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Third-Generation ALK Inhibitors for 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: Wednesday, Mar 22, 2017


Transcript:

Mark Socinski, MD:
There are some newer drugs coming along. We saw some data, I thought some very nice data, with brigatinib. And that’s close to being an FDA-approved agent. Lorlatinib has evolving data. What’s your perspective on these newer agents?

Alexander Drilon, MD: I like to call these drugs “later-generation drugs” because we can’t keep naming them “third” or “fourth.” It just gets very crazy. The difference with these drugs, compared to the second-generation drugs, is that they’re better against the wider profile of these ALK mutation-resistance mutations we talked about earlier. And lorlatinib, for example, can overcome the G1202R mutation. For brigatinib, there are the ALTA trial data that were presented and showed that patients did have a good progression-free survival on it. In fact, barring cross-trial comparisons, it was one of the higher progression-free survivals that we’ve seen and really deep responses on the waterfall plot. We’ve also, from ASCO, seen data on lorlatinib, not just in patients who have gotten 1 drug before, but 2 ALK inhibitors, where the response rate was in the order of 40%. So, it seems like we may be moving toward a phase where we might have a third drug to sequence after the first 2 have failed. Obviously, the question of what to do if alectinib becomes first-line therapy, is a good question. But it seems like a drug like lorlatinib, that might hit the G1202R, could be a reasonable choice after alectinib fails.

Mark Socinski, MD: Yes, and we have the ongoing trial of brigatinib versus crizotinib, which is very similar to the ALEX data.

Alexander Drilon, MD: The ALTA-1L trial.

Mark Socinski, MD: Each one of these agents, in the phase II setting, has focused on central nervous system activity. Again, these are reasonably sized phase II data. Do you get a sense that they all have a level of activity in the brain? Do you think one looks better than the other? My feeling is that brigatinib looks better, but it also had the fewest number of patients on their trial. So, that may inflate the benefit. Anyone have thoughts about that?

Vali Papadimitrakopoulou, MD: I think they all have activity, and brigatinib does look better by numbers. I think they also have done a very systematic approach. They have a very systematic approach in reporting the accurate numbers for response rate and progression-free survival, characterizing active brain metastases versus not, and distinguishing measurable versus nonmeasurable. This is a whole evolving field.

Mark Socinski, MD: And doing it prospectively.

Vali Papadimitrakopoulou, MD: That’s right. So, I think it would be important for us to be able to make comparisons to have across the different drugs, the same quality data that was produced from these studies, so that we could definitely pronounce an opinion on whether one looks better than the other.

Mark Socinski, MD: Right. We discussed T790M and the importance. It’s critical to rebiopsy, and retest whether it’s tissue, blood, or urine. In clinical practice today, is there a reason to rebiopsy or retest an ALK patient?

Alexander Drilon, MD: I try to, when I can.

Mark Socinski, MD: But why?

Alexander Drilon, MD: The different ALK inhibitors that we have, as I mentioned, have different activity levels against various mutations; for example, choosing between alectinib and ceritinib. Alectinib doesn’t work against the I1171 mutation.

Mark Socinski, MD: So, if you knew that, that would be informative, right?

Alexander Drilon, MD: If I knew that, I would think of doing ceritinib, despite the toxicity—maybe start at 450 mg. But the problem is that since the mutations are all over the map, you need a more comprehensive test and that takes a while to come back. So, you’re back in that same arena.

Mark Socinski, MD: Tracey, your thoughts?

Tracey Evans, MD: There are other mutations that can develop, too, and that can sometimes be actionable. We see, sometimes, EGFR mutations and KRAS mutations. So, those can be important to know about. I don’t routinely biopsy on the initial progression event if I haven’t gone, yet, to alectinib or ceritinib if they just progressed on crizotinib. I did have one patient, though, who was very informative. This was a patient on crizotinib who developed this strange waxing/waning inflammatory syndrome within his lungs, and it was so bothersome. We couldn’t tell what it was, so we biopsied it and found that he was having tumor emboli to his vasculature in his lungs that was causing an inflammatory response. So, that actually represented progressive disease, even though we didn’t see any other clear sites of progressive disease. He was very symptomatic from this. The amount of tumor tissue we got from even a wedge resection of his lung was insufficient to do molecular testing because they were just microscopic little things. But I sent plasma testing on him, and we found that he had G1202R. So, I was able to send him to Boston for one of the lorlatinib trials, and he’s been on it for over a year.

Mark Socinski, MD: Vali, what is your perspective on this issue of rebiopsy? How do you sequence? Do we have any trials that are going to address sequencing sort-of issues in the ALK space?

Vali Papadimitrakopoulou, MD: There has been a clinical trial, that the National Cancer Institute is sponsoring, that has been in the works for several years now: the ALK Master Protocol. It is still being designed to address the sequence questions. And this clinical trial, of course, would demand biopsies from patients that progressed, and sequential plasma testing, so that we can get this information. And I do believe that we need to at least attempt a rebiopsy for patients for the reasons that Tracey outlined, but also because we need a body of information to better characterize the resistance mechanisms. I have to remind everybody that the data we have are based on a very small series from individual academic institutions, and there are no robust data. We need this data, and it could be achieved with a NCI clinical trial or it could be achieved if we all agree that we need to collaborate in this setting to produce this data.

Mark Socinski, MD: Yes. I think I’m going to come back to Jared regarding what his message would be to the community oncologists. When I speak to many community oncologists, they may see 1 ALK patient a year, 2 if they’re lucky, or maybe 1 every other year. As we’ve talked about, it’s an incredibly complex situation. There’s an ever-expanding number of drugs. What would be your advice to the community oncologist? Should we send them all to you?

Jared Weiss, MD: Absolutely. I do a lot of traveling doing community lecturing, and I think the key message remains that it is mandatory to test for ALK in the first-line. I think, in this panel, we take that for granted. We move on. We want to talk about higher-brow stuff. That is still a real issue in the United States: nontesting of ALK in the first-line. We do have a FDA-approved drug to action it that can de-medicalize the patient’s life, can have lower toxicity and a longer progression-free survival. And upon progression, this is not of all of the places where I’m going to push rebiopsy on the community. I think that with 2 approved drugs that most patients will respond to, that might not be the hill to die on. But I think the bigger message is to use 1 of those 2 agents. After progression, these are patients that they should consider preferentially sending to an academic center to get rebiopsied and consider more advanced trials.

Transcript Edited for Clarity
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Transcript:

Mark Socinski, MD:
There are some newer drugs coming along. We saw some data, I thought some very nice data, with brigatinib. And that’s close to being an FDA-approved agent. Lorlatinib has evolving data. What’s your perspective on these newer agents?

Alexander Drilon, MD: I like to call these drugs “later-generation drugs” because we can’t keep naming them “third” or “fourth.” It just gets very crazy. The difference with these drugs, compared to the second-generation drugs, is that they’re better against the wider profile of these ALK mutation-resistance mutations we talked about earlier. And lorlatinib, for example, can overcome the G1202R mutation. For brigatinib, there are the ALTA trial data that were presented and showed that patients did have a good progression-free survival on it. In fact, barring cross-trial comparisons, it was one of the higher progression-free survivals that we’ve seen and really deep responses on the waterfall plot. We’ve also, from ASCO, seen data on lorlatinib, not just in patients who have gotten 1 drug before, but 2 ALK inhibitors, where the response rate was in the order of 40%. So, it seems like we may be moving toward a phase where we might have a third drug to sequence after the first 2 have failed. Obviously, the question of what to do if alectinib becomes first-line therapy, is a good question. But it seems like a drug like lorlatinib, that might hit the G1202R, could be a reasonable choice after alectinib fails.

Mark Socinski, MD: Yes, and we have the ongoing trial of brigatinib versus crizotinib, which is very similar to the ALEX data.

Alexander Drilon, MD: The ALTA-1L trial.

Mark Socinski, MD: Each one of these agents, in the phase II setting, has focused on central nervous system activity. Again, these are reasonably sized phase II data. Do you get a sense that they all have a level of activity in the brain? Do you think one looks better than the other? My feeling is that brigatinib looks better, but it also had the fewest number of patients on their trial. So, that may inflate the benefit. Anyone have thoughts about that?

Vali Papadimitrakopoulou, MD: I think they all have activity, and brigatinib does look better by numbers. I think they also have done a very systematic approach. They have a very systematic approach in reporting the accurate numbers for response rate and progression-free survival, characterizing active brain metastases versus not, and distinguishing measurable versus nonmeasurable. This is a whole evolving field.

Mark Socinski, MD: And doing it prospectively.

Vali Papadimitrakopoulou, MD: That’s right. So, I think it would be important for us to be able to make comparisons to have across the different drugs, the same quality data that was produced from these studies, so that we could definitely pronounce an opinion on whether one looks better than the other.

Mark Socinski, MD: Right. We discussed T790M and the importance. It’s critical to rebiopsy, and retest whether it’s tissue, blood, or urine. In clinical practice today, is there a reason to rebiopsy or retest an ALK patient?

Alexander Drilon, MD: I try to, when I can.

Mark Socinski, MD: But why?

Alexander Drilon, MD: The different ALK inhibitors that we have, as I mentioned, have different activity levels against various mutations; for example, choosing between alectinib and ceritinib. Alectinib doesn’t work against the I1171 mutation.

Mark Socinski, MD: So, if you knew that, that would be informative, right?

Alexander Drilon, MD: If I knew that, I would think of doing ceritinib, despite the toxicity—maybe start at 450 mg. But the problem is that since the mutations are all over the map, you need a more comprehensive test and that takes a while to come back. So, you’re back in that same arena.

Mark Socinski, MD: Tracey, your thoughts?

Tracey Evans, MD: There are other mutations that can develop, too, and that can sometimes be actionable. We see, sometimes, EGFR mutations and KRAS mutations. So, those can be important to know about. I don’t routinely biopsy on the initial progression event if I haven’t gone, yet, to alectinib or ceritinib if they just progressed on crizotinib. I did have one patient, though, who was very informative. This was a patient on crizotinib who developed this strange waxing/waning inflammatory syndrome within his lungs, and it was so bothersome. We couldn’t tell what it was, so we biopsied it and found that he was having tumor emboli to his vasculature in his lungs that was causing an inflammatory response. So, that actually represented progressive disease, even though we didn’t see any other clear sites of progressive disease. He was very symptomatic from this. The amount of tumor tissue we got from even a wedge resection of his lung was insufficient to do molecular testing because they were just microscopic little things. But I sent plasma testing on him, and we found that he had G1202R. So, I was able to send him to Boston for one of the lorlatinib trials, and he’s been on it for over a year.

Mark Socinski, MD: Vali, what is your perspective on this issue of rebiopsy? How do you sequence? Do we have any trials that are going to address sequencing sort-of issues in the ALK space?

Vali Papadimitrakopoulou, MD: There has been a clinical trial, that the National Cancer Institute is sponsoring, that has been in the works for several years now: the ALK Master Protocol. It is still being designed to address the sequence questions. And this clinical trial, of course, would demand biopsies from patients that progressed, and sequential plasma testing, so that we can get this information. And I do believe that we need to at least attempt a rebiopsy for patients for the reasons that Tracey outlined, but also because we need a body of information to better characterize the resistance mechanisms. I have to remind everybody that the data we have are based on a very small series from individual academic institutions, and there are no robust data. We need this data, and it could be achieved with a NCI clinical trial or it could be achieved if we all agree that we need to collaborate in this setting to produce this data.

Mark Socinski, MD: Yes. I think I’m going to come back to Jared regarding what his message would be to the community oncologists. When I speak to many community oncologists, they may see 1 ALK patient a year, 2 if they’re lucky, or maybe 1 every other year. As we’ve talked about, it’s an incredibly complex situation. There’s an ever-expanding number of drugs. What would be your advice to the community oncologist? Should we send them all to you?

Jared Weiss, MD: Absolutely. I do a lot of traveling doing community lecturing, and I think the key message remains that it is mandatory to test for ALK in the first-line. I think, in this panel, we take that for granted. We move on. We want to talk about higher-brow stuff. That is still a real issue in the United States: nontesting of ALK in the first-line. We do have a FDA-approved drug to action it that can de-medicalize the patient’s life, can have lower toxicity and a longer progression-free survival. And upon progression, this is not of all of the places where I’m going to push rebiopsy on the community. I think that with 2 approved drugs that most patients will respond to, that might not be the hill to die on. But I think the bigger message is to use 1 of those 2 agents. After progression, these are patients that they should consider preferentially sending to an academic center to get rebiopsied and consider more advanced trials.

Transcript Edited for Clarity
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