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Upfront Use of Next-Generation ALK Inhibitors in NSCLC

Panelists: Mark A. Socinski, MD, Florida Hospital Cancer Institute; Tracey L. Evans, MD, University of Pennsylvania; Alexander Drilon, MD, Memorial Sloan Kettering Cancer Center; Vali A. Papadimitrakopoulou, MD, The University of Texas MD Anderson Cancer Center; Jared Weiss, MD, UNC Lineberger Comprehensive Cancer Center
Published Online: Monday, Mar 20, 2017



Transcript:

Mark Socinski, MD:
In a newly diagnosed ALK patient in your clinic, today, what would you use first-line?

Alexander Drilon, MD: Based on what’s approved, crizotinib.

Tracey Evans, MD: Crizotinib.

Jared Weiss, MD: Crizotinib, with some guilt that, perhaps, I should be using alectinib.

Mark Socinski, MD: No central nervous system disease.

Vali Papadimitrakopoulou, MD: Okay, crizotinib.

Mark Socinski, MD: Okay. So, crizotinib remains the standard. We have second-line options, and the patient, 10 months later, progresses. What are you typically doing second-line?

Alexander Drilon, MD: Alectinib.

Tracey Evans, MD: Alectinib.

Jared Weiss, MD: Alectinib.

Vali Papadimitrakopoulou, MD: Alectinib.

Mark Socinski, MD: Is it based on toxicity?

Alexander Drilon, MD: Yes.

Vali Papadimitrakopoulou, MD: Yes.

Mark Socinski, MD: Is there not necessarily a perception that there’s a difference in efficacy?

Tracey Evans, MD: Correct.

Mark Socinski, MD: With ceritinib, I mentioned before that we had the 2 profile trials with crizotinib against standard of care. And then, we saw again, at the World Conference on Lung Cancer meeting, ASCEND-4, which was a trial of ceritinib versus standard chemotherapy. Could you walk us through that? I think this is important data, although I’m not sure how to apply this in practice because I don’t know that the comparator is chemotherapy at this point. But tell us about the data.

Vali Papadimitrakopoulou, MD: This was a comparison of standard-of-care chemotherapy versus ceritinib in first-line, treatment-naïve patients. It was a definitive trial to prove the point that the drug is superior to standard chemotherapy, and it was. The data were quite convincing. Progression-free survival was 16.6 months for ceritinib versus 8.1 months for chemotherapy, and the hazard ratio was an impressive 0.5 or so. Overall survival also was favoring ceritinib. The stumbling point of this data is, a little bit, regarding the toxicity profile because it was used with standard dosing: 750 mg. So, there was a significant discontinuation rate. About 69% of the patients had dose adjustments, which is significant. We know that’s what’s happening in our practice. The question of whether we should adopt ceritinib, based on data comparing it to chemotherapy as a first-line treatment versus crizotinib, is not easy to answer based on this data. They are impressive data, and 16 months is very long progression-free survival. We haven’t seen that.

Mark Socinski, MD: As part of the afatinib story, we do have the analysis of the LUX-Lung 3 and LUX-Lung 6 trials, where they looked at those patients that required dose reduction and didn’t see any decay of efficacy if you had to go down to 30 mg or 20 mg. Did they talk about that at all in ASCEND-4, in terms of looking at those, since the majority of the patients had to be dose-reduced?

Vali Papadimitrakopoulou, MD: It was not really discussed, but I’m hoping that it is in the database. I haven’t seen it, so we don’t really know. But in our clinical practice, in the second-line setting, dose reduction does not really affect activity of the drug. So, I wouldn’t be expecting it.

Mark Socinski, MD: Right. The other trial that was very exciting at ASCO 2016 was the J-ALEX trial, which was a first head-to-head comparison in this disease setting of crizotinib and alectinib. Your thoughts around that?

Tracey Evans, MD: This is the study that explains why Jared feels guilty when he uses crizotinib in the first-line setting, and this was a study that was done, completely, with Japanese patients—about 200 patients. They were randomly assigned to either crizotinib at the standard doses that we use, 250 mg/twice a day, versus alectinib at the Japanese standard dose, which is half the dose of what we use. In the study, the alectinib won by a long shot. The hazard ratio for progression-free survival was 0.3, so the progression-free survival median for crizotinib was what we’d expect to see: about 10 months. And it hadn’t even been reached for the alectinib. So, this was a dramatic benefit with a drug that has good CNS penetration, which is also a concern in these patients and is why we’re tempted to use this.

Now, will this apply to a non-Japanese patient population? The global ALEX study has completed accrual, and we’re waiting for data on that. So, a lot of us are waiting for that data before we begin using alectinib as our standard go-to, first-line. Of course, there is also the issue that alectinib is not yet approved first-line, so you have to fight with the insurance companies in order to get it. Jared Weiss, MD: One other thing from that data that helps drive my guilt was the superior toxicity profile of alectinib.

Tracey Evans, MD: That’s right.

Mark Socinski, MD: Talk about the dose.

Jared Weiss, MD: It was half the dose that we typically use.

Mark Socinski, MD: In a Japanese population, which may be appropriate. But it was half the dose. I don’t know if that makes a difference.

Tracey Evans, MD: Crizotinib came out pretty bad.

Mark Socinski, MD: It did.

Jared Weiss, MD: Yes.

Tracey Evans, MD: Crizotinib does have some challenging toxicities, but generally when I use it, it’s pretty tolerable. In that study, they had really high rates of dysgeusia, which I’ve only seen a handful of times. They had the visual disturbances. The only thing that the people on alectinib had was some constipation, and they tolerated it much better. But I don’t know, in our hands, if I get that impression that crizotinib is so hard to tolerate.

Jared Weiss, MD: Yes, and I think the ALEX study will help, a lot, there.

Mark Socinski, MD: So, you’re all using crizotinib for the newly diagnosed patient, but is there a patient that you would use alectinib in before crizotinib in your practice, today?

Vali Papadimitrakopoulou, MD: I already have discussed this with you, Mark. I think the CNS activity of alectinib is very impressive. So, the patient that has asymptomatic brain metastases at presentation, or even a patient that has been treated preemptively with stereotactic radiation therapy before it was discovered that they had ALK gene fusion, may be a very reasonable candidate for alectinib up-front.

Mark Socinski, MD: Others?

Alexander Drilon, MD: Yes, I’d do the same thing. In a patient with brain metastases, I would try to get alectinib, if possible. By what’s written on the label, if you have someone for some strange reason that can’t tolerate the crizotinib, you are allowed to give the alectinib.

Tracey Evans, MD: Do you have a lot of people who can’t tolerate crizotinib?

Alexander Drilon, MD: I think, actually, in that trial, it was probably a factor of people just being more vigilant and familiar with crizotinib and, thus, annotating the toxicities. This is why you saw much more than is clinically apparent.

Transcript Edited for Clarity

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Transcript:

Mark Socinski, MD:
In a newly diagnosed ALK patient in your clinic, today, what would you use first-line?

Alexander Drilon, MD: Based on what’s approved, crizotinib.

Tracey Evans, MD: Crizotinib.

Jared Weiss, MD: Crizotinib, with some guilt that, perhaps, I should be using alectinib.

Mark Socinski, MD: No central nervous system disease.

Vali Papadimitrakopoulou, MD: Okay, crizotinib.

Mark Socinski, MD: Okay. So, crizotinib remains the standard. We have second-line options, and the patient, 10 months later, progresses. What are you typically doing second-line?

Alexander Drilon, MD: Alectinib.

Tracey Evans, MD: Alectinib.

Jared Weiss, MD: Alectinib.

Vali Papadimitrakopoulou, MD: Alectinib.

Mark Socinski, MD: Is it based on toxicity?

Alexander Drilon, MD: Yes.

Vali Papadimitrakopoulou, MD: Yes.

Mark Socinski, MD: Is there not necessarily a perception that there’s a difference in efficacy?

Tracey Evans, MD: Correct.

Mark Socinski, MD: With ceritinib, I mentioned before that we had the 2 profile trials with crizotinib against standard of care. And then, we saw again, at the World Conference on Lung Cancer meeting, ASCEND-4, which was a trial of ceritinib versus standard chemotherapy. Could you walk us through that? I think this is important data, although I’m not sure how to apply this in practice because I don’t know that the comparator is chemotherapy at this point. But tell us about the data.

Vali Papadimitrakopoulou, MD: This was a comparison of standard-of-care chemotherapy versus ceritinib in first-line, treatment-naïve patients. It was a definitive trial to prove the point that the drug is superior to standard chemotherapy, and it was. The data were quite convincing. Progression-free survival was 16.6 months for ceritinib versus 8.1 months for chemotherapy, and the hazard ratio was an impressive 0.5 or so. Overall survival also was favoring ceritinib. The stumbling point of this data is, a little bit, regarding the toxicity profile because it was used with standard dosing: 750 mg. So, there was a significant discontinuation rate. About 69% of the patients had dose adjustments, which is significant. We know that’s what’s happening in our practice. The question of whether we should adopt ceritinib, based on data comparing it to chemotherapy as a first-line treatment versus crizotinib, is not easy to answer based on this data. They are impressive data, and 16 months is very long progression-free survival. We haven’t seen that.

Mark Socinski, MD: As part of the afatinib story, we do have the analysis of the LUX-Lung 3 and LUX-Lung 6 trials, where they looked at those patients that required dose reduction and didn’t see any decay of efficacy if you had to go down to 30 mg or 20 mg. Did they talk about that at all in ASCEND-4, in terms of looking at those, since the majority of the patients had to be dose-reduced?

Vali Papadimitrakopoulou, MD: It was not really discussed, but I’m hoping that it is in the database. I haven’t seen it, so we don’t really know. But in our clinical practice, in the second-line setting, dose reduction does not really affect activity of the drug. So, I wouldn’t be expecting it.

Mark Socinski, MD: Right. The other trial that was very exciting at ASCO 2016 was the J-ALEX trial, which was a first head-to-head comparison in this disease setting of crizotinib and alectinib. Your thoughts around that?

Tracey Evans, MD: This is the study that explains why Jared feels guilty when he uses crizotinib in the first-line setting, and this was a study that was done, completely, with Japanese patients—about 200 patients. They were randomly assigned to either crizotinib at the standard doses that we use, 250 mg/twice a day, versus alectinib at the Japanese standard dose, which is half the dose of what we use. In the study, the alectinib won by a long shot. The hazard ratio for progression-free survival was 0.3, so the progression-free survival median for crizotinib was what we’d expect to see: about 10 months. And it hadn’t even been reached for the alectinib. So, this was a dramatic benefit with a drug that has good CNS penetration, which is also a concern in these patients and is why we’re tempted to use this.

Now, will this apply to a non-Japanese patient population? The global ALEX study has completed accrual, and we’re waiting for data on that. So, a lot of us are waiting for that data before we begin using alectinib as our standard go-to, first-line. Of course, there is also the issue that alectinib is not yet approved first-line, so you have to fight with the insurance companies in order to get it. Jared Weiss, MD: One other thing from that data that helps drive my guilt was the superior toxicity profile of alectinib.

Tracey Evans, MD: That’s right.

Mark Socinski, MD: Talk about the dose.

Jared Weiss, MD: It was half the dose that we typically use.

Mark Socinski, MD: In a Japanese population, which may be appropriate. But it was half the dose. I don’t know if that makes a difference.

Tracey Evans, MD: Crizotinib came out pretty bad.

Mark Socinski, MD: It did.

Jared Weiss, MD: Yes.

Tracey Evans, MD: Crizotinib does have some challenging toxicities, but generally when I use it, it’s pretty tolerable. In that study, they had really high rates of dysgeusia, which I’ve only seen a handful of times. They had the visual disturbances. The only thing that the people on alectinib had was some constipation, and they tolerated it much better. But I don’t know, in our hands, if I get that impression that crizotinib is so hard to tolerate.

Jared Weiss, MD: Yes, and I think the ALEX study will help, a lot, there.

Mark Socinski, MD: So, you’re all using crizotinib for the newly diagnosed patient, but is there a patient that you would use alectinib in before crizotinib in your practice, today?

Vali Papadimitrakopoulou, MD: I already have discussed this with you, Mark. I think the CNS activity of alectinib is very impressive. So, the patient that has asymptomatic brain metastases at presentation, or even a patient that has been treated preemptively with stereotactic radiation therapy before it was discovered that they had ALK gene fusion, may be a very reasonable candidate for alectinib up-front.

Mark Socinski, MD: Others?

Alexander Drilon, MD: Yes, I’d do the same thing. In a patient with brain metastases, I would try to get alectinib, if possible. By what’s written on the label, if you have someone for some strange reason that can’t tolerate the crizotinib, you are allowed to give the alectinib.

Tracey Evans, MD: Do you have a lot of people who can’t tolerate crizotinib?

Alexander Drilon, MD: I think, actually, in that trial, it was probably a factor of people just being more vigilant and familiar with crizotinib and, thus, annotating the toxicities. This is why you saw much more than is clinically apparent.

Transcript Edited for Clarity
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