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ALTA-1L Trial: Do Results Affect ALK TKI Sequencing?

Insights From: Lyudmila A. Bazhenova, MD, UC San Diego Health; Ross Camidge, MD, PhD, University of Colorado Cancer Center
Published: Thursday, Feb 20, 2020



Transcript: 

Lyudmila A. Bazhenova, MD:
The challenge with deciding how to sequence ALK trials in kinase inhibitors is lack of data telling us how to sequence ALK trials in kinase inhibitors. I think we have established a sequencing paradigm for patients who develop resistance to crizotinib. A long time ago, when we were using crizotinib in the first line, upon progression you had pretty much 3 options. You had crizotinib, alectinib, and brigatinib. My personal choice at that time was brigatinib, because brigatinib showed the longest reported progression-free survival [PFS] in the ALTA-1L trial, which was more than 16 months.

Now that we’ve moved our second-generation ALK inhibitors to the first line based on the result of the ALEX trial, which compared alectinib to crizotinib, as well as the ALTA-1L trial, which compared brigatinib to crizotinib, we are pretty much in a data-free zone. The information we have about lorlatinib, which showed efficacy in the patients who develop resistance to second-generation ALK inhibitors, brigatinib patients were not very frequent in that dataset, so we really do not have a large number of patients who develop resistance to brigatinib and then responded to lorlatinib. We have a very small dataset using brigatinib after alectinib, showing responses anywhere between 30% and 40%. We have small datasets using alectinib after ceritinib and ceritinib after alectinib, again showing response rates in about 20%. We will have an answer to that question. There is a clinical trial that I would like to highlight, which is NRG-LU003, where patients who develop resistance to an ALK TKI [tyrosine kinase inhibitor] get post-progression biopsy, and they get assigned to different treatment baskets depending on the results of that post-progression biopsy. Each basket has more than 1 ALK inhibitor. So once the NRG-LU003 trial is completed, we actually will have scientific evidence of what is the right way of sequencing ALK tyrosine kinase inhibitors.

NRG-LU003 opened less than 12 months ago. It is accruing, but I do not expect the data to be available for a couple of more years. I strongly encourage you to look up that clinical trial on clinicaltrials.gov. There are over 400 sites in the United States, and I believe the trial is also enrolling outside of the United States, and if you have a patient who developed resistance to an ALK TKI, I highly, highly encourage you to refer your patient to a nearest clinical site so we can answer the question of what’s the correct sequencing of ALK tyrosine kinase inhibitors.

Ross Camidge, MD, PhD: If you look at the first-line trials that we’ve got—ALTA-L1 and ALEX—things are looking very similar in terms of the efficacy of these next-generation inhibitors. They’re both really good. One has got 8 pills a day; one’s got 1 pill a day. One has got not much in the way of adverse effects; one has got probably even less in the way of adverse effects. So you could just say, “Look, I’m going to look at what’s best for my patient. I want long-term control with minimal intervention of life. Going to give them 1 pill once a day. Best adverse effect profile I can find.” But we don’t live in isolation.

You’re going to start to think about where do you go next. And 1 thing you can do is you can just play the numbers game. There are data that brigatinib can work post alectinib. There are data that lorlatinib can work post alectinib; it can also work post brigatinib. So you might start to think, “Well, if I start alectinib, I can do lorlatinib, that’s FDA approved. Maybe I can even do brigatinib, it’s not FDA approved, but we’re seeing 50% response rates. PFS is about the same with lorlatinib, keep lorlatinib for later.” But I think what we’re going to see in the future is we’re going to actually be rebiopsying people after these next-generation inhibitors in deciding do we just play the numbers game and go onto another ALK inhibitor? Or do we start to personalize it in the second line? And that’s what I think will come in the next few years.

I think if I went on brigatinib and ALTA-1L in the frontline setting, and I was just starting to do that in a few of my patients now, of course you’re always trying to think, what’s the Plan B? What am I ready to put my patient onto next? Well, in the absence of other information, I put them on lorlatinib because that is the drug that technically has a license for post next-generation inhibitor.

It doesn’t technically have a license if you started on brigatinib, but no insurance so far seems to care. But what I would really do is if they progress on brigatinib, I’d be rebiopsying. I’d be looking for 1 of these ALK mutations, but also I’d be starting to ask, what is my panel looking for in terms of second drivers. Does it assess MET copy number?

I actually do MET FISH [fluorescence in situ hybridization testing] in addition to next-generation sequencing. Is it looking for MET exon 14 skipping mutations? Is it looking for other drivers that we can look at? That is still a work in progress.


Transcript Edited for Clarity
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Transcript: 

Lyudmila A. Bazhenova, MD:
The challenge with deciding how to sequence ALK trials in kinase inhibitors is lack of data telling us how to sequence ALK trials in kinase inhibitors. I think we have established a sequencing paradigm for patients who develop resistance to crizotinib. A long time ago, when we were using crizotinib in the first line, upon progression you had pretty much 3 options. You had crizotinib, alectinib, and brigatinib. My personal choice at that time was brigatinib, because brigatinib showed the longest reported progression-free survival [PFS] in the ALTA-1L trial, which was more than 16 months.

Now that we’ve moved our second-generation ALK inhibitors to the first line based on the result of the ALEX trial, which compared alectinib to crizotinib, as well as the ALTA-1L trial, which compared brigatinib to crizotinib, we are pretty much in a data-free zone. The information we have about lorlatinib, which showed efficacy in the patients who develop resistance to second-generation ALK inhibitors, brigatinib patients were not very frequent in that dataset, so we really do not have a large number of patients who develop resistance to brigatinib and then responded to lorlatinib. We have a very small dataset using brigatinib after alectinib, showing responses anywhere between 30% and 40%. We have small datasets using alectinib after ceritinib and ceritinib after alectinib, again showing response rates in about 20%. We will have an answer to that question. There is a clinical trial that I would like to highlight, which is NRG-LU003, where patients who develop resistance to an ALK TKI [tyrosine kinase inhibitor] get post-progression biopsy, and they get assigned to different treatment baskets depending on the results of that post-progression biopsy. Each basket has more than 1 ALK inhibitor. So once the NRG-LU003 trial is completed, we actually will have scientific evidence of what is the right way of sequencing ALK tyrosine kinase inhibitors.

NRG-LU003 opened less than 12 months ago. It is accruing, but I do not expect the data to be available for a couple of more years. I strongly encourage you to look up that clinical trial on clinicaltrials.gov. There are over 400 sites in the United States, and I believe the trial is also enrolling outside of the United States, and if you have a patient who developed resistance to an ALK TKI, I highly, highly encourage you to refer your patient to a nearest clinical site so we can answer the question of what’s the correct sequencing of ALK tyrosine kinase inhibitors.

Ross Camidge, MD, PhD: If you look at the first-line trials that we’ve got—ALTA-L1 and ALEX—things are looking very similar in terms of the efficacy of these next-generation inhibitors. They’re both really good. One has got 8 pills a day; one’s got 1 pill a day. One has got not much in the way of adverse effects; one has got probably even less in the way of adverse effects. So you could just say, “Look, I’m going to look at what’s best for my patient. I want long-term control with minimal intervention of life. Going to give them 1 pill once a day. Best adverse effect profile I can find.” But we don’t live in isolation.

You’re going to start to think about where do you go next. And 1 thing you can do is you can just play the numbers game. There are data that brigatinib can work post alectinib. There are data that lorlatinib can work post alectinib; it can also work post brigatinib. So you might start to think, “Well, if I start alectinib, I can do lorlatinib, that’s FDA approved. Maybe I can even do brigatinib, it’s not FDA approved, but we’re seeing 50% response rates. PFS is about the same with lorlatinib, keep lorlatinib for later.” But I think what we’re going to see in the future is we’re going to actually be rebiopsying people after these next-generation inhibitors in deciding do we just play the numbers game and go onto another ALK inhibitor? Or do we start to personalize it in the second line? And that’s what I think will come in the next few years.

I think if I went on brigatinib and ALTA-1L in the frontline setting, and I was just starting to do that in a few of my patients now, of course you’re always trying to think, what’s the Plan B? What am I ready to put my patient onto next? Well, in the absence of other information, I put them on lorlatinib because that is the drug that technically has a license for post next-generation inhibitor.

It doesn’t technically have a license if you started on brigatinib, but no insurance so far seems to care. But what I would really do is if they progress on brigatinib, I’d be rebiopsying. I’d be looking for 1 of these ALK mutations, but also I’d be starting to ask, what is my panel looking for in terms of second drivers. Does it assess MET copy number?

I actually do MET FISH [fluorescence in situ hybridization testing] in addition to next-generation sequencing. Is it looking for MET exon 14 skipping mutations? Is it looking for other drivers that we can look at? That is still a work in progress.


Transcript Edited for Clarity
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