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Managing CNS Metastases in EGFR-Positive NSCLC

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: Tuesday, Nov 07, 2017



Transcript: 

Suresh S. Ramalingam, MD: Let’s talk specifically about CNS metastases in patients with EGFR mutations. Giorgio, you touched upon brain metastases and how that might influence your treatment in the frontline setting. Are there any specific comments you want to share with our audience about the prevalence of the problem, how specifically one should look for it, and what they should do when they find it?

Giorgio Scagliotti, MD, PhD: When we started treating patients with the EGFR-sensitizing mutations, obviously for many of us, it was really a turning point because we saw, for the first time in the field of thoracic oncology, something melting away in a few weeks. That was not usual. It was usual only for small-cell lung cancer in the ’80s, but are still struggling with how to cure small-cell lung cancer.

We became progressively familiar that one of the most common sites of relapse was CNS metastases. And as I said before, 20% of our patients who are EGFR mutated are showing up clinically with brain metastases, but the most important point is that a considerable number of patients are relapsing in the brain. Subsequently, we found that the CNS penetration—as I said before of gefitinib and also erlotinib, but erlotinib is probably a little bit better—is not optimal in the CNS fluid. And that is probably reasonable.

But again, I’m also considering that in every disease, when you are pretty active with your frontline treatment, the problem of brain metastases is always coming up. That is not only true for lung cancer, it’s also true for other diseases. So, if you are changing the natural history of the disease, brain metastases are an issue. It’s a matter of fact that, based on the PK (pharmacokinetics) data that we have, we have evidence that osimertinib is a much better drug. That is true not only for osimertinib. It’s also true for the second-generation ALK inhibitor, and we will talk later on about that.

As I said before, I truly believe that if there is a space to consider osimertinib as a priority, it is for those patients with brain metastases. And again, following along the line that Benjamin said before, if we stay with the first- or second-generation EGFR TKI, we need to follow the patients and to check regularly for brain metastases and consequently switch to second-line osimertinib.

Suresh S. Ramalingam, MD: One of the challenges, of course, is when we look at all the randomized trials where patients with EGFR mutations got a TKI. There’s about a 20% to 30% subset in those trials that did not get any subsequent therapy, because their condition declines and they unfortunately die from the disease. So, for a lot of our patients we have to decide what’s the most active agent that we can give if they only have 1 shot, 1 opportunity, to get a TKI. My own feeling is that with osimertinib showing a medium PFS of 19 months, it’s hard not to use that option up front for the patient and derive maximum benefits. Obviously, we see that there are differences in how people are looking at the data, and there will be a lot of conversation about further subsets, CNS activity, and the system mechanisms, but the FLAURA study clearly brings a new dynamic into the EGFR landscape for all of us to consider.

Transcript Edited for Clarity 

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Transcript: 

Suresh S. Ramalingam, MD: Let’s talk specifically about CNS metastases in patients with EGFR mutations. Giorgio, you touched upon brain metastases and how that might influence your treatment in the frontline setting. Are there any specific comments you want to share with our audience about the prevalence of the problem, how specifically one should look for it, and what they should do when they find it?

Giorgio Scagliotti, MD, PhD: When we started treating patients with the EGFR-sensitizing mutations, obviously for many of us, it was really a turning point because we saw, for the first time in the field of thoracic oncology, something melting away in a few weeks. That was not usual. It was usual only for small-cell lung cancer in the ’80s, but are still struggling with how to cure small-cell lung cancer.

We became progressively familiar that one of the most common sites of relapse was CNS metastases. And as I said before, 20% of our patients who are EGFR mutated are showing up clinically with brain metastases, but the most important point is that a considerable number of patients are relapsing in the brain. Subsequently, we found that the CNS penetration—as I said before of gefitinib and also erlotinib, but erlotinib is probably a little bit better—is not optimal in the CNS fluid. And that is probably reasonable.

But again, I’m also considering that in every disease, when you are pretty active with your frontline treatment, the problem of brain metastases is always coming up. That is not only true for lung cancer, it’s also true for other diseases. So, if you are changing the natural history of the disease, brain metastases are an issue. It’s a matter of fact that, based on the PK (pharmacokinetics) data that we have, we have evidence that osimertinib is a much better drug. That is true not only for osimertinib. It’s also true for the second-generation ALK inhibitor, and we will talk later on about that.

As I said before, I truly believe that if there is a space to consider osimertinib as a priority, it is for those patients with brain metastases. And again, following along the line that Benjamin said before, if we stay with the first- or second-generation EGFR TKI, we need to follow the patients and to check regularly for brain metastases and consequently switch to second-line osimertinib.

Suresh S. Ramalingam, MD: One of the challenges, of course, is when we look at all the randomized trials where patients with EGFR mutations got a TKI. There’s about a 20% to 30% subset in those trials that did not get any subsequent therapy, because their condition declines and they unfortunately die from the disease. So, for a lot of our patients we have to decide what’s the most active agent that we can give if they only have 1 shot, 1 opportunity, to get a TKI. My own feeling is that with osimertinib showing a medium PFS of 19 months, it’s hard not to use that option up front for the patient and derive maximum benefits. Obviously, we see that there are differences in how people are looking at the data, and there will be a lot of conversation about further subsets, CNS activity, and the system mechanisms, but the FLAURA study clearly brings a new dynamic into the EGFR landscape for all of us to consider.

Transcript Edited for Clarity 
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