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Considerations for Sequencing in ALK+ NSCLC

Mark A. Socinski, MD
Published: Friday, Jun 16, 2017



Transcript:

Mark A. Socinski, MD:
The approval of ceritinib as a first-line option brings up the question of how to sequence now that we have multiple choices. And to date, there’s not a lot of information about the use of second-generation agents after another second-generation agent. We do know that when you use a second-generation drug, the rate of secondary ALK mutations is higher. We know that there’s a spectrum, at least 15 different secondary mutations described. We know that in some of the secondary mutations, brigatinib may be the preferred agent versus alectinib or some other agent. So, I think all 3 of the currently approved second-generation agents were approved because they were tested against crizotinib failures. What we don’t have are data to date: does alectinib work after ceritinib or vice versa? But we do have some case studies showing that depending upon the pattern of the secondary resistance mutation, there may be a drug, ceritinib for example, that may be the preferred agent because it’s known to be active in that secondary-resistant mutation profile.

I think we have a lot to learn. It’s nice to have choices, to have 3 active drugs, in this setting. It’s nice that all of these drugs have CNS activity. And I think we’re going to need some more trials to sort out how we sequence. What really matters is in the individual patient, how is that patient’s cancer going to behave and what’s the best sequence? There’s not going to be a one-size-fits-all. I think we’re going to have to be informed by repeat biopsies and repeat testing to see what the mechanism of resistance may be and then intervene with the appropriate agent based upon that informed data.

One of the things we like to do in building regimens to increase their efficacy is to start combination agents. An area of intense interest in non–small cell lung cancer, across the board, is immunotherapy. So, in this population of ALK-positive patients, is there a role for combining ALK TKIs with various immunotherapeutic agents? A couple of thoughts about that. One of the things that has been a consistent observation with the immunotherapy paradigm that we have now is that if you look at the activity of immunotherapy versus chemotherapy in never-smokers—which most of these outpatients are—it does not distinguish itself. It doesn’t seem to be active relative to chemotherapy in the never-smoking population.

We have some data with EGFR mutations. Again, those are typically adenocarcinomas and never-smokers or light smokers. Again, immunotherapy does not distinguish itself from chemotherapy in that population. In fact, a couple of studies have suggested a little advantage for the chemotherapy end versus the immunotherapy end. You have to wonder, what’s the role for combining immunotherapy with ALK inhibitors? These are generally never-smokers. The trial data that we have thus far with immunotherapy, there are very few ALK-positive patients in any of the second-line phase III or first-line trials. In fact, in the first-line trials, ALK-positive and EGFR-positive patients were excluded from enrolling on those trials. So, we have no information in the first-line setting.

On a clinical trial, I think it’s worthy of testing. I think we have to be very careful about toxicity patterns in this setting. I also think we have to be aware of the data generated thus far suggesting that immunotherapy may not be an overly efficacious strategy in a never-smoking oncogenically-driven situation. So, although I’m open to studying it on a clinical trial, I’m holding my breath in terms of, will it be a fruitful avenue of investigation for these patients? I’m not sure that that’s going to be the case.

Transcript Edited for Clarity
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Transcript:

Mark A. Socinski, MD:
The approval of ceritinib as a first-line option brings up the question of how to sequence now that we have multiple choices. And to date, there’s not a lot of information about the use of second-generation agents after another second-generation agent. We do know that when you use a second-generation drug, the rate of secondary ALK mutations is higher. We know that there’s a spectrum, at least 15 different secondary mutations described. We know that in some of the secondary mutations, brigatinib may be the preferred agent versus alectinib or some other agent. So, I think all 3 of the currently approved second-generation agents were approved because they were tested against crizotinib failures. What we don’t have are data to date: does alectinib work after ceritinib or vice versa? But we do have some case studies showing that depending upon the pattern of the secondary resistance mutation, there may be a drug, ceritinib for example, that may be the preferred agent because it’s known to be active in that secondary-resistant mutation profile.

I think we have a lot to learn. It’s nice to have choices, to have 3 active drugs, in this setting. It’s nice that all of these drugs have CNS activity. And I think we’re going to need some more trials to sort out how we sequence. What really matters is in the individual patient, how is that patient’s cancer going to behave and what’s the best sequence? There’s not going to be a one-size-fits-all. I think we’re going to have to be informed by repeat biopsies and repeat testing to see what the mechanism of resistance may be and then intervene with the appropriate agent based upon that informed data.

One of the things we like to do in building regimens to increase their efficacy is to start combination agents. An area of intense interest in non–small cell lung cancer, across the board, is immunotherapy. So, in this population of ALK-positive patients, is there a role for combining ALK TKIs with various immunotherapeutic agents? A couple of thoughts about that. One of the things that has been a consistent observation with the immunotherapy paradigm that we have now is that if you look at the activity of immunotherapy versus chemotherapy in never-smokers—which most of these outpatients are—it does not distinguish itself. It doesn’t seem to be active relative to chemotherapy in the never-smoking population.

We have some data with EGFR mutations. Again, those are typically adenocarcinomas and never-smokers or light smokers. Again, immunotherapy does not distinguish itself from chemotherapy in that population. In fact, a couple of studies have suggested a little advantage for the chemotherapy end versus the immunotherapy end. You have to wonder, what’s the role for combining immunotherapy with ALK inhibitors? These are generally never-smokers. The trial data that we have thus far with immunotherapy, there are very few ALK-positive patients in any of the second-line phase III or first-line trials. In fact, in the first-line trials, ALK-positive and EGFR-positive patients were excluded from enrolling on those trials. So, we have no information in the first-line setting.

On a clinical trial, I think it’s worthy of testing. I think we have to be very careful about toxicity patterns in this setting. I also think we have to be aware of the data generated thus far suggesting that immunotherapy may not be an overly efficacious strategy in a never-smoking oncogenically-driven situation. So, although I’m open to studying it on a clinical trial, I’m holding my breath in terms of, will it be a fruitful avenue of investigation for these patients? I’m not sure that that’s going to be the case.

Transcript Edited for Clarity
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TitleExpiration DateCME Credits
Community Practice Connections™: Oncology Best Practice™ Decision Points in Advanced NSCLC: Assessing Treatment Options Beyond Disease ProgressionNov 30, 20181.0
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