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Refining Use of EGFR TKIs, Adding Bevacizumab

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 08, 2016


Transcript:

Benjamin P. Levy, MD:
Let’s move on to the next section. We’ve defined that it is important to molecularly interrogate lung cancers, and the importance of that is really rooted in the fact that we have all these great drugs, targeted therapies, that have outperformed chemotherapy in most of the trials. EGFR is certainly no exception; it’s been the poster child for precision medicine. And we now have very good data that either first- or second-generation TKIs outperform chemotherapy in terms of response rate, in terms of progression-free survival, and, perhaps underrepresented, in terms of quality of life for these patients. We have a growing list of combination strategies that are being looked at for patients who are EGFR-mutated, and erlotinib/bevacizumab is one of those that’s being looked at. Sarah, maybe can you go over the data and where you see combination strategies. Are single agents fitting into your practice routinely?

Sarah B. Goldberg, MD, MPH: This is an area that has really been changing over the last few years. It’s been more than 10 years since we’ve known EGFR mutations predict for benefit from EGFR TKIs, and so now we have several options that are FDA-approved and that are standard treatments for patients. The first was the approval of erlotinib, which, as you mentioned, has benefit over chemotherapy in the first-line setting. So, that’s been our standard of care for several years now. And then over the last couple of years, we’ve had a few more standards that are also options for patients: afatinib and gefitinib. We have now three EGFR inhibitors that are all proven to be beneficial over chemotherapy.

The question then comes up, which one do you use? And that’s when it starts to get complicated. We know all of them are better than chemotherapy for patients with EGFR mutations, but which one is better? And we’re just starting to see some data on that. There was recently a trial of afatinib versus gefitinib, which I know that it’s really one of the first trials that puts them head-to-head. And it looks like there’s a suggestion that afatinib may be beneficial over gefitinib in some metrics. So, it looks like, overall, progression-free survival is improved with afatinib versus gefitinib. For the 1- and 2-year survival, we don’t have data on overall survival. We don’t know where erlotinib fits into that, but it’s suggesting that maybe there is something to afatinib over the first-generation EGFR inhibitors. Is that practice changing? For some people, it is; it’s the first suggestion that maybe there is a benefit there. But there are pros and cons to each approach. It seems that there’s more toxicity with afatinib. If you look at that trial I mentioned, overall, it looks like about the same percentage of toxicities, but anybody who’s had experience with the drugs will say there does seem to be more toxicity with afatinib. It’s manageable, you can dose reduce, you can treat patients with supportive care, but that does seem to be more.

And there are, as you mentioned, combinations now coming out. So, is one TKI-sufficient, or can we do better? We know that all of these TKIs have a high response rate, but patients progress at some point, and the median, no matter which of these trials, about a year is the time to progression. Can we do better with combinations? One of the combinations that is being looked at is, as you mentioned, erlotinib plus bevacizumab. That combination compared to erlotinib alone, there are some data saying that has a better progression-free survival. Again, will that translate to overall survival? We’re not sure.

There’s also an interesting study looking at patients who have pretreatment, T790M mutations. It’s something that we don’t really see that much when we do our standard mutation testing. But if you do very specific testing, you can find T790M pretreatment in patients. And it looks like the combination does seem to be beneficial in those patients.

So, I think all of this is an ongoing story, and I’m not sure where it’s going to end up. There’s a large trial comparing erlotinib plus bevacizumab to erlotinib alone. Although we’ll learn a lot, we don’t have that data yet. I’m curious to hear other people’s opinions on whether this is now standard of care or not. I personally am not using erlotinib and bevacizumab as a standard. I’m using just the single agent TKI as my first-line treatment—but I think it’s intriguing. The data do look very good for it, and we’re going to get more data soon on that.

Benjamin P. Levy, MD: Mark, your thoughts on erlotinib plus bevacizumab?

Mark G. Kris, MD: I am using it as standard, but I’m probably the only one at this table; there aren’t too many standards. People talk about PFS not being important. But to a patient, it’s unbelievably important. The longer you go free of a life-disrupting cancer, it’s inherently a good thing. And I must say that the data that the randomized trial presented at ASCO 2 years ago now, and published over a year ago, was pretty amazing. You get another 6 months by taking bevacizumab every 3 weeks; then it’s a pretty damn good life. So, I routinely give it, and it makes sense in improving that progression-free survival. And if you look at that Japanese data, too, the average number of doses people got was 14 or 15. And it’s pretty well tolerated. Yes, of course, you get the side effects, but they’re generally things we know how to deal with. I think the next issue, though, is moving the third-line drugs up front. And I know you’re going to get that information.

Benjamin P. Levy, MD: We’re going to definitely get there.

Sarah B. Goldberg, MD, MPH: I think one of the issues with using bevacizumab first-line, if there’s a clear advantage—something that patients will accept, but it sounds like your patients have accepted it already—part of the issue is they’re coming in every 3 weeks for an IV treatment as opposed to getting an oral drug. But it’s just something to consider when we don’t have phase III survival data.

Mark G. Kris, MD: Who has heard the line from patients that say, “I don’t see my doctor enough”? I’m sorry; these folks have stage IV lung cancer. It is a life-changing disease, and I think the time seeing your patients and developing a relationship when they’re well is an investment. And sadly there is a time when they’re not well, and that relationship you developed during the well time is an important one. I don’t have patients object, frankly, coming every 3 weeks.

Benjamin P. Levy, MD: Any other erlotinib/bevacizumab takers on the panel? I think the data are compelling.

Mark G. Kris, MD: It’s perfect. It’s about less than 20% of doctors in America where bevacizumab could be used; it’s just about right.

Benjamin P. Levy, MD: Fits the demographic nicely. I have been encouraged by the Japanese data. We’ll have some data from the US in an Alliance-led trial by Tom Stinchcombe. If the PFS advantages holds up, then I think it’s a consideration. Things are moving so quickly, however, with the third-generations moving up, I don’t know where this will all fit in.

Mark G. Kris, MD: That’s why we’re giving bevacizumab with osimertinib.

Benjamin P. Levy, MD: Yes. Do you want to talk a little bit about that experience with osimertinib and bevacizumab?

Mark G. Kris, MD: We haven’t started it, actually. The trial is going to be approved in the next couple of days. But we’ve embraced that; it makes a lot of sense to us. And by the way, as for the 6-month PFS improvement, the approval of bevacizumab was based on a 2-month PFS improvement. Okay, maybe it’s not 6; it’s only 3 months.

Transcript Edited for Clarity
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Transcript:

Benjamin P. Levy, MD:
Let’s move on to the next section. We’ve defined that it is important to molecularly interrogate lung cancers, and the importance of that is really rooted in the fact that we have all these great drugs, targeted therapies, that have outperformed chemotherapy in most of the trials. EGFR is certainly no exception; it’s been the poster child for precision medicine. And we now have very good data that either first- or second-generation TKIs outperform chemotherapy in terms of response rate, in terms of progression-free survival, and, perhaps underrepresented, in terms of quality of life for these patients. We have a growing list of combination strategies that are being looked at for patients who are EGFR-mutated, and erlotinib/bevacizumab is one of those that’s being looked at. Sarah, maybe can you go over the data and where you see combination strategies. Are single agents fitting into your practice routinely?

Sarah B. Goldberg, MD, MPH: This is an area that has really been changing over the last few years. It’s been more than 10 years since we’ve known EGFR mutations predict for benefit from EGFR TKIs, and so now we have several options that are FDA-approved and that are standard treatments for patients. The first was the approval of erlotinib, which, as you mentioned, has benefit over chemotherapy in the first-line setting. So, that’s been our standard of care for several years now. And then over the last couple of years, we’ve had a few more standards that are also options for patients: afatinib and gefitinib. We have now three EGFR inhibitors that are all proven to be beneficial over chemotherapy.

The question then comes up, which one do you use? And that’s when it starts to get complicated. We know all of them are better than chemotherapy for patients with EGFR mutations, but which one is better? And we’re just starting to see some data on that. There was recently a trial of afatinib versus gefitinib, which I know that it’s really one of the first trials that puts them head-to-head. And it looks like there’s a suggestion that afatinib may be beneficial over gefitinib in some metrics. So, it looks like, overall, progression-free survival is improved with afatinib versus gefitinib. For the 1- and 2-year survival, we don’t have data on overall survival. We don’t know where erlotinib fits into that, but it’s suggesting that maybe there is something to afatinib over the first-generation EGFR inhibitors. Is that practice changing? For some people, it is; it’s the first suggestion that maybe there is a benefit there. But there are pros and cons to each approach. It seems that there’s more toxicity with afatinib. If you look at that trial I mentioned, overall, it looks like about the same percentage of toxicities, but anybody who’s had experience with the drugs will say there does seem to be more toxicity with afatinib. It’s manageable, you can dose reduce, you can treat patients with supportive care, but that does seem to be more.

And there are, as you mentioned, combinations now coming out. So, is one TKI-sufficient, or can we do better? We know that all of these TKIs have a high response rate, but patients progress at some point, and the median, no matter which of these trials, about a year is the time to progression. Can we do better with combinations? One of the combinations that is being looked at is, as you mentioned, erlotinib plus bevacizumab. That combination compared to erlotinib alone, there are some data saying that has a better progression-free survival. Again, will that translate to overall survival? We’re not sure.

There’s also an interesting study looking at patients who have pretreatment, T790M mutations. It’s something that we don’t really see that much when we do our standard mutation testing. But if you do very specific testing, you can find T790M pretreatment in patients. And it looks like the combination does seem to be beneficial in those patients.

So, I think all of this is an ongoing story, and I’m not sure where it’s going to end up. There’s a large trial comparing erlotinib plus bevacizumab to erlotinib alone. Although we’ll learn a lot, we don’t have that data yet. I’m curious to hear other people’s opinions on whether this is now standard of care or not. I personally am not using erlotinib and bevacizumab as a standard. I’m using just the single agent TKI as my first-line treatment—but I think it’s intriguing. The data do look very good for it, and we’re going to get more data soon on that.

Benjamin P. Levy, MD: Mark, your thoughts on erlotinib plus bevacizumab?

Mark G. Kris, MD: I am using it as standard, but I’m probably the only one at this table; there aren’t too many standards. People talk about PFS not being important. But to a patient, it’s unbelievably important. The longer you go free of a life-disrupting cancer, it’s inherently a good thing. And I must say that the data that the randomized trial presented at ASCO 2 years ago now, and published over a year ago, was pretty amazing. You get another 6 months by taking bevacizumab every 3 weeks; then it’s a pretty damn good life. So, I routinely give it, and it makes sense in improving that progression-free survival. And if you look at that Japanese data, too, the average number of doses people got was 14 or 15. And it’s pretty well tolerated. Yes, of course, you get the side effects, but they’re generally things we know how to deal with. I think the next issue, though, is moving the third-line drugs up front. And I know you’re going to get that information.

Benjamin P. Levy, MD: We’re going to definitely get there.

Sarah B. Goldberg, MD, MPH: I think one of the issues with using bevacizumab first-line, if there’s a clear advantage—something that patients will accept, but it sounds like your patients have accepted it already—part of the issue is they’re coming in every 3 weeks for an IV treatment as opposed to getting an oral drug. But it’s just something to consider when we don’t have phase III survival data.

Mark G. Kris, MD: Who has heard the line from patients that say, “I don’t see my doctor enough”? I’m sorry; these folks have stage IV lung cancer. It is a life-changing disease, and I think the time seeing your patients and developing a relationship when they’re well is an investment. And sadly there is a time when they’re not well, and that relationship you developed during the well time is an important one. I don’t have patients object, frankly, coming every 3 weeks.

Benjamin P. Levy, MD: Any other erlotinib/bevacizumab takers on the panel? I think the data are compelling.

Mark G. Kris, MD: It’s perfect. It’s about less than 20% of doctors in America where bevacizumab could be used; it’s just about right.

Benjamin P. Levy, MD: Fits the demographic nicely. I have been encouraged by the Japanese data. We’ll have some data from the US in an Alliance-led trial by Tom Stinchcombe. If the PFS advantages holds up, then I think it’s a consideration. Things are moving so quickly, however, with the third-generations moving up, I don’t know where this will all fit in.

Mark G. Kris, MD: That’s why we’re giving bevacizumab with osimertinib.

Benjamin P. Levy, MD: Yes. Do you want to talk a little bit about that experience with osimertinib and bevacizumab?

Mark G. Kris, MD: We haven’t started it, actually. The trial is going to be approved in the next couple of days. But we’ve embraced that; it makes a lot of sense to us. And by the way, as for the 6-month PFS improvement, the approval of bevacizumab was based on a 2-month PFS improvement. Okay, maybe it’s not 6; it’s only 3 months.

Transcript Edited for Clarity
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