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Choosing Second-Line Therapy for 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: Tuesday, Apr 04, 2017


Transcript:

Alice Shaw, MD, PhD:
For ALK-positive patients who relapse on crizotinib, there are a number of options now. In the past, we really only had standard cytotoxic chemotherapy as an option, but now we actually have several different new targeted therapy options after crizotinib fails. And this really is the class of second-generation inhibitors—ceritinib, alectinib—and soon, in the United States, we may have brigatinib as an option as well. And so, now it has actually become even more complicated to think about choosing among these different pill options for patients. I would say, in my own practice right now, the standard options are chemotherapy and ceritinib or alectinib for patients who fail on crizotinib. And, typically, we will go with the targeted therapy. We believe the targeted therapy is superior to chemotherapy. That has been shown in the first-line setting, and recently, we also presented data on ceritinib versus chemotherapy in patients who had failed crizotinib. We showed that ceritinib was superior to chemotherapy in that second-line setting. That was the ASCEND-5 trial. So, I do believe that the targeted therapies are a superior option compared to standard chemotherapy, but I did want to just mention chemotherapy because in case a patient for some reason can’t access a targeted therapy, chemotherapy is a reasonable option to use.

Among the different targeted therapies in the post-crizotinib setting for ALK-positive patients, our main choices are ceritinib or alectinib. The efficacy is comparable, although comparing across trials, there’s a suggestion that perhaps the efficacy with alectinib may be higher. I would say that the efficacy of alectinib in the CNS, in the brain in particular, is definitely higher than that of ceritinib. And we’ve actually shown that alectinib can, in fact, be active in patients who have failed both crizotinib and ceritinib in the brain. So, we feel that alectinib does have superior intracranial activity. That could be one reason that sways us toward selecting alectinib in a patient who’s relapsing on crizotinib, because they have CNS progression. But I would say, overall, that the side effects need to be carefully considered as well. And it’s pretty clear from using the drugs, and from looking at all the trial data, that alectinib is a better-tolerated drug than ceritinib overall. And so, I would say for the general patients, even ones who may not have CNS metastases, alectinib is a preferred option because from a side effect standpoint, it tends to be tolerated better than ceritinib.

Again, I think in the second-line setting when the patient has failed crizotinib and you’re faced with the choice between ceritinib and alectinib, the preferred choice is generally alectinib because of its more favorable side effect profile and its comparable, and likely superior, efficacy in the central nervous system. Despite alectinib’s generally well-tolerated side effects though, I’ve had patients who cannot tolerate alectinib. I would say there is a group of patients who will develop significant myalgias, fatigue, and weakness on alectinib. And despite dose reductions to the lowest dose, which is 300 mg or half the standard dose, they still cannot tolerate alectinib. Those patients for sure would be good candidates for ceritinib. And, again, I think when we start a patient on ceritinib, we use this alternative dosing, which is the lower dose at 450 mg taken with food.

David Spigel, MD: It’s important to remember that the ALK-rearranged patient population is a small segment of the types of patients that oncologists see at large. And so, oncologists may not have a broad experience in seeing a lot of these patients and dealing with a lot of the different options that are available. We do have different options available beyond crizotinib, and the most available options right now are 2 medications. One is called ceritinib and one is called alectinib. These are both very active agents. They get into the CNS in a better way than crizotinib does.

How do we choose whether we use one of these drugs over the other? A lot of it has to do with comfort level. If you haven’t used any of these drugs before, or you’ve used one of them, you tend to stick with that drug. But I think with each medication, it’s about understanding the kinds of things that patients could have in terms of side effects, what kind of adjustments you can make to make these drugs more tolerable. Ceritinib was on the scene first, and so I think that was a medication most oncologists have had more experience with and often can require dose reductions to deal with GI toxicity mainly. But when you can use those dose reductions, you can usually maintain patients on the therapy for extended periods with good disease control. The promise of alectinib—and this is the newer therapy for a lot of the regions of the country because of its development occurring a little bit later—is that it may be a bit better tolerated drug, with less GI side effects, where you don’t have to make as many dose reductions. Obviously, I think patients, families, and providers want the easiest therapy to give to their patients that works the best. What we have right now is 2 very active agents. So, we don’t know that one works better than the other. But there are differences in toxicity profiles, and then there’ll be differences in comfort levels of the providers in terms of “I’ve always given ceritinib. I know how to make dose reductions” or “I’m more comfortable with alectinib because I don’t have to make as many dose reductions.” I think that’s where we’re at right now. No clear difference in the drugs in terms of how good they are at fighting cancer, but some differences in toxicities.

Tony Mok, MD: The options for patients who had progressed on crizotinib may include either ceritinib or alectinib. However, not all countries have the availability of alectinib at this point. Ceritinib had been approved in multiple countries, including in Hong Kong, where ceritinib is the only one that is approved. So, at this moment, I don’t have to choose. Now, on the other hand, you asked the question, if it becomes available, how do you choose? I think the toxicity has to be one consideration. Alectinib, in general, may have less of the GI toxicity, but then for ceritinib, there are new data coming out using the lower dose with the food that they may have equal pharmacokinetics and that may make the drug a little bit easier to accept. The other important thing is whether the brain metastases will make a difference between the 2. Certainly, the current data suggest that the CNS ability is similar, but then we cannot really have any comparator trial to say one drug is necessarily better than the other one in terms of CNS control. So, overall, I don’t think we can have anyone say, “I want drug A or drug B.” Both are options that are available for the doctor and the patients.

David Spigel, MD: When you’re managing any patient with cancer, but specifically in ALK-rearranged lung cancer, the way patients can progress will be different than, say, you manage a patient with more traditional squamous lung cancer or even nonsquamous non–small cell lung cancer. What can happen often is you’re doing scans and patients are feeling well, and you find new lesions in the brain. Patients are asymptomatic, so you have a little bit more time to make adjustments. You could continue their oral therapy and maybe use something, like radiation, to deal with those lesions or you could switch to a next-generation drug and not use radiation therapy and watch those patients for close periods to make sure there’s good control of those lesions. But there can be patients who go downhill rather quickly, who get good control of their cancer but then slowly start to progress. Maybe you’ve been watching them, watching that progression occur slowly. And there comes a point where you worry that you may be waiting too long. And so, when moving on to your next plane of therapy, it’s important to have a plan in place so that you’re not delaying a patient’s opportunity to still benefit from that next line of therapy. Ideally, that next line of therapy is an oral next-generation tyrosine kinase inhibitor. But sometimes you don’t have that option or you don’t have the availability or you can’t get the drug approved, and so you move on to chemotherapy. But that gap there, a lot of oncologists will recognize this gap can be a critical period where patients can get sick quickly, and you hope to restore their health very quickly as well. But it can’t be one of these things where you take many weeks to figure out what you’re going to do.

Transcript Edited for Clarity
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Transcript:

Alice Shaw, MD, PhD:
For ALK-positive patients who relapse on crizotinib, there are a number of options now. In the past, we really only had standard cytotoxic chemotherapy as an option, but now we actually have several different new targeted therapy options after crizotinib fails. And this really is the class of second-generation inhibitors—ceritinib, alectinib—and soon, in the United States, we may have brigatinib as an option as well. And so, now it has actually become even more complicated to think about choosing among these different pill options for patients. I would say, in my own practice right now, the standard options are chemotherapy and ceritinib or alectinib for patients who fail on crizotinib. And, typically, we will go with the targeted therapy. We believe the targeted therapy is superior to chemotherapy. That has been shown in the first-line setting, and recently, we also presented data on ceritinib versus chemotherapy in patients who had failed crizotinib. We showed that ceritinib was superior to chemotherapy in that second-line setting. That was the ASCEND-5 trial. So, I do believe that the targeted therapies are a superior option compared to standard chemotherapy, but I did want to just mention chemotherapy because in case a patient for some reason can’t access a targeted therapy, chemotherapy is a reasonable option to use.

Among the different targeted therapies in the post-crizotinib setting for ALK-positive patients, our main choices are ceritinib or alectinib. The efficacy is comparable, although comparing across trials, there’s a suggestion that perhaps the efficacy with alectinib may be higher. I would say that the efficacy of alectinib in the CNS, in the brain in particular, is definitely higher than that of ceritinib. And we’ve actually shown that alectinib can, in fact, be active in patients who have failed both crizotinib and ceritinib in the brain. So, we feel that alectinib does have superior intracranial activity. That could be one reason that sways us toward selecting alectinib in a patient who’s relapsing on crizotinib, because they have CNS progression. But I would say, overall, that the side effects need to be carefully considered as well. And it’s pretty clear from using the drugs, and from looking at all the trial data, that alectinib is a better-tolerated drug than ceritinib overall. And so, I would say for the general patients, even ones who may not have CNS metastases, alectinib is a preferred option because from a side effect standpoint, it tends to be tolerated better than ceritinib.

Again, I think in the second-line setting when the patient has failed crizotinib and you’re faced with the choice between ceritinib and alectinib, the preferred choice is generally alectinib because of its more favorable side effect profile and its comparable, and likely superior, efficacy in the central nervous system. Despite alectinib’s generally well-tolerated side effects though, I’ve had patients who cannot tolerate alectinib. I would say there is a group of patients who will develop significant myalgias, fatigue, and weakness on alectinib. And despite dose reductions to the lowest dose, which is 300 mg or half the standard dose, they still cannot tolerate alectinib. Those patients for sure would be good candidates for ceritinib. And, again, I think when we start a patient on ceritinib, we use this alternative dosing, which is the lower dose at 450 mg taken with food.

David Spigel, MD: It’s important to remember that the ALK-rearranged patient population is a small segment of the types of patients that oncologists see at large. And so, oncologists may not have a broad experience in seeing a lot of these patients and dealing with a lot of the different options that are available. We do have different options available beyond crizotinib, and the most available options right now are 2 medications. One is called ceritinib and one is called alectinib. These are both very active agents. They get into the CNS in a better way than crizotinib does.

How do we choose whether we use one of these drugs over the other? A lot of it has to do with comfort level. If you haven’t used any of these drugs before, or you’ve used one of them, you tend to stick with that drug. But I think with each medication, it’s about understanding the kinds of things that patients could have in terms of side effects, what kind of adjustments you can make to make these drugs more tolerable. Ceritinib was on the scene first, and so I think that was a medication most oncologists have had more experience with and often can require dose reductions to deal with GI toxicity mainly. But when you can use those dose reductions, you can usually maintain patients on the therapy for extended periods with good disease control. The promise of alectinib—and this is the newer therapy for a lot of the regions of the country because of its development occurring a little bit later—is that it may be a bit better tolerated drug, with less GI side effects, where you don’t have to make as many dose reductions. Obviously, I think patients, families, and providers want the easiest therapy to give to their patients that works the best. What we have right now is 2 very active agents. So, we don’t know that one works better than the other. But there are differences in toxicity profiles, and then there’ll be differences in comfort levels of the providers in terms of “I’ve always given ceritinib. I know how to make dose reductions” or “I’m more comfortable with alectinib because I don’t have to make as many dose reductions.” I think that’s where we’re at right now. No clear difference in the drugs in terms of how good they are at fighting cancer, but some differences in toxicities.

Tony Mok, MD: The options for patients who had progressed on crizotinib may include either ceritinib or alectinib. However, not all countries have the availability of alectinib at this point. Ceritinib had been approved in multiple countries, including in Hong Kong, where ceritinib is the only one that is approved. So, at this moment, I don’t have to choose. Now, on the other hand, you asked the question, if it becomes available, how do you choose? I think the toxicity has to be one consideration. Alectinib, in general, may have less of the GI toxicity, but then for ceritinib, there are new data coming out using the lower dose with the food that they may have equal pharmacokinetics and that may make the drug a little bit easier to accept. The other important thing is whether the brain metastases will make a difference between the 2. Certainly, the current data suggest that the CNS ability is similar, but then we cannot really have any comparator trial to say one drug is necessarily better than the other one in terms of CNS control. So, overall, I don’t think we can have anyone say, “I want drug A or drug B.” Both are options that are available for the doctor and the patients.

David Spigel, MD: When you’re managing any patient with cancer, but specifically in ALK-rearranged lung cancer, the way patients can progress will be different than, say, you manage a patient with more traditional squamous lung cancer or even nonsquamous non–small cell lung cancer. What can happen often is you’re doing scans and patients are feeling well, and you find new lesions in the brain. Patients are asymptomatic, so you have a little bit more time to make adjustments. You could continue their oral therapy and maybe use something, like radiation, to deal with those lesions or you could switch to a next-generation drug and not use radiation therapy and watch those patients for close periods to make sure there’s good control of those lesions. But there can be patients who go downhill rather quickly, who get good control of their cancer but then slowly start to progress. Maybe you’ve been watching them, watching that progression occur slowly. And there comes a point where you worry that you may be waiting too long. And so, when moving on to your next plane of therapy, it’s important to have a plan in place so that you’re not delaying a patient’s opportunity to still benefit from that next line of therapy. Ideally, that next line of therapy is an oral next-generation tyrosine kinase inhibitor. But sometimes you don’t have that option or you don’t have the availability or you can’t get the drug approved, and so you move on to chemotherapy. But that gap there, a lot of oncologists will recognize this gap can be a critical period where patients can get sick quickly, and you hope to restore their health very quickly as well. But it can’t be one of these things where you take many weeks to figure out what you’re going to do.

Transcript Edited for Clarity
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