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Sequencing Therapies for ALK-Rearranged NSCLC

Panelists: Benjamin P. Levy, MD, Johns Hopkins Sidney Kimmel Cancer Center; Hossein Borghaei, DO, MS, Fox Chase Cancer Center; Roy S. Herbst, MD, PhD, Yale Cancer Center; Suresh S. Ramalingam, MD, Emory University School of Medicine; Naiyer A. Rizvi, MD, Columbia University Medical Center; Thomas E. Stinchcombe, MD, Duke Cancer Institute
Published: Wednesday, Feb 28, 2018



Transcript: 

Benjamin P. Levy, MD: And just taking a step back, ALK testing in general, most people are doing IHC, NGS, FISH? What is the standard of the institutions?

Hossein Borghaei, DO, MS: Ours has been now sort of a standard, everybody gets a reflex testing, and we still do the FISH because that has been the established mechanism, but I think there are good data for IHC at this point.

Naiyer A. Rizvi, MD: Yes, IHC is an approved approach and we use IHC because it’s faster.

Roy S. Herbst, MD, PhD: Is it part of your next-generation profile, have you worked that in or you don’t have that?

Naiyer A. Rizvi, MD: But in terms of immediate results, I think that the IHC assay is much faster.

Roy S. Herbst, MD, PhD: See that’s the point. If you send the next-generation sequence off—we do the Oncomine at Yale now—it can take many weeks to come back. For us, there are 3 or 4 things that we need to know before we can treat.  So, you’re right, the IHC is, and then you can confirm it with FISH.

Benjamin P. Levy, MD: Right. As Suresh mentioned, this field has moved incredibly at a rapid pace. The discovery of ALK in 2007 and crizotinib being developed and approved in 2011 is one of the quickest times ever between the discovery of a mutation in the development of a drug. We have now, as mentioned, multiple ALK-directed therapies that are approved. One of them is brigatinib. We have data with brigatinib in the crizotinib-refractory space. Tom, do you want to talk to us about the brigatinib data because we’re trying to learn how to keep up with all these new drugs?

Thomas E. Stinchcombe, MD: It’s hard and it’s a dynamic landscape. Brigatinib is a very potent ALK inhibitor that has activity against many of the ALK-resistant mutations. And this was a randomized phase II trial in the post-crizotinib patient population that looked at 2 doses: 90 mg daily or 90 mg for 7 days followed by 180 mg daily. And what we found is the response rate is around 50% with both of those schedules, and the PFS in the 90-mg dose was around 9 months, and about 12 months in the 90-mg dose followed by 180 mg. And it was fairly well tolerated. We saw significant responses in the CMS.

This drug has a unique toxicity, early-onset pulmonary symptoms, and they can occur in about 5% of patients, generally in the first week. And that’s why you have to do the 90 mg per week and then dose escalate up to 180 mg as part of the toxicity management. I personally think the drug has a lot of promise but the post-crizotinib setting is not really the patient population that we’re seeing right now. Because now the question is, what’s the post selection of therapy and how are we treating those patients?

Naiyer A. Rizvi, MD: I remember I had one patient who got crizotinib first, then alectinib, and then brigatinib and actually had a pretty remarkable response to the brigatinib that lasted about 7 months.

Benjamin P. Levy, MD: And we need more data post alectinib. I think it’s nice to have post-crizotinib data. We had that with brigatinib, we’ve got that with ceritinib. We had that with alectinib, and they seem to have compared favorably, although the PFS with brigatinib post crizotinib is a little bit longer than the other 2 drugs. Has anybody used it in the treatment-naïve setting? It’s not approved in that way but has anybody used it?

Hossein Borghaei, DO, MS: I haven’t used in the treatment-naïve, no.

Roy S. Herbst, MD, PhD: It’s hard to do that with alectinib.

Thomas E. Stinchcombe, MD: There’s a phase III trial with the treatment-naïve, so I think that’s good. And I think Ram brought up the critical point, when we do these trials, it’s very important to get tissue because many times the people with the ALK mutations are going to be more susceptible to more potent ALK inhibition. But if they have a bypass track, they’re probably not going to get a lot of bang for their buck. With a hidden ALK pathway, it’s a little bit harder.

Benjamin P. Levy, MD: How do we interrogate post alectinib? Is it through plasma? Is it through rebiopsies? I think there are some ongoing data. Do people routinely do this in their practice?

Hossein Borghaei, DO, MS: Well, the couple of times that I’ve done the plasma have been a little bit of a setback because if a patient doesn’t have huge tumor burden and they have minor progression, you are unlikely to get a lot of information out of the serum-based assays. And you can correct me if I’m wrong, but that has been my general experience. So, I think in the patients like that, if you really are thinking about switching you might be obligated through a tumor biopsy, try to figure out what the mechanism of resistance is. I don’t know what everybody else is experiencing.

Suresh S. Ramalingam, MD: In the clinical trial setting, that’s good information to know. I think increasingly, I’m testing it even outside of a clinical trial. I want to know if the patient is G1202 or not because I might find a trial for that particular mutation. But for routine practice at this point, I would say that resistance mechanism will perhaps change therapy options. It’s soon to come in advance, I would say.

Benjamin P. Levy, MD: I think we need to mandate. Those trials, of course, mandate tissue and plasma, so we can understand how to direct these patients based on these mechanisms of resistance. The last drug that I’ll talk about is lorlatinib, which is yet another ALK-directed therapy that is quite potent. We had some data presented at ASCO last year, 2017—it has been updated—looking at lorlatinib in a highly pretreated group of patients. We have cohort 1, which was a group that was treatment-naïve and that was ALK therapy-naïve, and the response rate there was 90%.

That was a small number of patients, 30 patients, but 27 out of 30 responded. Interestingly though, the group, cohort 4 and 5, had either gotten 2 prior ALK-directed therapies or 3 prior ALK-directed therapies with or without chemotherapy, and those were fully combined in that group, 111 patients. And the response rate was north of 40%, which is pretty interesting to get that kind of response after that many ALK-directed therapies. Now, I don’t know which therapies were included there, but there was a PFS of around 7 months. Again, I think we’re trying to learn how to sequence these drugs. Lorlatinib certainly has activity against G1202R, probably the most potent activity against G1202R, so it might be a nice fit post alectinib. Any experience with lorlatinib thus far in the group?

Suresh S. Ramalingam, MD: So, I have used it, lorlatinib, as part of clinical trials and I found this to be a good drug. And the trial that you mentioned, the key number for patients with G1202, was the response rate was 58% with lorlatinib, which is incredible. And I think this drug will fill an important unmet need for ALK-positive patients when it becomes eventually available in clinical practice.

Roy S. Herbst, MD, PhD: Also, it’s very specific. Patients who have been on it have told me that the side effect profile is just very mild.

Benjamin P. Levy, MD: It’s got an interesting side effect with the hyperlipidemia. It has to be followed, but, other than that, I think that the drug…

Hossein Borghaei, DO, MS: The triglycerides, yes.

Thomas E. Stinchcombe, MD: And some CNS side effect, grade 1 or 2 or something.

Benjamin P. Levy, MD: So, we’ll just have to see. I think we have an embarrassment of riches in the ALK space, and we’ll have to better understand how to sequence these drugs. And the jury is still out, I think, but we’ve certainly made significant advances in this space over the past 5 years.

Transcript Edited for Clarity 

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Transcript: 

Benjamin P. Levy, MD: And just taking a step back, ALK testing in general, most people are doing IHC, NGS, FISH? What is the standard of the institutions?

Hossein Borghaei, DO, MS: Ours has been now sort of a standard, everybody gets a reflex testing, and we still do the FISH because that has been the established mechanism, but I think there are good data for IHC at this point.

Naiyer A. Rizvi, MD: Yes, IHC is an approved approach and we use IHC because it’s faster.

Roy S. Herbst, MD, PhD: Is it part of your next-generation profile, have you worked that in or you don’t have that?

Naiyer A. Rizvi, MD: But in terms of immediate results, I think that the IHC assay is much faster.

Roy S. Herbst, MD, PhD: See that’s the point. If you send the next-generation sequence off—we do the Oncomine at Yale now—it can take many weeks to come back. For us, there are 3 or 4 things that we need to know before we can treat.  So, you’re right, the IHC is, and then you can confirm it with FISH.

Benjamin P. Levy, MD: Right. As Suresh mentioned, this field has moved incredibly at a rapid pace. The discovery of ALK in 2007 and crizotinib being developed and approved in 2011 is one of the quickest times ever between the discovery of a mutation in the development of a drug. We have now, as mentioned, multiple ALK-directed therapies that are approved. One of them is brigatinib. We have data with brigatinib in the crizotinib-refractory space. Tom, do you want to talk to us about the brigatinib data because we’re trying to learn how to keep up with all these new drugs?

Thomas E. Stinchcombe, MD: It’s hard and it’s a dynamic landscape. Brigatinib is a very potent ALK inhibitor that has activity against many of the ALK-resistant mutations. And this was a randomized phase II trial in the post-crizotinib patient population that looked at 2 doses: 90 mg daily or 90 mg for 7 days followed by 180 mg daily. And what we found is the response rate is around 50% with both of those schedules, and the PFS in the 90-mg dose was around 9 months, and about 12 months in the 90-mg dose followed by 180 mg. And it was fairly well tolerated. We saw significant responses in the CMS.

This drug has a unique toxicity, early-onset pulmonary symptoms, and they can occur in about 5% of patients, generally in the first week. And that’s why you have to do the 90 mg per week and then dose escalate up to 180 mg as part of the toxicity management. I personally think the drug has a lot of promise but the post-crizotinib setting is not really the patient population that we’re seeing right now. Because now the question is, what’s the post selection of therapy and how are we treating those patients?

Naiyer A. Rizvi, MD: I remember I had one patient who got crizotinib first, then alectinib, and then brigatinib and actually had a pretty remarkable response to the brigatinib that lasted about 7 months.

Benjamin P. Levy, MD: And we need more data post alectinib. I think it’s nice to have post-crizotinib data. We had that with brigatinib, we’ve got that with ceritinib. We had that with alectinib, and they seem to have compared favorably, although the PFS with brigatinib post crizotinib is a little bit longer than the other 2 drugs. Has anybody used it in the treatment-naïve setting? It’s not approved in that way but has anybody used it?

Hossein Borghaei, DO, MS: I haven’t used in the treatment-naïve, no.

Roy S. Herbst, MD, PhD: It’s hard to do that with alectinib.

Thomas E. Stinchcombe, MD: There’s a phase III trial with the treatment-naïve, so I think that’s good. And I think Ram brought up the critical point, when we do these trials, it’s very important to get tissue because many times the people with the ALK mutations are going to be more susceptible to more potent ALK inhibition. But if they have a bypass track, they’re probably not going to get a lot of bang for their buck. With a hidden ALK pathway, it’s a little bit harder.

Benjamin P. Levy, MD: How do we interrogate post alectinib? Is it through plasma? Is it through rebiopsies? I think there are some ongoing data. Do people routinely do this in their practice?

Hossein Borghaei, DO, MS: Well, the couple of times that I’ve done the plasma have been a little bit of a setback because if a patient doesn’t have huge tumor burden and they have minor progression, you are unlikely to get a lot of information out of the serum-based assays. And you can correct me if I’m wrong, but that has been my general experience. So, I think in the patients like that, if you really are thinking about switching you might be obligated through a tumor biopsy, try to figure out what the mechanism of resistance is. I don’t know what everybody else is experiencing.

Suresh S. Ramalingam, MD: In the clinical trial setting, that’s good information to know. I think increasingly, I’m testing it even outside of a clinical trial. I want to know if the patient is G1202 or not because I might find a trial for that particular mutation. But for routine practice at this point, I would say that resistance mechanism will perhaps change therapy options. It’s soon to come in advance, I would say.

Benjamin P. Levy, MD: I think we need to mandate. Those trials, of course, mandate tissue and plasma, so we can understand how to direct these patients based on these mechanisms of resistance. The last drug that I’ll talk about is lorlatinib, which is yet another ALK-directed therapy that is quite potent. We had some data presented at ASCO last year, 2017—it has been updated—looking at lorlatinib in a highly pretreated group of patients. We have cohort 1, which was a group that was treatment-naïve and that was ALK therapy-naïve, and the response rate there was 90%.

That was a small number of patients, 30 patients, but 27 out of 30 responded. Interestingly though, the group, cohort 4 and 5, had either gotten 2 prior ALK-directed therapies or 3 prior ALK-directed therapies with or without chemotherapy, and those were fully combined in that group, 111 patients. And the response rate was north of 40%, which is pretty interesting to get that kind of response after that many ALK-directed therapies. Now, I don’t know which therapies were included there, but there was a PFS of around 7 months. Again, I think we’re trying to learn how to sequence these drugs. Lorlatinib certainly has activity against G1202R, probably the most potent activity against G1202R, so it might be a nice fit post alectinib. Any experience with lorlatinib thus far in the group?

Suresh S. Ramalingam, MD: So, I have used it, lorlatinib, as part of clinical trials and I found this to be a good drug. And the trial that you mentioned, the key number for patients with G1202, was the response rate was 58% with lorlatinib, which is incredible. And I think this drug will fill an important unmet need for ALK-positive patients when it becomes eventually available in clinical practice.

Roy S. Herbst, MD, PhD: Also, it’s very specific. Patients who have been on it have told me that the side effect profile is just very mild.

Benjamin P. Levy, MD: It’s got an interesting side effect with the hyperlipidemia. It has to be followed, but, other than that, I think that the drug…

Hossein Borghaei, DO, MS: The triglycerides, yes.

Thomas E. Stinchcombe, MD: And some CNS side effect, grade 1 or 2 or something.

Benjamin P. Levy, MD: So, we’ll just have to see. I think we have an embarrassment of riches in the ALK space, and we’ll have to better understand how to sequence these drugs. And the jury is still out, I think, but we’ve certainly made significant advances in this space over the past 5 years.

Transcript Edited for Clarity 
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