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EGFR-Positive NSCLC: Treatment at Progression

Panelists: Suresh S. Ramalingam, MD, Emory University School of Medicine; Benjamin Besse, MD, PhD, Gustave Roussy; Marina Garassino, MD National Cancer Institute; Giorgio Scagliotti, MD, PhD, University of Turin
Published Online: Thursday, Nov 09, 2017



Transcript: 

Suresh S. Ramalingam, MD: I want to ask you, Marina, a question. If patients receive osimertinib as first-line therapy, then what do you do for second-line therapy? That’s the argument, or that’s the clinical issue, that comes up for our physicians and patients.

Marina Garassino, MD: We know that there are several mechanisms of resistance that are already known for osimertinib, and we also have some missense mutations after osimertinib that potentially can be sensitive again to the first- and second-generation TKIs. But this must be proven, because the results are very scanty and we have to work at the academic level again. We also know that there are several other emerging mechanisms of resistance, such as the MET amplification, and we can also use chemotherapy for salvage therapy.

I think that, again, we have to work on the mechanisms of resistance and try to personalize how to follow these kinds of patients, but in a certain way chemotherapy now will represent the continuation of osimertinib.

Suresh S. Ramalingam, MD: Thank you.

Giorgio Scagliotti, MD, PhD: In this sense, it would be critical to show the overall survival data. Because I can reverse your point of view. It is true that the best drugs should be used first. And in this case, if you are using osimertinib first, the alternative choice is only chemotherapy, because with all the c-MET inhibitors there’s more cell transformation. All these other mechanisms of resistance are not druggable at the moment.

In the community practice, but also in the academic center, the only way, in addition to putting patients into clinical trials, is cytotoxic chemotherapy. So, considering that almost every patient will be crossed over to osimertinib in the control arm, it will be critical to show some differences in survival. Because at that time, you have evidence that giving osimertinib first is the best choice.

Otherwise, I’m speaking for Italy, for Europe in this case. I usually understand that in the United States, the story is totally different. But I still believe that there’s an ethical solution to using the first—for me it is first, but for others, it’s first or second—generation EGFR TKI followed by osimertinib, followed by chemotherapy. That is my personal opinion, but I would like to know what the others think.

Suresh S. Ramalingam, MD: Before we wrap up this discussion, we’ll quickly get everybody’s view on what the standard approach for patients with EGFR mutations moving forward is. Giorgio has indicated his preference for still sticking with the current paradigm, first-generation TKIs. Benjamin, I know you’ve mentioned similar thoughts?

Benjamin Besse, MD, PhD: I agree with Giorgio. It’s first followed by third. But I also fully agree with Marina, if you are able to closely follow one and detect this T790M mutation. And then, it’s chemotherapy, because chemotherapy works in these patients. One word, if you use chemotherapy after first- or third-generation TKI, don’t use any TKI with chemotherapy. It’s deleterious. The IMPRESS trial was very clear on that, but it’s always good to repeat that if you give chemotherapy, stop the TKI, otherwise it will be deleterious for the patient. As we said, immunotherapy is probably not the best option. It can be discussed post-chemotherapy, but it’s probably not the best option.

Suresh S. Ramalingam, MD: Marina?

Marina Garassino, MD: My opinion is that in 2017, patients must be more involved than before. I think that now, patients are coming very informed to our centers. So, I think that we can also discuss with the patient if they want everything from the beginning and just chemotherapy at the end. Or, trying to put all the pieces in the sequence. We also have to talk to the patients about how the toxicity of this drug is really low, so they can have really a normal life and to continue to survive, to work, and so on. So, I think that with the discussions with patients and considering, again, the center where you are, you can take a good decision.

Suresh S. Ramalingam, MD: To close up with my own thoughts on this, I would say that the median PFS of 19 months we saw on the FLAURA study and the hazard ratio of 0.46 when compared to erlotinib and gefitinib—to me, in a highly significant manner—is strong enough for me to consider osimertinib. In fact, when we gave the presentation, we made the point that these data support the notion that osimertinib should be a new standard of care in the front-line space.

The survival hazard ratio was 0.63. It did not meet statistical significance by the interim analysis standards, but it was still a P value of 0.00668. We also saw a 2-fold improvement in the duration of response for patients treated with osimertinib. So, I think this is something that, taken on top of the favorable tolerability of osimertinib compared to the other agents, makes a compelling case for using it in the front-line setting for my patients. Obviously, we’ll continue to discuss this topic moving forward. It’s indeed a new phase, or new beginning, as we said, for patients with EGFR mutation-positive lung cancer. More options are good.

Transcript Edited for Clarity 

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Transcript: 

Suresh S. Ramalingam, MD: I want to ask you, Marina, a question. If patients receive osimertinib as first-line therapy, then what do you do for second-line therapy? That’s the argument, or that’s the clinical issue, that comes up for our physicians and patients.

Marina Garassino, MD: We know that there are several mechanisms of resistance that are already known for osimertinib, and we also have some missense mutations after osimertinib that potentially can be sensitive again to the first- and second-generation TKIs. But this must be proven, because the results are very scanty and we have to work at the academic level again. We also know that there are several other emerging mechanisms of resistance, such as the MET amplification, and we can also use chemotherapy for salvage therapy.

I think that, again, we have to work on the mechanisms of resistance and try to personalize how to follow these kinds of patients, but in a certain way chemotherapy now will represent the continuation of osimertinib.

Suresh S. Ramalingam, MD: Thank you.

Giorgio Scagliotti, MD, PhD: In this sense, it would be critical to show the overall survival data. Because I can reverse your point of view. It is true that the best drugs should be used first. And in this case, if you are using osimertinib first, the alternative choice is only chemotherapy, because with all the c-MET inhibitors there’s more cell transformation. All these other mechanisms of resistance are not druggable at the moment.

In the community practice, but also in the academic center, the only way, in addition to putting patients into clinical trials, is cytotoxic chemotherapy. So, considering that almost every patient will be crossed over to osimertinib in the control arm, it will be critical to show some differences in survival. Because at that time, you have evidence that giving osimertinib first is the best choice.

Otherwise, I’m speaking for Italy, for Europe in this case. I usually understand that in the United States, the story is totally different. But I still believe that there’s an ethical solution to using the first—for me it is first, but for others, it’s first or second—generation EGFR TKI followed by osimertinib, followed by chemotherapy. That is my personal opinion, but I would like to know what the others think.

Suresh S. Ramalingam, MD: Before we wrap up this discussion, we’ll quickly get everybody’s view on what the standard approach for patients with EGFR mutations moving forward is. Giorgio has indicated his preference for still sticking with the current paradigm, first-generation TKIs. Benjamin, I know you’ve mentioned similar thoughts?

Benjamin Besse, MD, PhD: I agree with Giorgio. It’s first followed by third. But I also fully agree with Marina, if you are able to closely follow one and detect this T790M mutation. And then, it’s chemotherapy, because chemotherapy works in these patients. One word, if you use chemotherapy after first- or third-generation TKI, don’t use any TKI with chemotherapy. It’s deleterious. The IMPRESS trial was very clear on that, but it’s always good to repeat that if you give chemotherapy, stop the TKI, otherwise it will be deleterious for the patient. As we said, immunotherapy is probably not the best option. It can be discussed post-chemotherapy, but it’s probably not the best option.

Suresh S. Ramalingam, MD: Marina?

Marina Garassino, MD: My opinion is that in 2017, patients must be more involved than before. I think that now, patients are coming very informed to our centers. So, I think that we can also discuss with the patient if they want everything from the beginning and just chemotherapy at the end. Or, trying to put all the pieces in the sequence. We also have to talk to the patients about how the toxicity of this drug is really low, so they can have really a normal life and to continue to survive, to work, and so on. So, I think that with the discussions with patients and considering, again, the center where you are, you can take a good decision.

Suresh S. Ramalingam, MD: To close up with my own thoughts on this, I would say that the median PFS of 19 months we saw on the FLAURA study and the hazard ratio of 0.46 when compared to erlotinib and gefitinib—to me, in a highly significant manner—is strong enough for me to consider osimertinib. In fact, when we gave the presentation, we made the point that these data support the notion that osimertinib should be a new standard of care in the front-line space.

The survival hazard ratio was 0.63. It did not meet statistical significance by the interim analysis standards, but it was still a P value of 0.00668. We also saw a 2-fold improvement in the duration of response for patients treated with osimertinib. So, I think this is something that, taken on top of the favorable tolerability of osimertinib compared to the other agents, makes a compelling case for using it in the front-line setting for my patients. Obviously, we’ll continue to discuss this topic moving forward. It’s indeed a new phase, or new beginning, as we said, for patients with EGFR mutation-positive lung cancer. More options are good.

Transcript Edited for Clarity 
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