As was suggested from earlier trials, there was more toxicity in the afatinib arm as well. Interestingly, the differences in these two trials didn’t really come until toward the end of the curves. If you look at the first 6 months or thereabouts, they’re right next to each other. I’m not sure what’s driving that, and I notice it is a relatively small trial, and that kind of does serve as a little bit of caveat, in my idea, that all these drugs are the same.

Mark A. Socinski, MD: But also response rates were higher for the afatinib.

Gregory J. Riely, MD, PhD: That’s right. Response rate, progression-free survival were both higher. We don’t have overall survival data. That’s very immature data. Given that with these patients now, we can expect to have median overall survivals on the order of 3 years.

Mark A. Socinski, MD: So, in a patient, let’s say you go back to your practice tomorrow, a new exon 19 walks in and says, “Doctor, I want the best treatment for my mutation.” I mean, given the data we have from the LUX-Lung 3 and 6 combined analysis, the LUX-Lung-7, wouldn’t you have to say afatinib?

Gregory J. Riely, MD, PhD: So, if I’m thinking about my patient with an EGFR exon 19 deletion that has the best therapy, I might offer them erlotinib plus bevacizumab as the optimal choice, given the prospective data from Japan demonstrating clear, long progression-free survival when you combine erlotinib plus bevacizumab. Now, we have to confirm this data in a larger trial. We have an ongoing cooperative group trial here in the United States, and I think that’s a really important question to ask.

Mark A. Socinski, MD: That really changes the playing field, right?

Gregory J. Riely, MD, PhD: Truly, truly.

Mark A. Socinski, MD: From giving IV bevacizumab?

Gregory J. Riely, MD, PhD: To go from handing a patient a prescription for one pill to committing them to an every-3-week IV treatment is a dramatic change. But I have to say I’m impressed by the preliminary data we’ve seen.

Mark A. Socinski, MD: Do others feel like that should be an option for patients? Tom, you’re heading up the phase III trial, right?

Thomas E. Stinchcombe, MD: Yes, phase III. It’s very similar to the Japanese trial in design, looking at erlotinib and erlotinib/bevacizumab. And I think if you look at the combination, the Japanese trial had a median progression-free survival of 16 months.

Mark A. Socinski, MD: Very impressive.

Thomas E. Stinchcombe, MD: The Swiss trial was 14.4 months, so these numbers are a little bit higher with the hazards across trial comparison. In the US trial, we enrolled 74 of 86 patients, so I’m hoping to complete enrollment in the next couple months so that, hopefully, that will be confirmatory to the very promising data from Japan. I wouldn’t use it off of a trial right now. It’s still not an FDA-approved combination, and there is an incremental risk of the bevacizumab, albeit small, in the trial.

Mark A. Socinski, MD: Jared, your perspective on the choice of TKI in the first-line setting: any differing opinions?

Jared Weiss, MD: Well, I think you’ve brought up before the priorities of the patient, and this is a case where that really drives it. With gefitinib, I think we have, at least at the standard FDA-approved doses, we have perhaps the best toxicity profile. I think we have the greatest comfort with erlotinib if we want to be in the box and what we’re comfortable with.

Mark A. Socinski, MD: And the best data with afatinib.

Jared Weiss, MD: Yes, and then you get into the question of erlotinib/bevacizumab, where you’re medicalizing the life of a patient that you would have liked to de-medicalize, but with a hope of a real PFS improvement. This is classic territory where you have to ask open-ended questions and then listen.

Benjamin P. Levy, MD: And I think there are competing standards. I think afatinib does have a compelling story to tell with the deletion 19 story and the head-to-head comparison. But we have to put the efficacy in the context of tolerability, and afatinib does have, at least in my patient population, a little higher AE events. Interestingly, that deletion 19 story seemed to be shaken a little bit from the subset analysis from the LUX-Lung-7, showing no differences between the two TKIs and deletion 19. I think the data is there, but we always have to make decisions based on both efficacy and toxicity.

Mark A. Socinski, MD: I do think the deletion 19s are more sensitive no matter what you use.

Benjamin P. Levy, MD: No matter what you do. And there’s data on first-generation TKIs showing that, retrospectively, deletion 19 tends to be a more sensitive mutation no matter what TKI you give.

Transcript Edited for Clarity
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