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Emerging Data in EGFR-Mutant Lung Cancer

Panelists: Luis E. Raez, MD, FACP, FCCP, Memorial Cancer Institute; Benjamin P. Levy, MD, Johns Hopkins Kimmel Cancer Center; Philip C. Mack, PhD, UC Davis Cancer center
Published: Tuesday, Aug 01, 2017


Transcript:

Benjamin P. Levy, MD: Osimertinib works very well in the EGFR TKI-refractory setting for patients who are T790M-positive. It works so well that it’s now being evaluated frontline in the FLAURA study. It’s a very clean study. Patients with EGFR-sensitizing mutations are randomized to either osimertinib or erlotinib. Keep in mind, osimertinib is a wonderful T790M-directed therapy, but it also happens to hit very well with sensitizing mutations.

This is a head-to-head comparison between the 2. I think we’ll know results by the end of this year—2017—or perhaps sooner. The study is already fully accrued. If the study shows a positive result and dramatic improvement in progression-free survival, I think it’s going to be hard not to use this drug. The phase I study with this drug showed a response rate in the high 70s with a progression-free survival of around 19 months. That’s unprecedented with any first-line drug. I think we’re all very excited, but we should temper that enthusiasm and excitement until we see the head-to-head comparison.

We don’t know how to manage patients post-osimertinib. We know some signals of resistance to osimertinib, including C797S mutations—which is different than with erlotinib. We know the resistant mechanisms for erlotinib—T790M—in which we could deliver osimertinib. So, we’ll have to see. The phase I data look very compelling. This is why we do the head-to-head trial: to get a better understanding. If that study is drastically positive with a huge benefit in progression-free survival, I would argue that osimertinib be the de facto standard of care for all EGFR-mutant stage 4 lung cancers.

Luis E. Raez, MD: What is the future for patients with these EGFR mutations? Well, now we have first-line therapy with tyrosine kinase inhibitors, and we have second-line therapy with osimertinib. The question is if instead of waiting for the patients to develop resistance to radiation therapy, can we put them on osimertinib up front so they can benefit from the best drug up front? That makes a lot of sense, and we have an ongoing study to prove that. We have a study comparing osimertinib to erlotinib and gefitinib, trying to prove which one is better. And osimertinib may be a better agent. But what bothers us is that we’re still not curing lung cancer. We don’t have a lot of agents for lung cancer. Nowadays, a patient with an EGFR mutation gets a tyrosine kinase inhibitor—whichever of the 3 you want to choose—and you buy 1 more year of life for the patient. When the patient fails, hopefully you buy another year of life with osimertinib. You still can, after 2 years, start palliative chemotherapy and hopefully get another year of life. We would love to have osimertinib in the first line, but the threshold is very high for the drug because we want to see that osimertinib will give us the benefit of a real TKI—9 to 12 months of progression-free survival and then still show the benefit of osimertinib for another similar period of time. So, that’s our only concern. Even if the study comes back positive—that osimertinib is better than the other TKIs—we hope that osimertinib can get us there and give us all the benefits that we’re getting from TKIs now so it’s worth making the change and putting the drug in the frontline.

Benjamin P. Levy, MD: One of the combination strategies being looked at is with antiangiogenic strategies—or antiangiogenic drugs. There have been some nice Japanese data comparing erlotinib to erlotinib plus bevacizumab showing a dramatic improvement in progression-free survival. This study is now being redone in a United States population to see if the addition of bevacizumab to erlotinib over erlotinib alone shows any benefit. I think that’s promising.

I think many in the United States have started using bevacizumab in combination with erlotinib for patients who have EGFR-mutant lung cancer based on those Japanese data. I don’t routinely do it yet, although I may change once the United States data come out. I think there are several different strategies looking at EGFR TKIs in combination with immunotherapy, although that strategy has been halted by some toxicity signals that we should keep in mind. I don’t know whether that will pan out in later trials.

We also had some nice data looking at chemotherapy with TKIs that fell under the radar. Pemetrexed in combination with gefitinib improved progression-free survival more than gefitinib alone. Those were data, again, a little bit underrepresented in the web blasts, but they’re the in the JCO this year showing a benefit as well. We’ll have to see, and things may change dramatically if osimertinib becomes frontline. Then we have to alter all the trials again to advance the science if osimertinib comes frontline. But I think antiangiogenic strategies, potentially immunotherapy—although there are some safety signals to consider—and some chemotherapeutic strategies are being looked at.

Luis E. Raez, MD: In the EGFR setting, it’s very challenging because remember, when the patient develops mutations after first-line therapy, we are talking about only T790M and the use of osimertinib now. We have to remember that another 40% of the patients have other pathways of resistance, apart from a histologic transformation of the tumor with small cell lung cancer. We probably have another 30% of patients who develop other pathways to escape the inhibition and become resistant, like c-MET or PI3 kinase. All these pathways need to be targeted. That’s why our interest is to find drugs to block these pathways now, so if a patient develops resistance and does not carry T790M, he will not get osimertinib but does not necessarily have to go for chemotherapy if we can give a c-MET inhibitor, for example. That’s one option for the second line. If the patient has a T790M, and the patient fails osimertinib, that’s another area of challenge for us because if the patient develops resistance to the T790M, the most popular mutation is C797S. There was a presentation last year in ASCO that very clearly showed that of the 15 patients who failed T790M-targeted treatment, 6 or 7 developed the C797S mutation. So, we can now target this mutation and try to find new drugs that can work on that. In that way, the patient doesn’t have to go for palliative chemotherapy yet. These areas are areas under investigation, and they are very interesting for us. That’s why we should be doing serial biopsies, and if serial biopsy of the tissue is too complicated for the patient, the serial liquid biopsy can be a good alternative.

Transcript Edited for Clarity
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Transcript:

Benjamin P. Levy, MD: Osimertinib works very well in the EGFR TKI-refractory setting for patients who are T790M-positive. It works so well that it’s now being evaluated frontline in the FLAURA study. It’s a very clean study. Patients with EGFR-sensitizing mutations are randomized to either osimertinib or erlotinib. Keep in mind, osimertinib is a wonderful T790M-directed therapy, but it also happens to hit very well with sensitizing mutations.

This is a head-to-head comparison between the 2. I think we’ll know results by the end of this year—2017—or perhaps sooner. The study is already fully accrued. If the study shows a positive result and dramatic improvement in progression-free survival, I think it’s going to be hard not to use this drug. The phase I study with this drug showed a response rate in the high 70s with a progression-free survival of around 19 months. That’s unprecedented with any first-line drug. I think we’re all very excited, but we should temper that enthusiasm and excitement until we see the head-to-head comparison.

We don’t know how to manage patients post-osimertinib. We know some signals of resistance to osimertinib, including C797S mutations—which is different than with erlotinib. We know the resistant mechanisms for erlotinib—T790M—in which we could deliver osimertinib. So, we’ll have to see. The phase I data look very compelling. This is why we do the head-to-head trial: to get a better understanding. If that study is drastically positive with a huge benefit in progression-free survival, I would argue that osimertinib be the de facto standard of care for all EGFR-mutant stage 4 lung cancers.

Luis E. Raez, MD: What is the future for patients with these EGFR mutations? Well, now we have first-line therapy with tyrosine kinase inhibitors, and we have second-line therapy with osimertinib. The question is if instead of waiting for the patients to develop resistance to radiation therapy, can we put them on osimertinib up front so they can benefit from the best drug up front? That makes a lot of sense, and we have an ongoing study to prove that. We have a study comparing osimertinib to erlotinib and gefitinib, trying to prove which one is better. And osimertinib may be a better agent. But what bothers us is that we’re still not curing lung cancer. We don’t have a lot of agents for lung cancer. Nowadays, a patient with an EGFR mutation gets a tyrosine kinase inhibitor—whichever of the 3 you want to choose—and you buy 1 more year of life for the patient. When the patient fails, hopefully you buy another year of life with osimertinib. You still can, after 2 years, start palliative chemotherapy and hopefully get another year of life. We would love to have osimertinib in the first line, but the threshold is very high for the drug because we want to see that osimertinib will give us the benefit of a real TKI—9 to 12 months of progression-free survival and then still show the benefit of osimertinib for another similar period of time. So, that’s our only concern. Even if the study comes back positive—that osimertinib is better than the other TKIs—we hope that osimertinib can get us there and give us all the benefits that we’re getting from TKIs now so it’s worth making the change and putting the drug in the frontline.

Benjamin P. Levy, MD: One of the combination strategies being looked at is with antiangiogenic strategies—or antiangiogenic drugs. There have been some nice Japanese data comparing erlotinib to erlotinib plus bevacizumab showing a dramatic improvement in progression-free survival. This study is now being redone in a United States population to see if the addition of bevacizumab to erlotinib over erlotinib alone shows any benefit. I think that’s promising.

I think many in the United States have started using bevacizumab in combination with erlotinib for patients who have EGFR-mutant lung cancer based on those Japanese data. I don’t routinely do it yet, although I may change once the United States data come out. I think there are several different strategies looking at EGFR TKIs in combination with immunotherapy, although that strategy has been halted by some toxicity signals that we should keep in mind. I don’t know whether that will pan out in later trials.

We also had some nice data looking at chemotherapy with TKIs that fell under the radar. Pemetrexed in combination with gefitinib improved progression-free survival more than gefitinib alone. Those were data, again, a little bit underrepresented in the web blasts, but they’re the in the JCO this year showing a benefit as well. We’ll have to see, and things may change dramatically if osimertinib becomes frontline. Then we have to alter all the trials again to advance the science if osimertinib comes frontline. But I think antiangiogenic strategies, potentially immunotherapy—although there are some safety signals to consider—and some chemotherapeutic strategies are being looked at.

Luis E. Raez, MD: In the EGFR setting, it’s very challenging because remember, when the patient develops mutations after first-line therapy, we are talking about only T790M and the use of osimertinib now. We have to remember that another 40% of the patients have other pathways of resistance, apart from a histologic transformation of the tumor with small cell lung cancer. We probably have another 30% of patients who develop other pathways to escape the inhibition and become resistant, like c-MET or PI3 kinase. All these pathways need to be targeted. That’s why our interest is to find drugs to block these pathways now, so if a patient develops resistance and does not carry T790M, he will not get osimertinib but does not necessarily have to go for chemotherapy if we can give a c-MET inhibitor, for example. That’s one option for the second line. If the patient has a T790M, and the patient fails osimertinib, that’s another area of challenge for us because if the patient develops resistance to the T790M, the most popular mutation is C797S. There was a presentation last year in ASCO that very clearly showed that of the 15 patients who failed T790M-targeted treatment, 6 or 7 developed the C797S mutation. So, we can now target this mutation and try to find new drugs that can work on that. In that way, the patient doesn’t have to go for palliative chemotherapy yet. These areas are areas under investigation, and they are very interesting for us. That’s why we should be doing serial biopsies, and if serial biopsy of the tissue is too complicated for the patient, the serial liquid biopsy can be a good alternative.

Transcript Edited for Clarity
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