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Emerging Therapies in EGFR-Positive NSCLC

Panelists: Benjamin P. Levy, MD, Johns Hopkins Sidney Kimmel Cancer Center; Lyudmila A. Bazhenova, MD, University of California San Diego; Alexander Drilon, MD, Memorial Sloan Kettering Cancer Center; Zofia Piotrowska, MD, Massachusetts General Hospital Cancer Center; Jonathan W. Riess, MD, MS, UC Davis Comprehensive Cancer Center
Published: Monday, Aug 27, 2018



Transcript: 

Benjamin P. Levy, MD: Let’s move on to this year’s ASCO Annual Meeting. Some interesting data have emerged in the EGFR space. We’re going to learn more about this in the coming days. We’ve got a dacomitinib trial. We have erlotinib plus bevacizumab. And then, importantly, we are looking at the role of immunotherapy in EGFR-mutant lung cancer. Lyudmila, do you want to talk about the dacomitinib trial?

Lyudmila A. Bazhenova, MD: The dacomitinib trial, ARCHER 1050, was a randomized clinical trial for patients with newly diagnosed stage 4 non–small cell lung cancer with an EGFR-sensitizing mutation. It randomized patients to dacomitinib versus gefitinib. We just spent a half-hour talking about the fact that gefitinib is no longer a standard of care in any of our hands. To put this trial into perspective, the comparison arm is not technically the arm that we use. But what’s interesting about the study is that this is the first study that ever showed improvement in survival when you compared 2 different TKIs—with the exception of the combined analysis of LUX-Lung 3 and LUX-Lung 6, which we’re not going to talk about today.

The overall survival in the dacomitinib arm was 34 months. In the gefitinib arm, it was 26.8 months. My perspective of the study is that the overall survival could be positive. That’s what I take away from that study. When you look at the hazard ratios, the hazard ratio for the dacomitinib trial was 0.76. The hazard ratio in the osimertinib study, FLAURA, which was osimertinib versus erlotinib, where the data are not mature, was 0.67. I think it is very possible that this is a preview for what we’re going to see from the FLAURA study. It doesn’t change my practice. My first choice for EGFR-mutant patients is still osimertinib, but it gives me some hope that the overall survival data will be positive.

Zofia Piotrowska, MD: In that dacomitinib study, it’s also notable that the rates of toxicity were pretty significant with the second-generation EGFR inhibitor. I think that also plays into decision making for the first-line options.

Jonathan W. Riess, MD, MS: The other thing that I’d also like to note is that unlike osimertinib, where untreated brain metastases were allowed, for dacomitinib, it was not. It seems to have less blood-brain barrier penetration.

Alexander Drilon, MD: And lastly, if you look at the FLAURA publication, the survival curves do actually separate. And if you didn’t look closely, the P value was less than 0.05. For that number of events, you needed a much lower P value to reach significance. So, again, there are encouraging data. Hopefully we will see a difference in survival.

Benjamin P. Levy, MD: Yes. Kudos to the ARCHER 1050 trial for showing an overall survival advantage. I just think that the toxicities are a big challenge with that drug, having participated in some of the phase I experience. It is not an easy drug to give, but I’m looking forward to seeing the data.

We’ve had other data with erlotinib plus bevacizumab—antiangiogenesis added to the TKI. There’s a lot of preclinical rationale for synergy there. Jonathan, do you want to walk us through what we may see with some of these trials that are looking at a TKI plus an antiangiogenic agent?

Jonathan W. Riess, MD, MS: There are 2 studies out of Japan that are going to be presented. One is a follow up of a phase II trial that compared erlotinib to erlotinib and bevacizumab. This time it reported overall survival. Previously, it showed a good progression-free survival benefit. Researchers now looked at overall survival and showed that there was a median overall survival of about 4 years in both groups, which is very good. But there didn’t seem to be any significant difference between erlotinib and bevacizumab and erlotinib alone, although there was a slight trend toward the erlotinib and bevacizumab regimen.
The phase III trial, also conducted in Japan, randomized patients to erlotinib versus erlotinib and bevacizumab, and the results showed a progression-free survival benefit: a median of 16.9 months for receiving bevacizumab and about 13.3 months for erlotinib, alone. That was statistically significant. It does seem to have some benefit in terms of progression-free survival. The overall survival is still a bit unclear.

Osimertinib, alone, although cross-trial comparisons can be problematic, showed a median overall survival of about 19 months. With bevacizumab, you have to come in and get it intravenously every 3 weeks. Whereas otherwise, patients can be on an oral TKI. I think that antiangiogenic drugs, with osimertinib and with some next-generation TKIs, should be explored. There may benefit, building upon these studies. With osimertinib in the first-line setting, I have not used bevacizumab with erlotinib.

Benjamin P. Levy, MD: OK. I can’t remember who we’re tossing this one out to, but the lack of immunotherapy benefits in EGFR-mutant lung cancer patients, there was going to be a trial looking at pembrolizumab in EGFR-mutant lung cancer. I’m not sure who wants to tackle this one. Zofia, is that you?

Zofia Piotrowska, MD: Yes. I thought this was a very intriguing and informative study. This was a small phase II study of first-line pembrolizumab for patients with previously untreated EGFR-mutant lung cancer. The study size should have been 25 patients. They actually only treated 11 patients and stopped the study prematurely due to a lack in efficacy. Among those 11 patients who had been TKI-naïve but were treated with first-line pembrolizumab, only 1 patient had a response. And strikingly, that 1 patient, on further testing, was found not to have an EGFR mutation. So, no responses were seen among the true EGFR-mutant patients, which is consistent with the data that we’ve seen in later lines of therapy—although I think the hope of the study had been that maybe there was more activity in a newly diagnosed patient.

Benjamin P. Levy, MD: Especially those who are PD-L1 high.

Zofia Piotrowska, MD: Exactly. That’s a very good point. These patients were PD-L1 high, and we still found no activity. What was particularly striking was the toxicity. In particular, the authors actually followed these patients for toxicities. Even after the end of pembrolizumab therapy, they noted 2 deaths within 6 months from pembrolizumab, including 1 case of fatal pneumonitis. I think this really highlights the fact that immunotherapy has toxicities not only during treatment, but even after the end of treatment. There’s likely some overlap and some synergy, even potentially between the side effects of immunotherapy and some of the toxicities that we see with EGFR inhibitors. And so, for newly diagnosed patients, the right therapy is not immunotherapy. Rather, it’s an EGFR inhibitor.

Sometimes that can be tricky. The PD-L1 usually comes back much faster than the molecular testing. I’ve certainly been in the position of seeing that the PD-L1 is 80%. I’m all set to go with immunotherapy. And then, I find the EGFR mutation. For those patients, that really is essential to treat them with the EGFR inhibitor. We don’t know what that interplay will be in larger numbers with the toxicities, and it’s really a tragedy when patients die before they’re able to get the TKI.

Jonathan W. Riess, MD, MS: As you pointed out with the potential toxicity of immunotherapy and TKI therapy, these immunotherapy drugs, such as pembrolizumab, have a long half-life. Getting pembrolizumab and then getting started on a TKI, there’s some potential toxicity that could have been synergistic that led to that pneumonitis. Sometimes people continue EGFR TKIs through lines of progression. There’s some rationale for that, but particularly with immunotherapy, outside of a clinical trial, I would not do that. There is a risk for synergistic toxicity. Oftentimes, because of the lack of benefit outside of the clinical trial, in terms of giving immunotherapy, I usually wait for later lines of therapy and look at other options.

Benjamin P. Levy, MD: Much later.

Jonathan W. Riess, MD, MS: Much later. The IMpower150 study with carboplatin, Taxol (paclitaxel), bevacizumab, and atezolizumab has been provocative enough that, with chemotherapy and bevacizumab, it may lead to a reevaluation. But that was still a subset analysis.

Benjamin P. Levy, MD: It was a subset analysis of about 100 patients. I agree. I think single-agent immunotherapy is probably not a great option for EGFR-mutant lung cancer patients as first, second, third, or potentially fourth-line therapy. We need to exhaust TKIs and chemotherapy.

Jonathan W. Riess, MD, MS: That could be a discussion with patients. A lot of patients, even with EGFR-mutant lung cancer, want immunotherapy. They want the Jimmy Carter drug. People flat out say, “Give it to me,” because of all of the hype surrounding it. While it is well founded, it doesn’t help everyone. And so, as single agents, I discourage that—except for very later lines of therapy. I often ask them to seek out clinical trials of combination therapies that may have more benefit.

Transcript Edited for Clarity 

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Transcript: 

Benjamin P. Levy, MD: Let’s move on to this year’s ASCO Annual Meeting. Some interesting data have emerged in the EGFR space. We’re going to learn more about this in the coming days. We’ve got a dacomitinib trial. We have erlotinib plus bevacizumab. And then, importantly, we are looking at the role of immunotherapy in EGFR-mutant lung cancer. Lyudmila, do you want to talk about the dacomitinib trial?

Lyudmila A. Bazhenova, MD: The dacomitinib trial, ARCHER 1050, was a randomized clinical trial for patients with newly diagnosed stage 4 non–small cell lung cancer with an EGFR-sensitizing mutation. It randomized patients to dacomitinib versus gefitinib. We just spent a half-hour talking about the fact that gefitinib is no longer a standard of care in any of our hands. To put this trial into perspective, the comparison arm is not technically the arm that we use. But what’s interesting about the study is that this is the first study that ever showed improvement in survival when you compared 2 different TKIs—with the exception of the combined analysis of LUX-Lung 3 and LUX-Lung 6, which we’re not going to talk about today.

The overall survival in the dacomitinib arm was 34 months. In the gefitinib arm, it was 26.8 months. My perspective of the study is that the overall survival could be positive. That’s what I take away from that study. When you look at the hazard ratios, the hazard ratio for the dacomitinib trial was 0.76. The hazard ratio in the osimertinib study, FLAURA, which was osimertinib versus erlotinib, where the data are not mature, was 0.67. I think it is very possible that this is a preview for what we’re going to see from the FLAURA study. It doesn’t change my practice. My first choice for EGFR-mutant patients is still osimertinib, but it gives me some hope that the overall survival data will be positive.

Zofia Piotrowska, MD: In that dacomitinib study, it’s also notable that the rates of toxicity were pretty significant with the second-generation EGFR inhibitor. I think that also plays into decision making for the first-line options.

Jonathan W. Riess, MD, MS: The other thing that I’d also like to note is that unlike osimertinib, where untreated brain metastases were allowed, for dacomitinib, it was not. It seems to have less blood-brain barrier penetration.

Alexander Drilon, MD: And lastly, if you look at the FLAURA publication, the survival curves do actually separate. And if you didn’t look closely, the P value was less than 0.05. For that number of events, you needed a much lower P value to reach significance. So, again, there are encouraging data. Hopefully we will see a difference in survival.

Benjamin P. Levy, MD: Yes. Kudos to the ARCHER 1050 trial for showing an overall survival advantage. I just think that the toxicities are a big challenge with that drug, having participated in some of the phase I experience. It is not an easy drug to give, but I’m looking forward to seeing the data.

We’ve had other data with erlotinib plus bevacizumab—antiangiogenesis added to the TKI. There’s a lot of preclinical rationale for synergy there. Jonathan, do you want to walk us through what we may see with some of these trials that are looking at a TKI plus an antiangiogenic agent?

Jonathan W. Riess, MD, MS: There are 2 studies out of Japan that are going to be presented. One is a follow up of a phase II trial that compared erlotinib to erlotinib and bevacizumab. This time it reported overall survival. Previously, it showed a good progression-free survival benefit. Researchers now looked at overall survival and showed that there was a median overall survival of about 4 years in both groups, which is very good. But there didn’t seem to be any significant difference between erlotinib and bevacizumab and erlotinib alone, although there was a slight trend toward the erlotinib and bevacizumab regimen.
The phase III trial, also conducted in Japan, randomized patients to erlotinib versus erlotinib and bevacizumab, and the results showed a progression-free survival benefit: a median of 16.9 months for receiving bevacizumab and about 13.3 months for erlotinib, alone. That was statistically significant. It does seem to have some benefit in terms of progression-free survival. The overall survival is still a bit unclear.

Osimertinib, alone, although cross-trial comparisons can be problematic, showed a median overall survival of about 19 months. With bevacizumab, you have to come in and get it intravenously every 3 weeks. Whereas otherwise, patients can be on an oral TKI. I think that antiangiogenic drugs, with osimertinib and with some next-generation TKIs, should be explored. There may benefit, building upon these studies. With osimertinib in the first-line setting, I have not used bevacizumab with erlotinib.

Benjamin P. Levy, MD: OK. I can’t remember who we’re tossing this one out to, but the lack of immunotherapy benefits in EGFR-mutant lung cancer patients, there was going to be a trial looking at pembrolizumab in EGFR-mutant lung cancer. I’m not sure who wants to tackle this one. Zofia, is that you?

Zofia Piotrowska, MD: Yes. I thought this was a very intriguing and informative study. This was a small phase II study of first-line pembrolizumab for patients with previously untreated EGFR-mutant lung cancer. The study size should have been 25 patients. They actually only treated 11 patients and stopped the study prematurely due to a lack in efficacy. Among those 11 patients who had been TKI-naïve but were treated with first-line pembrolizumab, only 1 patient had a response. And strikingly, that 1 patient, on further testing, was found not to have an EGFR mutation. So, no responses were seen among the true EGFR-mutant patients, which is consistent with the data that we’ve seen in later lines of therapy—although I think the hope of the study had been that maybe there was more activity in a newly diagnosed patient.

Benjamin P. Levy, MD: Especially those who are PD-L1 high.

Zofia Piotrowska, MD: Exactly. That’s a very good point. These patients were PD-L1 high, and we still found no activity. What was particularly striking was the toxicity. In particular, the authors actually followed these patients for toxicities. Even after the end of pembrolizumab therapy, they noted 2 deaths within 6 months from pembrolizumab, including 1 case of fatal pneumonitis. I think this really highlights the fact that immunotherapy has toxicities not only during treatment, but even after the end of treatment. There’s likely some overlap and some synergy, even potentially between the side effects of immunotherapy and some of the toxicities that we see with EGFR inhibitors. And so, for newly diagnosed patients, the right therapy is not immunotherapy. Rather, it’s an EGFR inhibitor.

Sometimes that can be tricky. The PD-L1 usually comes back much faster than the molecular testing. I’ve certainly been in the position of seeing that the PD-L1 is 80%. I’m all set to go with immunotherapy. And then, I find the EGFR mutation. For those patients, that really is essential to treat them with the EGFR inhibitor. We don’t know what that interplay will be in larger numbers with the toxicities, and it’s really a tragedy when patients die before they’re able to get the TKI.

Jonathan W. Riess, MD, MS: As you pointed out with the potential toxicity of immunotherapy and TKI therapy, these immunotherapy drugs, such as pembrolizumab, have a long half-life. Getting pembrolizumab and then getting started on a TKI, there’s some potential toxicity that could have been synergistic that led to that pneumonitis. Sometimes people continue EGFR TKIs through lines of progression. There’s some rationale for that, but particularly with immunotherapy, outside of a clinical trial, I would not do that. There is a risk for synergistic toxicity. Oftentimes, because of the lack of benefit outside of the clinical trial, in terms of giving immunotherapy, I usually wait for later lines of therapy and look at other options.

Benjamin P. Levy, MD: Much later.

Jonathan W. Riess, MD, MS: Much later. The IMpower150 study with carboplatin, Taxol (paclitaxel), bevacizumab, and atezolizumab has been provocative enough that, with chemotherapy and bevacizumab, it may lead to a reevaluation. But that was still a subset analysis.

Benjamin P. Levy, MD: It was a subset analysis of about 100 patients. I agree. I think single-agent immunotherapy is probably not a great option for EGFR-mutant lung cancer patients as first, second, third, or potentially fourth-line therapy. We need to exhaust TKIs and chemotherapy.

Jonathan W. Riess, MD, MS: That could be a discussion with patients. A lot of patients, even with EGFR-mutant lung cancer, want immunotherapy. They want the Jimmy Carter drug. People flat out say, “Give it to me,” because of all of the hype surrounding it. While it is well founded, it doesn’t help everyone. And so, as single agents, I discourage that—except for very later lines of therapy. I often ask them to seek out clinical trials of combination therapies that may have more benefit.

Transcript Edited for Clarity 
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