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Next-Generation ALK Inhibitors for NSCLC

Insights From:Alice T. Shaw, MD, PhD, Massachusetts General Hospital; Gregory J. Riely, MD, Memorial Sloan Kettering; Mark A. Socinski, MD, UPMC
Published: Monday, Feb 29, 2016


Transcript:

Gregory J. Riely, MD:
When patients receive initial treatment with crizotinib, one of the clear mechanisms of resistance to crizotinib are mutations in the ALK gene. These mutations can be targeted with these second- and third-generation ALK inhibitors. We talk about ceritinib as the FDA-approved ALK inhibitor. We’ve seen a lot of data on alectinib, as well as brigatinib. Alectinib is another ALK inhibitor. The side-effect profile is somewhat different from ceritinib, and the mutation inhibition profile is somewhat different as well. The data we have, thus far, looks at patients who’ve had prior crizotinib, and looks at the effectiveness of alectinib in that patient population.

It looks to be an effective drug in that patient population with response rates in progression-free survival are like we hope to see for patients with oncogene-driven cancers. Response rates are above 50%, and median progression-free survival is approaching a year. So I think alectinib is going to be a great option for our patients with non–small cell lung cancer who have ALK gene rearrangements. The side effect profile is a bit of a different story from ceritinib, and it may be a bit easier to tolerate, but we’re going to have to see how this is in clinical practice.

When we think about these next generation ALK inhibitors, sometimes the question is how can we move these into first-line therapy? Just as we consider second- and third-line chemotherapies and moving them into first-line, we also think about this for targeted therapies. The ALEX trial is a trial that takes patients with ALK-positive lung cancer, and for their first-line ALK inhibitor, randomizes them to either crizotinib or alectinib. This trial is designed to see what the most effective first-line ALK inhibitor is.

I think an important component of this is looking at those patients who receive initial crizotinib and then go on to alectinib. Which is better, is it to get crizotinib first, followed by alectinib, or to get alectinib as your first-line therapy? I think there’s going to be a lot of subset analyses from this trial. And it’s going to be really important to dictate how we treat patients with ALK-positive lung cancer going forward.

Alice T. Shaw, MD, PhD: In addition to ceritinib, there are actually a number of other next-generation ALK inhibitors that are all being studied in the setting of crizotinib resistance. There are at least eight next-generation ALK inhibitors out there including ceritinib. We’ve heard some data recently on one of them called brigatinib—its previous name was AP26113. It’s an ALK inhibitor made by Ariad. Like, ceritinib, it’s very potent in inhibiting ALK, more potent than crizotinib. It also has some activity against ROS1 and a few other targets as well. So brigatinib has been studied in a phase I/II study, and the data have been reported, most recently at the World Lung Cancer conference, by Dr. Gettinger. And this ALK inhibitor, like ceritinib, is showing very promising activity in patients who have failed crizotinib.

In fact, the activity of brigatinib is even potentially higher, although these are all single-arm trials, so it’s a little difficult to compare. But what we’ve seen in this phase I study of brigatinib is that the response rate among crizotinib-resistant patients is very high, higher than 70%. And the median progression-free survival in this single-arm study of brigatinib was exceeding 12 months, so quite a long and impressive response that we see with the next-generation ALK inhibitor, brigatinib, after crizotinib failure.

However, brigatinib is interesting in that it has a toxicity that none of the other ALK inhibitors has shown, which is an early-onset pulmonary toxicity. And this is really distinct from interstitial lung disease, which we’re all very familiar with. TKIs, as a class, can cause interstitial lung disease. This is different because this can occur, and typically does occur, after a single dose of the brigatinib compound. A typical example would be a patient is dosed in the clinic and then later that evening, it’s probably about eight or 10 hours later, they become short of breath; they may be coughing more. And that can actually progress to severe respiratory symptoms and even respiratory failure. Fortunately, it’s only been seen in a small percentage of patients, less than 10%, but it has been consistently reported now from a number of different sites. I believe it is a real toxicity of this drug that is unique. And so, I think this drug does require extra close monitoring of patients when they first start on it.

There are other next-generation ALK inhibitors in addition to ceritinib, alectinib, and brigatinib. We heard at World Lung and ASCO this year about the newest of the next-generation ALK inhibitors. This is a new ALK inhibitor developed by Pfizer. Pfizer makes crizotinib and now they have their own next-generation ALK inhibitor, which now has a name, lorlatinib, previously called PF-6463922. Again, a phase I study has been done focusing on patients with ALK or ROS1-rearranged lung cancer. And the data from the phase I are very promising. Many of these patients, who enrolled on the phase I, had failed not only crizotinib but, in some cases, multiple ALK inhibitors. And we actually saw that the response rate to this new lorlatinib compound in this heavily pretreated population was about 50%. So these patients are potentially responding to even a third- or fourth-line ALK inhibitor.

Overall, the toxicity of lorlatinib was fairly good, meaning fairly mild side effects. I would say this drug also has some unique side effects that have not been seen with other ALK inhibitors. One of the most common ones that we see in almost every patient treated with lorlatinib is an increase in cholesterol and triglycerides, and we’re not sure what the mechanism is. But most patients will end up going on to a statin therapy for this. And then the other somewhat unique side effect we’ve seen with lorlatinib is some mild neurocognitive side effects, including slowing of the speech, feeling like the memory is not as good or as sharp as before or the recall not as quick. And so this is something that’s important to note with this drug in particular. This drug has been developed and optimized to penetrate into the central nervous system to help address the problem of CNS relapses, and that’s probably why we’re seeing some of these mild neurocognitive side effects emerge.
                                                                                                                                                                                                                                                                                                                
Transcript Edited for Clarity
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Transcript:

Gregory J. Riely, MD:
When patients receive initial treatment with crizotinib, one of the clear mechanisms of resistance to crizotinib are mutations in the ALK gene. These mutations can be targeted with these second- and third-generation ALK inhibitors. We talk about ceritinib as the FDA-approved ALK inhibitor. We’ve seen a lot of data on alectinib, as well as brigatinib. Alectinib is another ALK inhibitor. The side-effect profile is somewhat different from ceritinib, and the mutation inhibition profile is somewhat different as well. The data we have, thus far, looks at patients who’ve had prior crizotinib, and looks at the effectiveness of alectinib in that patient population.

It looks to be an effective drug in that patient population with response rates in progression-free survival are like we hope to see for patients with oncogene-driven cancers. Response rates are above 50%, and median progression-free survival is approaching a year. So I think alectinib is going to be a great option for our patients with non–small cell lung cancer who have ALK gene rearrangements. The side effect profile is a bit of a different story from ceritinib, and it may be a bit easier to tolerate, but we’re going to have to see how this is in clinical practice.

When we think about these next generation ALK inhibitors, sometimes the question is how can we move these into first-line therapy? Just as we consider second- and third-line chemotherapies and moving them into first-line, we also think about this for targeted therapies. The ALEX trial is a trial that takes patients with ALK-positive lung cancer, and for their first-line ALK inhibitor, randomizes them to either crizotinib or alectinib. This trial is designed to see what the most effective first-line ALK inhibitor is.

I think an important component of this is looking at those patients who receive initial crizotinib and then go on to alectinib. Which is better, is it to get crizotinib first, followed by alectinib, or to get alectinib as your first-line therapy? I think there’s going to be a lot of subset analyses from this trial. And it’s going to be really important to dictate how we treat patients with ALK-positive lung cancer going forward.

Alice T. Shaw, MD, PhD: In addition to ceritinib, there are actually a number of other next-generation ALK inhibitors that are all being studied in the setting of crizotinib resistance. There are at least eight next-generation ALK inhibitors out there including ceritinib. We’ve heard some data recently on one of them called brigatinib—its previous name was AP26113. It’s an ALK inhibitor made by Ariad. Like, ceritinib, it’s very potent in inhibiting ALK, more potent than crizotinib. It also has some activity against ROS1 and a few other targets as well. So brigatinib has been studied in a phase I/II study, and the data have been reported, most recently at the World Lung Cancer conference, by Dr. Gettinger. And this ALK inhibitor, like ceritinib, is showing very promising activity in patients who have failed crizotinib.

In fact, the activity of brigatinib is even potentially higher, although these are all single-arm trials, so it’s a little difficult to compare. But what we’ve seen in this phase I study of brigatinib is that the response rate among crizotinib-resistant patients is very high, higher than 70%. And the median progression-free survival in this single-arm study of brigatinib was exceeding 12 months, so quite a long and impressive response that we see with the next-generation ALK inhibitor, brigatinib, after crizotinib failure.

However, brigatinib is interesting in that it has a toxicity that none of the other ALK inhibitors has shown, which is an early-onset pulmonary toxicity. And this is really distinct from interstitial lung disease, which we’re all very familiar with. TKIs, as a class, can cause interstitial lung disease. This is different because this can occur, and typically does occur, after a single dose of the brigatinib compound. A typical example would be a patient is dosed in the clinic and then later that evening, it’s probably about eight or 10 hours later, they become short of breath; they may be coughing more. And that can actually progress to severe respiratory symptoms and even respiratory failure. Fortunately, it’s only been seen in a small percentage of patients, less than 10%, but it has been consistently reported now from a number of different sites. I believe it is a real toxicity of this drug that is unique. And so, I think this drug does require extra close monitoring of patients when they first start on it.

There are other next-generation ALK inhibitors in addition to ceritinib, alectinib, and brigatinib. We heard at World Lung and ASCO this year about the newest of the next-generation ALK inhibitors. This is a new ALK inhibitor developed by Pfizer. Pfizer makes crizotinib and now they have their own next-generation ALK inhibitor, which now has a name, lorlatinib, previously called PF-6463922. Again, a phase I study has been done focusing on patients with ALK or ROS1-rearranged lung cancer. And the data from the phase I are very promising. Many of these patients, who enrolled on the phase I, had failed not only crizotinib but, in some cases, multiple ALK inhibitors. And we actually saw that the response rate to this new lorlatinib compound in this heavily pretreated population was about 50%. So these patients are potentially responding to even a third- or fourth-line ALK inhibitor.

Overall, the toxicity of lorlatinib was fairly good, meaning fairly mild side effects. I would say this drug also has some unique side effects that have not been seen with other ALK inhibitors. One of the most common ones that we see in almost every patient treated with lorlatinib is an increase in cholesterol and triglycerides, and we’re not sure what the mechanism is. But most patients will end up going on to a statin therapy for this. And then the other somewhat unique side effect we’ve seen with lorlatinib is some mild neurocognitive side effects, including slowing of the speech, feeling like the memory is not as good or as sharp as before or the recall not as quick. And so this is something that’s important to note with this drug in particular. This drug has been developed and optimized to penetrate into the central nervous system to help address the problem of CNS relapses, and that’s probably why we’re seeing some of these mild neurocognitive side effects emerge.
                                                                                                                                                                                                                                                                                                                
Transcript Edited for Clarity
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