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ALTA-1L Regimen: Patient Selection Versus Other ALK TKIs

Insights From: Lyudmila A. Bazhenova, MD, UC San Diego Health; Ross Camidge, MD, PhD, University of Colorado Cancer Center
Published: Wednesday, Feb 12, 2020



Transcript: 

Ross Camidge, MD, PhD:
Obviously 1 of the elephants in the room is that crizotinib is not the first-line choice any more. What brigatinib has done is it’s provided data that say, in the first-line setting, it is astonishingly similar to alectinib’s efficacy. So there’s a little bit of a game in terms of how you compare like with like.

One tended to have blinded, independent radiology review end points, one tended to have investigator assessed end points. Investigators are always more optimistic. But if you do try comparing like with like—so let’s look at the investigator assessed end points, the 2-year non-progression rate for alectinib in ALEX was 56%. In ALTA-1L it was 56%. If you look at the investigator assessed hazard ratio comparing between those 2 curves, it was 0.43 for ALTA-1L. It was 0.43 for ALEX. If you look at the point estimate for the median, if you look for the independent radiology review assessment, it was something like 25 months for alectinib; it was 24 months with brigatinib. If you look at the investigator assessed, it was about 29-1/2 months with brigatinib. It was longer, about 5 months longer, with alectinib, or something like 34 months. But the confidence intervals are very wide, and there’s a plateau in the curve and they overlap.

So they look very similar. If you view these data purely in isolation, how do you make a choice? Well, you’ve got 8 pills a day for alectinib. You’ve gone 1 pill a day for brigatinib. You’ve got quality of life. These are people who are going to be on a treatment for months, if not years, and even small differences in quality of life are going to matter.

There were health-related quality of life assessments done in ALEX, and yes, they could show that a few domains were slightly better with alectinib than with crizotinib, particularly with regular kinds of constipation and diarrhea. But there was no real statistically significant difference. It’s only in that ALTA-1L study that they could actually show a significant difference between the quality of life. Some of that is because the drug is better at controlling the disease for longer, but some of it is it’s actually a better tolerated drug.

All other things being equal, now we have an alternative to alectinib in the first-line setting, with a lower pill burden and better tolerability. So there’s the possibility that now you have a choice.

Lyudmila A. Bazhenova, MD: According to the NCCN [National Comprehensive Cancer Network] guidelines, and according to all clinical trials we have to date, there are 4 tyrosine kinase inhibitors [TKIs] that have data in first-line setting: crizotinib, ceritinib, alectinib, and brigatinib. Crizotinib gained its approval in first-line due to a clinical trial that randomized patients to crizotinib versus platinum doublet. Ceritinib had a very similar trial design of ceritinib versus platinum doublet. Both alectinib and brigatinib gained  approval based on randomization to crizotinib. Both of those trials showed improvement in outcomes with second-generation ALK TKIs, specifically alectinib and brigatinib compared to crizotinib on multiple end points: response rate, duration of response, progression-free survival, most importantly CNS [central nervous system] activity, as well as including CNS response rate, durability of CNS responses, as well as intracranial progression-free survival. So to me, the answer is actually quite simple. I no longer believe that crizotinib is an appropriate option for patients with newly diagnosed ALK-fused non–small cell lung cancer. I also do not think that ceritinib is an appropriate option, because we now have 2 studies comparing TKI to TKI, when ceritinib was compared to chemotherapy. Right now, I think the decision lies between alectinib as a first line, as well as brigatinib as a first line.

CNS coverage is important for our patient with ALK-fused non–small cell lung cancer. We know that ALK patients have a high likelihood of having CNS progression or CNS metastases throughout their lifetime. We also know that because our tyrosine kinase inhibitors are so effective, those patients enjoy prolonged survival, and therefore, they also have more chances of developing brain metastasis. So when I select my first-line options, CNS coverage is very important.

I definitely think that because of both systemic as well as CNS penetration, crizotinib would not be an appropriate choice. Both alectinib and brigatinib have a CNS coverage. In that situation, I would use either of those 2 drugs. Some would even not pay attention to the CNS because activity of both of the second-generation ALK inhibitors, in this situation alectinib and brigatinib, have been shown regardless of CNS presence, regardless of presence of CNS metastasis. I no longer believe that crizotinib is the right agent, so when I make my decisions, I usually do not pay attention to CNS metastasis or not because among my choices that I have, alectinib and brigatinib, both have excellent CNS coverage. Both of those drugs have very similar progression-free survival, they have similar toxicity, they have similar discontinuation rate, and overall tolerability of those drugs is comparable.

ALK tyrosine kinase inhibitors are not created equal. Based on the preclinical data, we clearly see different activities against different resistant mutations that can develop in our patients who become resistant to crizotinib. How that affects the efficacy of second-generation ALK tyrosine kinase inhibitors in first line remains to be seen. Certainly the fact that brigatinib covers the G1202R resistant mutation might give one a little bit more confidence that should the resistant mutation develop, brigatinib has the ability to interrupt that signaling.


Transcript Edited for Clarity 
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Transcript: 

Ross Camidge, MD, PhD:
Obviously 1 of the elephants in the room is that crizotinib is not the first-line choice any more. What brigatinib has done is it’s provided data that say, in the first-line setting, it is astonishingly similar to alectinib’s efficacy. So there’s a little bit of a game in terms of how you compare like with like.

One tended to have blinded, independent radiology review end points, one tended to have investigator assessed end points. Investigators are always more optimistic. But if you do try comparing like with like—so let’s look at the investigator assessed end points, the 2-year non-progression rate for alectinib in ALEX was 56%. In ALTA-1L it was 56%. If you look at the investigator assessed hazard ratio comparing between those 2 curves, it was 0.43 for ALTA-1L. It was 0.43 for ALEX. If you look at the point estimate for the median, if you look for the independent radiology review assessment, it was something like 25 months for alectinib; it was 24 months with brigatinib. If you look at the investigator assessed, it was about 29-1/2 months with brigatinib. It was longer, about 5 months longer, with alectinib, or something like 34 months. But the confidence intervals are very wide, and there’s a plateau in the curve and they overlap.

So they look very similar. If you view these data purely in isolation, how do you make a choice? Well, you’ve got 8 pills a day for alectinib. You’ve gone 1 pill a day for brigatinib. You’ve got quality of life. These are people who are going to be on a treatment for months, if not years, and even small differences in quality of life are going to matter.

There were health-related quality of life assessments done in ALEX, and yes, they could show that a few domains were slightly better with alectinib than with crizotinib, particularly with regular kinds of constipation and diarrhea. But there was no real statistically significant difference. It’s only in that ALTA-1L study that they could actually show a significant difference between the quality of life. Some of that is because the drug is better at controlling the disease for longer, but some of it is it’s actually a better tolerated drug.

All other things being equal, now we have an alternative to alectinib in the first-line setting, with a lower pill burden and better tolerability. So there’s the possibility that now you have a choice.

Lyudmila A. Bazhenova, MD: According to the NCCN [National Comprehensive Cancer Network] guidelines, and according to all clinical trials we have to date, there are 4 tyrosine kinase inhibitors [TKIs] that have data in first-line setting: crizotinib, ceritinib, alectinib, and brigatinib. Crizotinib gained its approval in first-line due to a clinical trial that randomized patients to crizotinib versus platinum doublet. Ceritinib had a very similar trial design of ceritinib versus platinum doublet. Both alectinib and brigatinib gained  approval based on randomization to crizotinib. Both of those trials showed improvement in outcomes with second-generation ALK TKIs, specifically alectinib and brigatinib compared to crizotinib on multiple end points: response rate, duration of response, progression-free survival, most importantly CNS [central nervous system] activity, as well as including CNS response rate, durability of CNS responses, as well as intracranial progression-free survival. So to me, the answer is actually quite simple. I no longer believe that crizotinib is an appropriate option for patients with newly diagnosed ALK-fused non–small cell lung cancer. I also do not think that ceritinib is an appropriate option, because we now have 2 studies comparing TKI to TKI, when ceritinib was compared to chemotherapy. Right now, I think the decision lies between alectinib as a first line, as well as brigatinib as a first line.

CNS coverage is important for our patient with ALK-fused non–small cell lung cancer. We know that ALK patients have a high likelihood of having CNS progression or CNS metastases throughout their lifetime. We also know that because our tyrosine kinase inhibitors are so effective, those patients enjoy prolonged survival, and therefore, they also have more chances of developing brain metastasis. So when I select my first-line options, CNS coverage is very important.

I definitely think that because of both systemic as well as CNS penetration, crizotinib would not be an appropriate choice. Both alectinib and brigatinib have a CNS coverage. In that situation, I would use either of those 2 drugs. Some would even not pay attention to the CNS because activity of both of the second-generation ALK inhibitors, in this situation alectinib and brigatinib, have been shown regardless of CNS presence, regardless of presence of CNS metastasis. I no longer believe that crizotinib is the right agent, so when I make my decisions, I usually do not pay attention to CNS metastasis or not because among my choices that I have, alectinib and brigatinib, both have excellent CNS coverage. Both of those drugs have very similar progression-free survival, they have similar toxicity, they have similar discontinuation rate, and overall tolerability of those drugs is comparable.

ALK tyrosine kinase inhibitors are not created equal. Based on the preclinical data, we clearly see different activities against different resistant mutations that can develop in our patients who become resistant to crizotinib. How that affects the efficacy of second-generation ALK tyrosine kinase inhibitors in first line remains to be seen. Certainly the fact that brigatinib covers the G1202R resistant mutation might give one a little bit more confidence that should the resistant mutation develop, brigatinib has the ability to interrupt that signaling.


Transcript Edited for Clarity 
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