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ALK-Rearranged Lung Cancer

Panelists: Joshua Bauml, MD, University of Pennsylvania; D. Ross Camidge, MD, University of Colorado School of Medicine; Robert Doebele, MD, PhD, University of Colorado School of Medicine; Benjamin Levy, MD, Johns Hopkins Sidney Kimmel Cancer Center; Zofia Piotrowska, MD, Harvard Medical School
Published: Friday, Aug 16, 2019



Transcript:

Benjamin Levy, MD: For the sake of time we’re going to move on to ALK. And yet another mutation. We’ve seen a lot of movement, a crowded space of drugs. Ross, you’ve led a lot of the studies and lead the way with this particular genotype. Do you want to first talk about the prognosis of ALK-rearranged lung cancer? There’s been some nice work you published recently.

D. Ross Camidge, MD: There are a few publications out there. There was a study looking in community sites, which only had about a 2-and-a-half-year prognosis. There was one from Zofia’s center, I think it was about a 4-and-a-half-year prognosis. Of course, I’m going to tell you about ours, which is something like a 6.8-, nearly 7-year prognosis, which is hardly a randomized study, I’d just like to point out.

What all of them have in common is what determines your prognosis. It tends to be access to multiple lines of therapy. I think there’s a reflection of when these studies were done, and so obviously as more and more drugs come out, I think the prognosis is going up. It goes back to some of the things we talked about. You have to think about these patients with stage IV disease who are going to live for years, possibly with very good quality of life. They may return to work. They may do all of the things they want to do in their life. We shouldn’t be giving them whole brain radiotherapy. And even small toxicities are going to start to matter, because they want normal quality of life.

Benjamin Levy, MD: Yes, incredible longevity for these patients though due to the sequencing strategy. Speaking of sequencing strategy, walk us through, Ross, how you approach a newly diagnosed ALK-rearranged lung cancer patient. What’s your drug of choice, how do you sequence? Are there factors that go into what you’re using up front?

D. Ross Camidge, MD: In terms of first-line drugs, we have FDA approved, crizotinib, ceritinib, and alectinib. Out of those 3 is a pretty easy choice because alectinib has beaten crizotinib, and ceritinib was only compared to chemotherapy and it’s pretty toxic, and they don’t even have a sales force for ceritinib any more, Novartis folk tell me.

Listed in the NCCN [National Comprehensive Cancer Network] guidelines there’s also brigatinib. Now brigatinib data were only presented in the fall of 2018, and the data are still immature. I think all we can say about brigatinib is it looks at least as good as alectinib. But I think the key thing to take home is in the post-crizotinib setting brigatinib is clearly much better than alectinib, median PFS [progression-free survival] 16 months as opposed to 7 or 8 months. We saw at this ASCO [American Society of Clinical Oncology annual meeting] in the post next-generation inhibitors now we’re seeing response rates of brigatinib in the 40% to 50% range, essentially comparable to lorlatinib. It looks like even though it’s technically called a second-generation drug, it’s clearly in a different class.

And I think when you look at ALTA-1L, that first-line study, we know that the hazard ratio matures over time, and it’s got a hazard ratio that is the same as ALEX, but with almost 10 months less follow-up. When we move forward, how much better is it going to be? I think it’s the one to watch.

Benjamin Levy, MD: Do you still consider alectinib your standard of care for first-line ALK-rearranged lung cancer?

D. Ross Camidge, MD: If I’m restricted by the FDA approval, then yes. If I can finagle it for NCCN, or if… you said they were all sitting on the table in front of me, which one would I put myself on, I would put myself on brigatinib.

Benjamin Levy, MD: OK.

Zofia Piotrowska, MD: Can you tell us how you dose when you start brigatinib? I’m curious about how you manage the early pulmonary toxicities and how you watch those patients.

D. Ross Camidge, MD: I think what we’re starting to realize, first of all, it’s relatively rare. Unless you’re going to see 30 ALK-positive patients, you’re never going to see a case, so it runs at about somewhere between 3% and 6%. We think it’s now a completely unique pathophysiology. It’s not the pneumonitis that you see with other TKIs [tyrosine kinase inhibitors]. It happens pretty much on the first or second day, and if you stay on the drug, the symptoms completely disappear by about day 5. So a completely unique pathophysiology. It almost fits with the vascular spasm.

The way to think about it is probably this event is not a random event like Russian roulette and you don’t know who it’s going to happen in. Imagine it’s actually happening in every single one of your patients, and they for about 5 days will drop their respiratory function by 10% or 20%. If the patient in front of you is like Josh, a fit young guy, obviously very buff looking, then he would tolerate it very well. But if it was a bit more like Ben, he could barely make his way up the stairs, then I would actually proactively do a more shallow step-up regime, 30 mg for 3 days, 60 mg, 90 mg, and Ben will be fine because we’d sneak up on that event.

Joshua Bauml, MD: I’m glad Ben’s going to be fine.

Benjamin Levy, MD: Thank you. Are other people’s choice of therapy for ALK-positive disease, treatment naïve, is everyone debating between brigatinib or alectinib, more convinced with alectinib? Median PFS updated for the alectinib?

D. Ross Camidge, MD: Thirty four months.

Benjamin Levy, MD: Who would have thought 5 years ago, 3 years on that drug?

D. Ross Camidge, MD: We should point out, because we have a letter in the press from the ALEX investigators, that the median looks great. You need to remember, because it’s actually a plateau in the curve, it’s probably not the best thing, and the hazard ratio is much more important. The mature hazard ratio is 0.43. So that’s what brigatinib has got to try and beat.

Benjamin Levy, MD: Other people’s thoughts on how to manage upfront ALK-positive patients?

Robert Doebele, MD, PhD: Clearly alectinib and brigatinib are fantastic options with really outstanding CNS [central nervous system] control. I think both are very reasonable options. Again, alectinib is the current FDA-approved choice. I’m keeping my eye on the brigatinib data though.

Benjamin Levy, MD: One more question. Does the fusion partner matter up front on what you select? Are there any data on that?

D. Ross Camidge, MD: So far no. There were some interesting data on whether the variant within the EML4 mattered. But at least when we looked in ALEX in a larger data set, it didn’t seem to be statistically significantly different. There was some provocative data from your own center, but that was just, was it a single center? I can’t remember. Maybe you combined with a couple of other centers.

Zofia Piotrowska, MD: I believe it was single center, but don’t quote me on that.

Robert Doebele, MD, PhD: It seems to generate different resistance mechanisms, but it’s not clear yet whether that leads to PFS differences.

Transcript Edited for Clarity

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Transcript:

Benjamin Levy, MD: For the sake of time we’re going to move on to ALK. And yet another mutation. We’ve seen a lot of movement, a crowded space of drugs. Ross, you’ve led a lot of the studies and lead the way with this particular genotype. Do you want to first talk about the prognosis of ALK-rearranged lung cancer? There’s been some nice work you published recently.

D. Ross Camidge, MD: There are a few publications out there. There was a study looking in community sites, which only had about a 2-and-a-half-year prognosis. There was one from Zofia’s center, I think it was about a 4-and-a-half-year prognosis. Of course, I’m going to tell you about ours, which is something like a 6.8-, nearly 7-year prognosis, which is hardly a randomized study, I’d just like to point out.

What all of them have in common is what determines your prognosis. It tends to be access to multiple lines of therapy. I think there’s a reflection of when these studies were done, and so obviously as more and more drugs come out, I think the prognosis is going up. It goes back to some of the things we talked about. You have to think about these patients with stage IV disease who are going to live for years, possibly with very good quality of life. They may return to work. They may do all of the things they want to do in their life. We shouldn’t be giving them whole brain radiotherapy. And even small toxicities are going to start to matter, because they want normal quality of life.

Benjamin Levy, MD: Yes, incredible longevity for these patients though due to the sequencing strategy. Speaking of sequencing strategy, walk us through, Ross, how you approach a newly diagnosed ALK-rearranged lung cancer patient. What’s your drug of choice, how do you sequence? Are there factors that go into what you’re using up front?

D. Ross Camidge, MD: In terms of first-line drugs, we have FDA approved, crizotinib, ceritinib, and alectinib. Out of those 3 is a pretty easy choice because alectinib has beaten crizotinib, and ceritinib was only compared to chemotherapy and it’s pretty toxic, and they don’t even have a sales force for ceritinib any more, Novartis folk tell me.

Listed in the NCCN [National Comprehensive Cancer Network] guidelines there’s also brigatinib. Now brigatinib data were only presented in the fall of 2018, and the data are still immature. I think all we can say about brigatinib is it looks at least as good as alectinib. But I think the key thing to take home is in the post-crizotinib setting brigatinib is clearly much better than alectinib, median PFS [progression-free survival] 16 months as opposed to 7 or 8 months. We saw at this ASCO [American Society of Clinical Oncology annual meeting] in the post next-generation inhibitors now we’re seeing response rates of brigatinib in the 40% to 50% range, essentially comparable to lorlatinib. It looks like even though it’s technically called a second-generation drug, it’s clearly in a different class.

And I think when you look at ALTA-1L, that first-line study, we know that the hazard ratio matures over time, and it’s got a hazard ratio that is the same as ALEX, but with almost 10 months less follow-up. When we move forward, how much better is it going to be? I think it’s the one to watch.

Benjamin Levy, MD: Do you still consider alectinib your standard of care for first-line ALK-rearranged lung cancer?

D. Ross Camidge, MD: If I’m restricted by the FDA approval, then yes. If I can finagle it for NCCN, or if… you said they were all sitting on the table in front of me, which one would I put myself on, I would put myself on brigatinib.

Benjamin Levy, MD: OK.

Zofia Piotrowska, MD: Can you tell us how you dose when you start brigatinib? I’m curious about how you manage the early pulmonary toxicities and how you watch those patients.

D. Ross Camidge, MD: I think what we’re starting to realize, first of all, it’s relatively rare. Unless you’re going to see 30 ALK-positive patients, you’re never going to see a case, so it runs at about somewhere between 3% and 6%. We think it’s now a completely unique pathophysiology. It’s not the pneumonitis that you see with other TKIs [tyrosine kinase inhibitors]. It happens pretty much on the first or second day, and if you stay on the drug, the symptoms completely disappear by about day 5. So a completely unique pathophysiology. It almost fits with the vascular spasm.

The way to think about it is probably this event is not a random event like Russian roulette and you don’t know who it’s going to happen in. Imagine it’s actually happening in every single one of your patients, and they for about 5 days will drop their respiratory function by 10% or 20%. If the patient in front of you is like Josh, a fit young guy, obviously very buff looking, then he would tolerate it very well. But if it was a bit more like Ben, he could barely make his way up the stairs, then I would actually proactively do a more shallow step-up regime, 30 mg for 3 days, 60 mg, 90 mg, and Ben will be fine because we’d sneak up on that event.

Joshua Bauml, MD: I’m glad Ben’s going to be fine.

Benjamin Levy, MD: Thank you. Are other people’s choice of therapy for ALK-positive disease, treatment naïve, is everyone debating between brigatinib or alectinib, more convinced with alectinib? Median PFS updated for the alectinib?

D. Ross Camidge, MD: Thirty four months.

Benjamin Levy, MD: Who would have thought 5 years ago, 3 years on that drug?

D. Ross Camidge, MD: We should point out, because we have a letter in the press from the ALEX investigators, that the median looks great. You need to remember, because it’s actually a plateau in the curve, it’s probably not the best thing, and the hazard ratio is much more important. The mature hazard ratio is 0.43. So that’s what brigatinib has got to try and beat.

Benjamin Levy, MD: Other people’s thoughts on how to manage upfront ALK-positive patients?

Robert Doebele, MD, PhD: Clearly alectinib and brigatinib are fantastic options with really outstanding CNS [central nervous system] control. I think both are very reasonable options. Again, alectinib is the current FDA-approved choice. I’m keeping my eye on the brigatinib data though.

Benjamin Levy, MD: One more question. Does the fusion partner matter up front on what you select? Are there any data on that?

D. Ross Camidge, MD: So far no. There were some interesting data on whether the variant within the EML4 mattered. But at least when we looked in ALEX in a larger data set, it didn’t seem to be statistically significantly different. There was some provocative data from your own center, but that was just, was it a single center? I can’t remember. Maybe you combined with a couple of other centers.

Zofia Piotrowska, MD: I believe it was single center, but don’t quote me on that.

Robert Doebele, MD, PhD: It seems to generate different resistance mechanisms, but it’s not clear yet whether that leads to PFS differences.

Transcript Edited for Clarity
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