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Frontline Treatment for EGFR+ NSCLC

Panelists: Charu Aggarwal, MD, MPH, Hospital of the University of Pennsylvania; Hossein Borghaei, DO, Fox Chase Cancer Center; H. Jack West, MD, Swedish Cancer Institute
Published: Wednesday, Feb 13, 2019



Transcript:

H. Jack West, MD: Let’s turn to the subgroup of patients with an EGFR mutation, an activating EGFR mutation. We have the FLAURA trial, which showed a significant PFS [progression-free survival] benefit in the patients who got that in the first line, compared with a first-generation EGFR TKI [tyrosine kinase inhibitor]—gefitinib or erlotinib—and more recently, a publication of better results in terms of CNS [central nervous system] activity. Is osimertinib your standard of care, first line, for these patients, Charu?

Charu Aggarwal, MD, MPH: Absolutely, I think, for several reasons: tolerability, I think availability, ease of use. And then you can’t really argue against the CNS activity as well as the survival and the response rates. I think it’s a clear winner on all fronts, and it’s been our first choice.

Hossein Borghaei, DO: Yes, me too.

H. Jack West, MD: I think that we have, as a community of thoracic oncologists, really landed on this as a very strong choice based on that combination of efficacy, very good tolerability, and CNS control. And now that we can achieve it, we think about it more and more, and it matters more than we had previously considered. There are also data that came out on the concept of first-line chemotherapy integrated with gefitinib. This was the NEJ009 trial out of Japan that looked pretty impressive, in fact quite impressive, not just for PFS but even with a 14-month overall survival benefit. And that was using an agent that is really the weakest sibling in that family of EGFR TKIs. But the median overall survival was 52 months. I think that was a surprise winner, along with chemotherapy combined with whatever at ASCO [the American Society of Clinical Oncology]. But does this make a difference? And if so, how are we ever going to incorporate this concept into our treatment paradigm, Hoss?

Hossein Borghaei, DO: Well, I’m not incorporating it into my treatment paradigm. I think it might be an outlier for all I know at this point. It’s 1 study, and the results are so overwhelmingly positive. You know, you get an occasional study that, despite everything that you think, is either really, really positive or really, really negative. And I think that’s why we need confirmatory studies. First of all, it was a different patient population, right? It was done in Asia. Predominantly, there are pharmacodynamic differences. The response to EGFR therapy is a little bit different. And even though, as you said, they used a weaker sibling of all the TKIs in a first-generation gefitinib in this study, the way the patients might be responding to these treatments might be a little bit different in Asia than it is in a North American or northern European patient population.

As we just discussed, osimertinib is our standard of care. Am I willing to let go with a single drug with such good tolerability and efficacy in favor or chemotherapy plus TKI? We didn’t see any CNS data for chemotherapy plus gefitinib. So there are a lot of things that tell me the study is provocative. I think it’s hypothesis generating. But unless I see a study similar to this with maybe osimertinib in a patient that I see in my clinic, I don’t think I’m willing to sort of switch my treatment and go to the chemo-plus-gefitinib route at this point. And I don’t know whether you can argue that you can substitute either your favorite TKI and just give them the chemotherapy. I think that’s a little bit risky. So I like this study. I think it is something we should pay attention to. But in the absence of a confirmatory study, I’m not sure I want to switch my practice.

Charu Aggarwal, MD, MPH: Although having said that, we know that a fair majority of patients do either lose their performance status or run out of options, or they’re just not good candidates to get second- or third-line therapy. I do like the study design, in which you’re giving your best approach first. And I do think that there is some value to that. Again, the study was done with gefitinib and not with osimertinib, so we can’t really just plunk in osimertinib for gefitinib in that study and offer carbo [carboplatin], pem [pemetrexed], and osimertinib to our patients. I don’t think we’ll have any shred of evidence to say, “Yes, this is superior to just using osimertinib.” But I do like the concept of coming in with a combination, so you can perhaps improve overall survival, not just PFS.

Hossein Borghaei, DO: Would you do that in the second-line setting if somebody progresses on osimertinib? Are you willing to consider chemotherapy plus gefitinib as a second-line option?

Charu Aggarwal, MD, MPH: I don’t think we have data on that.

Hossein Borghaei, DO: We have no data on that.

H. Jack West, MD: No. I would have to say, though, that we—we, as a society and NCCN [National Comprehensive Cancer Network]—adopted erlotinib first-line in a heartbeat after Japanese-only data with gefitinib. It wasn’t even the same TKI, and it definitely wasn’t a non-Japanese population. So I think that our readiness to accept Japanese data depends on our biases at the time.

Hossein Borghaei, DO: Well, I don’t think it’s that, Jack. It’s a different era. We’ve come a long way since then. A lot of stuff has happened in that time period. We’re not as desperate for drugs. We’re not as desperate for a treatment option that’s reasonable for our patient population. And I’m not saying I’m refuting this study because it’s done in an Asian patient population. I’m just highlighting the fact that there are clear differences. Look at the ALK [anaplastic lymphoma kinase] story. Half the dose of the US drug is used in Japan with good clinical efficacy, so clearly there are differences.

H. Jack West, MD: That’s fair to say that the context is different, and so I just would say I think that there are potentially differences, but we have generally and frankly, in J-ALEX versus ALEX, looked at those differences. Even if the dose was different, the results were the same.

Hossein Borghaei, DO: Yeah, exactly.

H. Jack West, MD: And I’ve never felt bad about recommending alectinib in that setting, pre. But I think there’s no question. We don’t have the data yet. I think it is a potential competitor. I think it’s most interesting to look at what osimertinib and chemotherapy could do, and I think that could end up being a remarkable benefit in just that the best opportunity is, again, to ensure that everyone gets the available lines of treatment. And the fact that a quarter of the patients who started on gefitinib alone never got chemotherapy, and this is in Japan, where they have a pretty good ability to cross over these patients. I think that, to me, suggests that hitting it up front may have a particular benefit, but admittedly we need to study this more.

One of the other concepts that came out of Japan, and we have debated how well we should generalize this, is erlotinib with bevacizumab. And a phase II trial looked very positive for progression-free survival. That did not pan out for overall survival. We’ve seen an additional study out of Japan that looked quite similar. Do erlotinib and bevacizumab have any place that you can see, or is that a dead concept?

Charu Aggarwal, MD, MPH: So I think VEGF inhibition is a valid target in EGFR-mutant lung cancer. I don’t know if erlotinib and bevacizumab is the way to go in the second-line setting. But I would be very curious to look at the results of osimertinib and bevacizumab, which is currently enrolling, and actually, interim data were presented that looked quite promising. So I’m not ready to abandon the VEGF inhibition approach. I think it’s very valid, it makes sense, and it’s scientifically found. I just don’t know where I would use erlotinib and bevacizumab in the second-line setting.

Hossein Borghaei, DO: I agree. I think VEGF inhibition is definitely still a valid concept in this patient population. I’ll tell you a couple of examples where I have used it: just adding bevacizumab to somebody who might have been on erlotinib in the beginning and was at a time of slight progression—if it was something that I couldn’t radiate or it was more of a global here and there, and I really didn’t have a lot of options, and I have added bevacizumab. And I cannot tell you I’ve had spectacular responses, but I’ve definitely seen disease stability over a prolonged time, again going to the PFS being better but maybe not necessarily the overall survival. So I have used the agent in that type of a setting. I haven’t added it to osimertinib yet. I haven’t had that kind of a scenario come up, so I don’t know what that’s going to be like. But as you said, I’m hoping that the results of osimertinib and bevacizumab would give us yet another option for this patient population.

Transcript Edited for Clarity

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Transcript:

H. Jack West, MD: Let’s turn to the subgroup of patients with an EGFR mutation, an activating EGFR mutation. We have the FLAURA trial, which showed a significant PFS [progression-free survival] benefit in the patients who got that in the first line, compared with a first-generation EGFR TKI [tyrosine kinase inhibitor]—gefitinib or erlotinib—and more recently, a publication of better results in terms of CNS [central nervous system] activity. Is osimertinib your standard of care, first line, for these patients, Charu?

Charu Aggarwal, MD, MPH: Absolutely, I think, for several reasons: tolerability, I think availability, ease of use. And then you can’t really argue against the CNS activity as well as the survival and the response rates. I think it’s a clear winner on all fronts, and it’s been our first choice.

Hossein Borghaei, DO: Yes, me too.

H. Jack West, MD: I think that we have, as a community of thoracic oncologists, really landed on this as a very strong choice based on that combination of efficacy, very good tolerability, and CNS control. And now that we can achieve it, we think about it more and more, and it matters more than we had previously considered. There are also data that came out on the concept of first-line chemotherapy integrated with gefitinib. This was the NEJ009 trial out of Japan that looked pretty impressive, in fact quite impressive, not just for PFS but even with a 14-month overall survival benefit. And that was using an agent that is really the weakest sibling in that family of EGFR TKIs. But the median overall survival was 52 months. I think that was a surprise winner, along with chemotherapy combined with whatever at ASCO [the American Society of Clinical Oncology]. But does this make a difference? And if so, how are we ever going to incorporate this concept into our treatment paradigm, Hoss?

Hossein Borghaei, DO: Well, I’m not incorporating it into my treatment paradigm. I think it might be an outlier for all I know at this point. It’s 1 study, and the results are so overwhelmingly positive. You know, you get an occasional study that, despite everything that you think, is either really, really positive or really, really negative. And I think that’s why we need confirmatory studies. First of all, it was a different patient population, right? It was done in Asia. Predominantly, there are pharmacodynamic differences. The response to EGFR therapy is a little bit different. And even though, as you said, they used a weaker sibling of all the TKIs in a first-generation gefitinib in this study, the way the patients might be responding to these treatments might be a little bit different in Asia than it is in a North American or northern European patient population.

As we just discussed, osimertinib is our standard of care. Am I willing to let go with a single drug with such good tolerability and efficacy in favor or chemotherapy plus TKI? We didn’t see any CNS data for chemotherapy plus gefitinib. So there are a lot of things that tell me the study is provocative. I think it’s hypothesis generating. But unless I see a study similar to this with maybe osimertinib in a patient that I see in my clinic, I don’t think I’m willing to sort of switch my treatment and go to the chemo-plus-gefitinib route at this point. And I don’t know whether you can argue that you can substitute either your favorite TKI and just give them the chemotherapy. I think that’s a little bit risky. So I like this study. I think it is something we should pay attention to. But in the absence of a confirmatory study, I’m not sure I want to switch my practice.

Charu Aggarwal, MD, MPH: Although having said that, we know that a fair majority of patients do either lose their performance status or run out of options, or they’re just not good candidates to get second- or third-line therapy. I do like the study design, in which you’re giving your best approach first. And I do think that there is some value to that. Again, the study was done with gefitinib and not with osimertinib, so we can’t really just plunk in osimertinib for gefitinib in that study and offer carbo [carboplatin], pem [pemetrexed], and osimertinib to our patients. I don’t think we’ll have any shred of evidence to say, “Yes, this is superior to just using osimertinib.” But I do like the concept of coming in with a combination, so you can perhaps improve overall survival, not just PFS.

Hossein Borghaei, DO: Would you do that in the second-line setting if somebody progresses on osimertinib? Are you willing to consider chemotherapy plus gefitinib as a second-line option?

Charu Aggarwal, MD, MPH: I don’t think we have data on that.

Hossein Borghaei, DO: We have no data on that.

H. Jack West, MD: No. I would have to say, though, that we—we, as a society and NCCN [National Comprehensive Cancer Network]—adopted erlotinib first-line in a heartbeat after Japanese-only data with gefitinib. It wasn’t even the same TKI, and it definitely wasn’t a non-Japanese population. So I think that our readiness to accept Japanese data depends on our biases at the time.

Hossein Borghaei, DO: Well, I don’t think it’s that, Jack. It’s a different era. We’ve come a long way since then. A lot of stuff has happened in that time period. We’re not as desperate for drugs. We’re not as desperate for a treatment option that’s reasonable for our patient population. And I’m not saying I’m refuting this study because it’s done in an Asian patient population. I’m just highlighting the fact that there are clear differences. Look at the ALK [anaplastic lymphoma kinase] story. Half the dose of the US drug is used in Japan with good clinical efficacy, so clearly there are differences.

H. Jack West, MD: That’s fair to say that the context is different, and so I just would say I think that there are potentially differences, but we have generally and frankly, in J-ALEX versus ALEX, looked at those differences. Even if the dose was different, the results were the same.

Hossein Borghaei, DO: Yeah, exactly.

H. Jack West, MD: And I’ve never felt bad about recommending alectinib in that setting, pre. But I think there’s no question. We don’t have the data yet. I think it is a potential competitor. I think it’s most interesting to look at what osimertinib and chemotherapy could do, and I think that could end up being a remarkable benefit in just that the best opportunity is, again, to ensure that everyone gets the available lines of treatment. And the fact that a quarter of the patients who started on gefitinib alone never got chemotherapy, and this is in Japan, where they have a pretty good ability to cross over these patients. I think that, to me, suggests that hitting it up front may have a particular benefit, but admittedly we need to study this more.

One of the other concepts that came out of Japan, and we have debated how well we should generalize this, is erlotinib with bevacizumab. And a phase II trial looked very positive for progression-free survival. That did not pan out for overall survival. We’ve seen an additional study out of Japan that looked quite similar. Do erlotinib and bevacizumab have any place that you can see, or is that a dead concept?

Charu Aggarwal, MD, MPH: So I think VEGF inhibition is a valid target in EGFR-mutant lung cancer. I don’t know if erlotinib and bevacizumab is the way to go in the second-line setting. But I would be very curious to look at the results of osimertinib and bevacizumab, which is currently enrolling, and actually, interim data were presented that looked quite promising. So I’m not ready to abandon the VEGF inhibition approach. I think it’s very valid, it makes sense, and it’s scientifically found. I just don’t know where I would use erlotinib and bevacizumab in the second-line setting.

Hossein Borghaei, DO: I agree. I think VEGF inhibition is definitely still a valid concept in this patient population. I’ll tell you a couple of examples where I have used it: just adding bevacizumab to somebody who might have been on erlotinib in the beginning and was at a time of slight progression—if it was something that I couldn’t radiate or it was more of a global here and there, and I really didn’t have a lot of options, and I have added bevacizumab. And I cannot tell you I’ve had spectacular responses, but I’ve definitely seen disease stability over a prolonged time, again going to the PFS being better but maybe not necessarily the overall survival. So I have used the agent in that type of a setting. I haven’t added it to osimertinib yet. I haven’t had that kind of a scenario come up, so I don’t know what that’s going to be like. But as you said, I’m hoping that the results of osimertinib and bevacizumab would give us yet another option for this patient population.

Transcript Edited for Clarity
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