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Upfront Use of Second-Generation TKIs in 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 Online: Thursday, Apr 20, 2017



Transcript:

Tony Mok, MD: T
he ASCEND-4 data had options, but I don’t think it would change in all patients with ALK-positive disease. As I stated earlier, both crizotinib and ceritinib are potential options, but I don’t think they’re replacements entirely. On the other hand, when the ALEX study come out, then it becomes debatable if there is a definite phase III study showing alectinib to be superior to crizotinib.

David Spigel, MD: So, the results of ASCEND-4 really are quite remarkable because it takes a more active, next-generation drug, ceritinib, and potentially moves it into first-line use. We know from ASCEND-4 that ceritinib is better than chemotherapy. It’s not yet approved to be used as your first-line therapy, but we expect that to happen. And so, what patients and providers will have available to them is the option of crizotinib, or ceritinib, as first-line therapy. We don’t yet have head-to-head comparison data of crizotinib versus ceritinib, but we know that ceritinib has been a more active drug and appears to get into the CNS in a better way than crizotinib. And so, it’s likely that that would become the more preferred strategy in the first-line setting.

Alice Shaw, MD, PhD: Right now, most oncologists are still favoring sequential treatment with first-generation followed by second-generation inhibitors. However, based on ASCEND-4 and other first-line trials that will soon be resulting, I anticipate that that will be moving more toward upfront use of second-generation inhibitors. And so, then a natural question that comes up is, what do we do after failure of a first-line ceritinib patient, for example? And here, I think resistance mechanisms are going to become very important because understanding why those patients are relapsing on a second-generation inhibitor will help us to tailor the selection of the next therapy.

In the case of first-line ceritinib, I’m imagining that we will see a significant proportion of patients developing ALK-resistant mutations for which we will be able to select another ALK inhibitor for them. Some patients may develop MET amplification because ceritinib and alectinib, unlike crizotinib, actually do not inhibit MET at all. And MET is a common bypass mechanism, so I actually expect to see MET emerge more commonly after first-line use of ceritinib. So, there will be a role for combination therapies after failure of a second-generation inhibitor, but we really need to identify the resistance mechanism before knowing what to do.

Tony Mok, MD: The current recognized standard dose of ceritinib is 750 mg daily, 5 tablets taken at the same time. Now a lot of these patients may actually experience nausea and vomiting rather quickly after ingestion of the drug. The question is, how can we improve the situation? For such, there is actually a new pharmacokinetic study that actually has just been released. One of the theories of not being able to give food is that the food is going to increase the absorption of the drug, such that you actually have a higher drug level after you use food and the drug together. So, therefore, they suggest you not to do it. But, on the other hand, the drug itself may have a local irritative effect if you do not take in any food. Therefore, with this pharmacokinetic study, they actually give a low dose at 450 mg and allow the patient to take food. So, as a result, they will have a pharmacokinetic picture very similar to 750 mg without the food. In that case, they serve the purpose of being able to have the same dosage effect, but with less of the GI upset.

Alice Shaw, MD, PhD: J-ALEX is a phase III randomized trial conducted in Japan that was comparing alectinib versus crizotinib as first-line ALK TKI in patients with advanced ALK-positive lung cancer. The data that were presented at ASCO in 2016 were data from the second planned interim analysis of J-ALEX. The interim analysis was very positive in favor of alectinib, so, in fact, the trial was halted at that point. This trial was a little bit different than some of the other trials in a sense that this was conducted only in Japanese patients. The dose of alectinib was different than what is considered the standard dose in this country. In the J-ALEX study, they used a dose of 300 mg twice a day, whereas our standard dose of alectinib is 600 mg twice a day. And then, I would also note that for patients to be eligible for J-ALEX, most of them had double positivity on the diagnostic test. So, they had to be FISH-positive as well as IHC-positive. And, typically, for most of our ALK trials, including the Global ALEX study and the ASCEND-4 study, we really have required typically 1 positive test. So, the testing was different in J-ALEX as well. However, J-ALEX was very notable because it’s a very positive study. The hazard ratio favoring alectinib was 0.34. It was a highly statistically significant P value. The median progression-free survival with alectinib was not reached at the time of this interim analysis. And with crizotinib, the median progression-free survival was about 10 months, which is in line with other studies of first-line crizotinib.

In the subgroup analysis that was done within J-ALEX, most subgroups derived benefit from alectinib over crizotinib. But what was particularly notable was the subset of patients who had brain metastases at baseline when they enrolled on the study. And while the subgroup was small, this subgroup seemed to particularly benefit from alectinib over crizotinib with a hazard ratio of 0.08 at that interim analysis. This really shows a tremendous benefit to alectinib, which we know is CNS-penetrant compared to crizotinib. The other thing that was important about J-ALEX is that—again, a head-to-head comparison—we were able to compare the side effects of alectinib versus crizotinib. And in this population of Japanese ALK-positive patients, alectinib did appear to be better tolerated than crizotinib with fewer requirements for dose interruption or dose reduction.

So, J-ALEX is really very exciting. I think many of us are very excited about the Global ALEX study, which is similar but has some important differences to this J-ALEX study. And Global ALEX will be comparing first-line alectinib to first-line crizotinib in newly diagnosed ALK-positive patients. We expect the results to be presented at ASCO this year.

Transcript Edited for Clarity
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Transcript:

Tony Mok, MD: T
he ASCEND-4 data had options, but I don’t think it would change in all patients with ALK-positive disease. As I stated earlier, both crizotinib and ceritinib are potential options, but I don’t think they’re replacements entirely. On the other hand, when the ALEX study come out, then it becomes debatable if there is a definite phase III study showing alectinib to be superior to crizotinib.

David Spigel, MD: So, the results of ASCEND-4 really are quite remarkable because it takes a more active, next-generation drug, ceritinib, and potentially moves it into first-line use. We know from ASCEND-4 that ceritinib is better than chemotherapy. It’s not yet approved to be used as your first-line therapy, but we expect that to happen. And so, what patients and providers will have available to them is the option of crizotinib, or ceritinib, as first-line therapy. We don’t yet have head-to-head comparison data of crizotinib versus ceritinib, but we know that ceritinib has been a more active drug and appears to get into the CNS in a better way than crizotinib. And so, it’s likely that that would become the more preferred strategy in the first-line setting.

Alice Shaw, MD, PhD: Right now, most oncologists are still favoring sequential treatment with first-generation followed by second-generation inhibitors. However, based on ASCEND-4 and other first-line trials that will soon be resulting, I anticipate that that will be moving more toward upfront use of second-generation inhibitors. And so, then a natural question that comes up is, what do we do after failure of a first-line ceritinib patient, for example? And here, I think resistance mechanisms are going to become very important because understanding why those patients are relapsing on a second-generation inhibitor will help us to tailor the selection of the next therapy.

In the case of first-line ceritinib, I’m imagining that we will see a significant proportion of patients developing ALK-resistant mutations for which we will be able to select another ALK inhibitor for them. Some patients may develop MET amplification because ceritinib and alectinib, unlike crizotinib, actually do not inhibit MET at all. And MET is a common bypass mechanism, so I actually expect to see MET emerge more commonly after first-line use of ceritinib. So, there will be a role for combination therapies after failure of a second-generation inhibitor, but we really need to identify the resistance mechanism before knowing what to do.

Tony Mok, MD: The current recognized standard dose of ceritinib is 750 mg daily, 5 tablets taken at the same time. Now a lot of these patients may actually experience nausea and vomiting rather quickly after ingestion of the drug. The question is, how can we improve the situation? For such, there is actually a new pharmacokinetic study that actually has just been released. One of the theories of not being able to give food is that the food is going to increase the absorption of the drug, such that you actually have a higher drug level after you use food and the drug together. So, therefore, they suggest you not to do it. But, on the other hand, the drug itself may have a local irritative effect if you do not take in any food. Therefore, with this pharmacokinetic study, they actually give a low dose at 450 mg and allow the patient to take food. So, as a result, they will have a pharmacokinetic picture very similar to 750 mg without the food. In that case, they serve the purpose of being able to have the same dosage effect, but with less of the GI upset.

Alice Shaw, MD, PhD: J-ALEX is a phase III randomized trial conducted in Japan that was comparing alectinib versus crizotinib as first-line ALK TKI in patients with advanced ALK-positive lung cancer. The data that were presented at ASCO in 2016 were data from the second planned interim analysis of J-ALEX. The interim analysis was very positive in favor of alectinib, so, in fact, the trial was halted at that point. This trial was a little bit different than some of the other trials in a sense that this was conducted only in Japanese patients. The dose of alectinib was different than what is considered the standard dose in this country. In the J-ALEX study, they used a dose of 300 mg twice a day, whereas our standard dose of alectinib is 600 mg twice a day. And then, I would also note that for patients to be eligible for J-ALEX, most of them had double positivity on the diagnostic test. So, they had to be FISH-positive as well as IHC-positive. And, typically, for most of our ALK trials, including the Global ALEX study and the ASCEND-4 study, we really have required typically 1 positive test. So, the testing was different in J-ALEX as well. However, J-ALEX was very notable because it’s a very positive study. The hazard ratio favoring alectinib was 0.34. It was a highly statistically significant P value. The median progression-free survival with alectinib was not reached at the time of this interim analysis. And with crizotinib, the median progression-free survival was about 10 months, which is in line with other studies of first-line crizotinib.

In the subgroup analysis that was done within J-ALEX, most subgroups derived benefit from alectinib over crizotinib. But what was particularly notable was the subset of patients who had brain metastases at baseline when they enrolled on the study. And while the subgroup was small, this subgroup seemed to particularly benefit from alectinib over crizotinib with a hazard ratio of 0.08 at that interim analysis. This really shows a tremendous benefit to alectinib, which we know is CNS-penetrant compared to crizotinib. The other thing that was important about J-ALEX is that—again, a head-to-head comparison—we were able to compare the side effects of alectinib versus crizotinib. And in this population of Japanese ALK-positive patients, alectinib did appear to be better tolerated than crizotinib with fewer requirements for dose interruption or dose reduction.

So, J-ALEX is really very exciting. I think many of us are very excited about the Global ALEX study, which is similar but has some important differences to this J-ALEX study. And Global ALEX will be comparing first-line alectinib to first-line crizotinib in newly diagnosed ALK-positive patients. We expect the results to be presented at ASCO this year.

Transcript Edited for Clarity
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