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EGFR Inhibition and Resistance Mechanisms

Insights From:Alice T. Shaw, MD, PhD, Massachusetts General Hospital; Gregory J. Riely, MD, Memorial Sloan Kettering; Mark A. Socinski, MD, UPMC
Published: Monday, Feb 01, 2016


Transcript:

Alice T. Shaw, MD, PhD:
Overall, EGFR inhibitors, like gefitinib, erlotinib, and afatinib, are reasonably well tolerated but they do have some characteristic side effects. There are a number of different EGFR inhibitors that we have for our patients who have EGFR-mutant lung cancer. As first-line therapy for our patients with metastatic EGFR-mutant lung cancer, we have three different EGFR inhibitors that we can use in this country: gefitinib, erlotinib, and afatinib. There are great data for all three of these, which is why they are approved agents.

In terms of how we use them, it depends on the provider, depending on what you’re used to using and what you’ve potentially, read about in terms of potential advantages like side effects. I would say that it’s very common in this country to use erlotinib. That’s been the approved agent for many years now, so many oncologists are familiar with erlotinib. We primarily use erlotinib for patients who have newly diagnosed metastatic EGFR-mutant lung cancer.

However, more recently, both gefitinib, and afatinib are now approved agents as well. Gefitinib tends to have a better toxicity profile and seems to have comparable efficacy. So now that it’s an approved agent in this country, it’s possible that we will see more of a shift toward gefitinib use. In my own clinic, if I have a patient who is a little more tenuous in terms of their performance status, or has a lot of medical issues—one who I may worry about in terms of tolerating side effects of erlotinib—I’m very comfortable using gefitinib in place of erlotinib.

We also have afatinib that we can use, and I would say the main use that we’re seeing for afatinib, is in patients who have a specific EGFR-activating mutation; that’s the exon 19 deletion. And there are data from the LUX-Lung trials that show that there may be an overall survival benefit of afatinib, particularly in the exon 19 deletion. And so I would say, again, in this country we’re seeing more and more use of afatinib, particularly for that particular type of EGFR mutation. In my own clinic, I will use afatinib for patients who have EGFR exon 19 deletions, but generally those patients who are perhaps younger, and very fit, and who can tolerate some of the side effects that we see with afatinib —which tend to be a little bit more than the other EGFR inhibitors.

The EGFR inhibitors overall are quite well-tolerated, but they do have some characteristic side effects. Overall, EGFR inhibitors, the current batch of first- and second-generation inhibitors, like gefitinib, erlotinib, and afatinib, all have rash and diarrhea as side effects due to inhibition of wild-type EGFR. I would say we see the most side effects with afatinib, compared to erlotinib and gefitinib.

Gefitinib, among the three, tends to be better tolerated in terms of those side effects, so that is one that we may choose to use in a patient who is more frail than someone else, because of its better safety and side effect profile. We see rash and diarrhea pretty consistently with erlotinib, probably in the range of 70% to 80% of patients will have rash and will have diarrhea. Usually those can be very easily managed with various medications, for example, topical antibiotics for the rash, sometimes oral antibiotics, and antidiarrheals for the diarrhea caused by the EGFR inhibitors. Sometimes though, we have to just hold the drug and dose reduce, so often times when we start erlotinib, for example, at 150 mg/day, which is the standard dose, because of difficult-to-control rash or diarrhea, we may need to hold and dose reduce to 100 or even 75 mg/day.

Afatinib, which is a second-generation inhibitor, also an approved agent for us in this country, is a little more difficult, in my experience, than erlotinib or gefitinib. Again, there’s rash and diarrhea, and with afatinib I also see a little bit more mucositis than I’d see with the other agents. And that can be difficult for patients in terms of their eating and drinking. So I find afatinib can be challenging. Many of the patients on afatinib will require a hold and a dose reduction in order to make the drug more tolerable.

Mark A. Socinski, MD: The studies that have pursued re-biopsy of patients with EGFR mutations, once they have progressed on first or second-generation EGFR tyrosine kinase inhibitors, have really been invaluable. What I’m talking about is patients who are initially diagnosed with an EGFR mutation, who are treated with a first-generation— either erlotinib or gefitinib—or a second-generation agent—afatinib—and who, on average, may go nine to twelve months before they start progressing.

Obviously, if their cancer is getting worse, they’re breaking through the inhibitory effect of those first- or second-generation agents. When you re-biopsy those patients, you understand that in 50% to 60% of those patients, a secondary mutation occurs—an exon 20 referred to as T790M. This changes the binding site for inhibition for the TKIs and allows them to break through the inhibitory effect of those agents. We are now in an era of being able to target that with a third-generation TKI.

Osimertinib was recently approved for use in T790M-specific patients. Now, that’s an important advance because prior to that approval, we would divert to standard chemotherapy for these patients, but the use of the third-generation TKI gives them another oral targeted option that was not previously available.

In the other 40% to 50%, there’s actually been a variety of resistance mechanisms: MET amplification, PI3 kinase abnormalities, HER2 abnormalities, BRAF abnormalities, and also this entity of histologic transformation. It’s interesting that in the EGFR mutation patients, these are almost always adenocarcinoma in predominantly light or never-smokers.

The observation has been on these re-biopsy studies to see histologic transformation to small cell lung cancer. We’ve had a few cases at our center where there’s more of a sarcomatoid carcinoma appearance of the biopsy—and this is important. Certainly, if you diagnose a small cell transformation on a re-biopsy, that would demand a change in the direction of your therapy. You would use a standard regimen for small cell lung cancer, such as a platinum etoposide, and these patients respond to that. But that mechanism, or how that histologic transformation occurs, at least by me, is not well understood. But certainly it has been documented in the literature. And, we see this in our practice with EGFR-mutant-positive patients.

The approval of osimertinib, and having a T790M strategy, is vitally important. This is 50% to 60% of the patients. For the remaining 40%, there’s a variety of mechanisms that we still have a little bit of work to do to know the optimal way forward in that proportion of the refractory mutant patients.
                                                                                                                                                                                                                                                                                                                
Transcript Edited for Clarity
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Transcript:

Alice T. Shaw, MD, PhD:
Overall, EGFR inhibitors, like gefitinib, erlotinib, and afatinib, are reasonably well tolerated but they do have some characteristic side effects. There are a number of different EGFR inhibitors that we have for our patients who have EGFR-mutant lung cancer. As first-line therapy for our patients with metastatic EGFR-mutant lung cancer, we have three different EGFR inhibitors that we can use in this country: gefitinib, erlotinib, and afatinib. There are great data for all three of these, which is why they are approved agents.

In terms of how we use them, it depends on the provider, depending on what you’re used to using and what you’ve potentially, read about in terms of potential advantages like side effects. I would say that it’s very common in this country to use erlotinib. That’s been the approved agent for many years now, so many oncologists are familiar with erlotinib. We primarily use erlotinib for patients who have newly diagnosed metastatic EGFR-mutant lung cancer.

However, more recently, both gefitinib, and afatinib are now approved agents as well. Gefitinib tends to have a better toxicity profile and seems to have comparable efficacy. So now that it’s an approved agent in this country, it’s possible that we will see more of a shift toward gefitinib use. In my own clinic, if I have a patient who is a little more tenuous in terms of their performance status, or has a lot of medical issues—one who I may worry about in terms of tolerating side effects of erlotinib—I’m very comfortable using gefitinib in place of erlotinib.

We also have afatinib that we can use, and I would say the main use that we’re seeing for afatinib, is in patients who have a specific EGFR-activating mutation; that’s the exon 19 deletion. And there are data from the LUX-Lung trials that show that there may be an overall survival benefit of afatinib, particularly in the exon 19 deletion. And so I would say, again, in this country we’re seeing more and more use of afatinib, particularly for that particular type of EGFR mutation. In my own clinic, I will use afatinib for patients who have EGFR exon 19 deletions, but generally those patients who are perhaps younger, and very fit, and who can tolerate some of the side effects that we see with afatinib —which tend to be a little bit more than the other EGFR inhibitors.

The EGFR inhibitors overall are quite well-tolerated, but they do have some characteristic side effects. Overall, EGFR inhibitors, the current batch of first- and second-generation inhibitors, like gefitinib, erlotinib, and afatinib, all have rash and diarrhea as side effects due to inhibition of wild-type EGFR. I would say we see the most side effects with afatinib, compared to erlotinib and gefitinib.

Gefitinib, among the three, tends to be better tolerated in terms of those side effects, so that is one that we may choose to use in a patient who is more frail than someone else, because of its better safety and side effect profile. We see rash and diarrhea pretty consistently with erlotinib, probably in the range of 70% to 80% of patients will have rash and will have diarrhea. Usually those can be very easily managed with various medications, for example, topical antibiotics for the rash, sometimes oral antibiotics, and antidiarrheals for the diarrhea caused by the EGFR inhibitors. Sometimes though, we have to just hold the drug and dose reduce, so often times when we start erlotinib, for example, at 150 mg/day, which is the standard dose, because of difficult-to-control rash or diarrhea, we may need to hold and dose reduce to 100 or even 75 mg/day.

Afatinib, which is a second-generation inhibitor, also an approved agent for us in this country, is a little more difficult, in my experience, than erlotinib or gefitinib. Again, there’s rash and diarrhea, and with afatinib I also see a little bit more mucositis than I’d see with the other agents. And that can be difficult for patients in terms of their eating and drinking. So I find afatinib can be challenging. Many of the patients on afatinib will require a hold and a dose reduction in order to make the drug more tolerable.

Mark A. Socinski, MD: The studies that have pursued re-biopsy of patients with EGFR mutations, once they have progressed on first or second-generation EGFR tyrosine kinase inhibitors, have really been invaluable. What I’m talking about is patients who are initially diagnosed with an EGFR mutation, who are treated with a first-generation— either erlotinib or gefitinib—or a second-generation agent—afatinib—and who, on average, may go nine to twelve months before they start progressing.

Obviously, if their cancer is getting worse, they’re breaking through the inhibitory effect of those first- or second-generation agents. When you re-biopsy those patients, you understand that in 50% to 60% of those patients, a secondary mutation occurs—an exon 20 referred to as T790M. This changes the binding site for inhibition for the TKIs and allows them to break through the inhibitory effect of those agents. We are now in an era of being able to target that with a third-generation TKI.

Osimertinib was recently approved for use in T790M-specific patients. Now, that’s an important advance because prior to that approval, we would divert to standard chemotherapy for these patients, but the use of the third-generation TKI gives them another oral targeted option that was not previously available.

In the other 40% to 50%, there’s actually been a variety of resistance mechanisms: MET amplification, PI3 kinase abnormalities, HER2 abnormalities, BRAF abnormalities, and also this entity of histologic transformation. It’s interesting that in the EGFR mutation patients, these are almost always adenocarcinoma in predominantly light or never-smokers.

The observation has been on these re-biopsy studies to see histologic transformation to small cell lung cancer. We’ve had a few cases at our center where there’s more of a sarcomatoid carcinoma appearance of the biopsy—and this is important. Certainly, if you diagnose a small cell transformation on a re-biopsy, that would demand a change in the direction of your therapy. You would use a standard regimen for small cell lung cancer, such as a platinum etoposide, and these patients respond to that. But that mechanism, or how that histologic transformation occurs, at least by me, is not well understood. But certainly it has been documented in the literature. And, we see this in our practice with EGFR-mutant-positive patients.

The approval of osimertinib, and having a T790M strategy, is vitally important. This is 50% to 60% of the patients. For the remaining 40%, there’s a variety of mechanisms that we still have a little bit of work to do to know the optimal way forward in that proportion of the refractory mutant patients.
                                                                                                                                                                                                                                                                                                                
Transcript Edited for Clarity
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