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Alectinib for Relapsed/Refractory ALK+ NSCLC

Insights From: Tony Mok, MD, Chinese University of Hong Kong; David Spigel, MD, Sarah Cannon Research Institute; Alice Shaw, MD, PhD, Harvard Medical School
Published: Thursday, Mar 30, 2017


Transcript:

Alice Shaw, MD, PhD:
Alectinib is another second-generation inhibitor in the same general class as ceritinib and brigatinib. Alectinib was first developed in Japan by Chugai and was first tested in Japanese patients. This group of Japanese patients had ALK-rearranged lung cancer and had not received prior crizotinib, so they were a TKI-naïve group. And they reported in their first study of alectinib that it was highly efficacious in this population. So, that was already a sign that this is a very active drug. The response rate was over 93%, and the median progression-free survival was exceeding 29 months in a TKI-naïve population. Based on that work and some other work, there were phase I and phase II studies launched outside of Japan, and actually, 2 phase II studies eventually led to accelerated approval of alectinib for crizotinib-resistant patients. One of the phase II studies was a global study for alectinib in patients with crizotinib resistance. The second phase II study was a North American study that enrolled just crizotinib-resistant patients. And the 2 studies were remarkably similar in terms of the results, so what they found is that alectinib is highly active in crizotinib-resistant patients. The response rate in both studies was around 50%, and the median progression-free survival in both studies was between 8 and 9 months.

Now it’s very difficult to do cross-trial comparisons, but extrapolating from the ceritinib data, the ceritinib studies, and now the alectinib studies, some might suggest that alectinib may be a little more active. However, I think we would need a head-to-head comparison to really be able to compare these second-generation inhibitors. All we can really tell from these separate trials is that these second-generation inhibitors are very active.

I would say that for alectinib, in particular, the CNS activity has been very notable. ALK-positive patients, unfortunately, have a propensity to develop central nervous system metastases, including parenchymal brain metastases, leptomeningeal disease, and intramedullary spinal cord metastases. They’re very susceptible to the spread of disease to the CNS, so this is a huge problem in this particular population of lung cancer patients. And, fortunately, alectinib is very active in the CNS. It penetrates the blood–brain barrier to very high levels, achieving concentrations near even what’s achieved in the plasma. And what we saw in the phase II studies of alectinib is that alectinib was able to induce responses in the CNS in over half of the patients. So, their intracranial response rates ranged from about 50% to 70% in the phase II studies. Now the efficacy from those 2 phase II studies led to FDA approval, and also approval outside the United States as well.

Alectinib is a very well-tolerated drug, again comparing to other ALK inhibitors. I think some would even argue that alectinib may be the easiest of all the ALK inhibitors in terms of side effects. However, there are some common side effects. I would say the most common ones are fatigue, constipation, muscle aches, and edema. I think the one that is most notable with alectinib is myalgias, or muscle aches. It’s somewhat unique with alectinib compared to other ALK inhibitors. Patients often will describe feeling like they ran a marathon and all of their muscles are very sore. We know that this can be due to irritation of the muscles, and so we do track a particular lab test called CPK, or creatinine phosphokinase. We track that every 2 weeks for the first few months of therapy. And, often times, that marker will track with a patient’s muscle symptoms. Now the interesting thing about the myalgias from alectinib is that it generally is a short-lived phenomenon. It tends to peak in the first 1 to 2 months and then, assuming patients are tolerating it well, often times the muscle symptoms will resolve on their own. And then, as patients continue on treatment, they generally do not report that those muscle symptoms recur.

The other side effect to stay on top of with alectinib is constipation. Often, I do have to remind my patients about drinking plenty of fluids and being on a regular bowel regimen, so that the constipation doesn’t become a bigger problem. And then, the last side effect, again to make sure that you’re on top of with alectinib-treated patients, is edema. It’s typically not as significant as with crizotinib, but it can occur in patients. It can be cumulative, meaning that it worsens over time, and sometimes it will require diuretic therapy.

David Spigel, MD: One of the bigger problems in clinical care in patients with ALK-rearranged lung cancer is progression in the brain, or CNS. Crizotinib has been a very effective therapy at controlling systemic disease, is a drug that does get into the brain, and can delay or prevent CNS progression. But ultimately, that is the source of most patient’s progression—it’s going to be in the brain. Can we find a strategy to either delay that or deal with it when it occurs? We already have traditional things like radiation therapy in the form of whole brain radiation or stereotactic radiosurgery, and we even use surgery in some cases with patients with isolated metastases. But ultimately, the promise of second- or next-generation TKIs, such as ceritinib and alectinib, is to get better control of cancer in the brain, and that’s really where these drugs have shown great utility so far, that you can have a patient do very well on crizotinib. You can have progression in the brain. And then, you can employ ceritinib, alectinib and get control of those lesions in the brain, and maintain control or regain control systemically as well. It has been a great addition for patients.

Tony Mok, MD: The second-generation TKI is distinguished from the first-generation by its ability to penetrate the CNS system. There have been studies of this second-generation TKI in patients with brain metastases, namely there’s an exon 2 and exon 3, and there is actually a subgroup of patients with no brain metastases. However, only a portion of them had measurable disease, so their response rate is estimated in anywhere between about 35% to about 50%. So, there is a reasonable chance a patient having a brain metastases from the ALK-positive tumor may have a response to ceritinib.

Now on the other hand, alectinib has also been known to have a CNS penetration effect, namely using a single-arm study reported by Dr. Ou. There is approximately a 50% chance of the tumor being responsive to alectinib. So, in other words, overall, we’re looking at similar types of CNS response rate with ceritinib or alectinib in patients with brain metastases.

Transcript Edited for Clarity
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Transcript:

Alice Shaw, MD, PhD:
Alectinib is another second-generation inhibitor in the same general class as ceritinib and brigatinib. Alectinib was first developed in Japan by Chugai and was first tested in Japanese patients. This group of Japanese patients had ALK-rearranged lung cancer and had not received prior crizotinib, so they were a TKI-naïve group. And they reported in their first study of alectinib that it was highly efficacious in this population. So, that was already a sign that this is a very active drug. The response rate was over 93%, and the median progression-free survival was exceeding 29 months in a TKI-naïve population. Based on that work and some other work, there were phase I and phase II studies launched outside of Japan, and actually, 2 phase II studies eventually led to accelerated approval of alectinib for crizotinib-resistant patients. One of the phase II studies was a global study for alectinib in patients with crizotinib resistance. The second phase II study was a North American study that enrolled just crizotinib-resistant patients. And the 2 studies were remarkably similar in terms of the results, so what they found is that alectinib is highly active in crizotinib-resistant patients. The response rate in both studies was around 50%, and the median progression-free survival in both studies was between 8 and 9 months.

Now it’s very difficult to do cross-trial comparisons, but extrapolating from the ceritinib data, the ceritinib studies, and now the alectinib studies, some might suggest that alectinib may be a little more active. However, I think we would need a head-to-head comparison to really be able to compare these second-generation inhibitors. All we can really tell from these separate trials is that these second-generation inhibitors are very active.

I would say that for alectinib, in particular, the CNS activity has been very notable. ALK-positive patients, unfortunately, have a propensity to develop central nervous system metastases, including parenchymal brain metastases, leptomeningeal disease, and intramedullary spinal cord metastases. They’re very susceptible to the spread of disease to the CNS, so this is a huge problem in this particular population of lung cancer patients. And, fortunately, alectinib is very active in the CNS. It penetrates the blood–brain barrier to very high levels, achieving concentrations near even what’s achieved in the plasma. And what we saw in the phase II studies of alectinib is that alectinib was able to induce responses in the CNS in over half of the patients. So, their intracranial response rates ranged from about 50% to 70% in the phase II studies. Now the efficacy from those 2 phase II studies led to FDA approval, and also approval outside the United States as well.

Alectinib is a very well-tolerated drug, again comparing to other ALK inhibitors. I think some would even argue that alectinib may be the easiest of all the ALK inhibitors in terms of side effects. However, there are some common side effects. I would say the most common ones are fatigue, constipation, muscle aches, and edema. I think the one that is most notable with alectinib is myalgias, or muscle aches. It’s somewhat unique with alectinib compared to other ALK inhibitors. Patients often will describe feeling like they ran a marathon and all of their muscles are very sore. We know that this can be due to irritation of the muscles, and so we do track a particular lab test called CPK, or creatinine phosphokinase. We track that every 2 weeks for the first few months of therapy. And, often times, that marker will track with a patient’s muscle symptoms. Now the interesting thing about the myalgias from alectinib is that it generally is a short-lived phenomenon. It tends to peak in the first 1 to 2 months and then, assuming patients are tolerating it well, often times the muscle symptoms will resolve on their own. And then, as patients continue on treatment, they generally do not report that those muscle symptoms recur.

The other side effect to stay on top of with alectinib is constipation. Often, I do have to remind my patients about drinking plenty of fluids and being on a regular bowel regimen, so that the constipation doesn’t become a bigger problem. And then, the last side effect, again to make sure that you’re on top of with alectinib-treated patients, is edema. It’s typically not as significant as with crizotinib, but it can occur in patients. It can be cumulative, meaning that it worsens over time, and sometimes it will require diuretic therapy.

David Spigel, MD: One of the bigger problems in clinical care in patients with ALK-rearranged lung cancer is progression in the brain, or CNS. Crizotinib has been a very effective therapy at controlling systemic disease, is a drug that does get into the brain, and can delay or prevent CNS progression. But ultimately, that is the source of most patient’s progression—it’s going to be in the brain. Can we find a strategy to either delay that or deal with it when it occurs? We already have traditional things like radiation therapy in the form of whole brain radiation or stereotactic radiosurgery, and we even use surgery in some cases with patients with isolated metastases. But ultimately, the promise of second- or next-generation TKIs, such as ceritinib and alectinib, is to get better control of cancer in the brain, and that’s really where these drugs have shown great utility so far, that you can have a patient do very well on crizotinib. You can have progression in the brain. And then, you can employ ceritinib, alectinib and get control of those lesions in the brain, and maintain control or regain control systemically as well. It has been a great addition for patients.

Tony Mok, MD: The second-generation TKI is distinguished from the first-generation by its ability to penetrate the CNS system. There have been studies of this second-generation TKI in patients with brain metastases, namely there’s an exon 2 and exon 3, and there is actually a subgroup of patients with no brain metastases. However, only a portion of them had measurable disease, so their response rate is estimated in anywhere between about 35% to about 50%. So, there is a reasonable chance a patient having a brain metastases from the ALK-positive tumor may have a response to ceritinib.

Now on the other hand, alectinib has also been known to have a CNS penetration effect, namely using a single-arm study reported by Dr. Ou. There is approximately a 50% chance of the tumor being responsive to alectinib. So, in other words, overall, we’re looking at similar types of CNS response rate with ceritinib or alectinib in patients with brain metastases.

Transcript Edited for Clarity
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