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Sequencing Therapy in ALK+ NSCLC

Panelists: Charu Aggarwal, MD, MPH, Hospital of the University of Pennsylvania; Hossein Borghaei, DO, Fox Chase Cancer Center; H. Jack West, MD, Swedish Cancer Institute
Published: Tuesday, Feb 26, 2019



Transcript:

H. Jack West, MD:
When do you turn from ALK-directed therapy to chemotherapy? Particularly, let’s dispense with crizotinib. The second-generation agents are more effective, but do you have any confidence that brigatinib after alectinib is a high-yield change, or would you go straight to lorlatinib? Or when do you stop going to the well, move to chemotherapy, and maybe come back to an ALK inhibitor therapy later?

Hossein Borghaei, DO: So that’s a difficult question you’re asking, again because we don’t really have clear data to guide us. I think if I’m done with alectinib and I don’t think we’re going to get any more clinical efficacy, my first choice would be to use lorlatinib because I think the data in that setting are much stronger with that particular agent. But, as far as when to go to chemotherapy and all of that, there are a couple of scenarios. (A) I’ve gone through 2 or 3 TKIs [tyrosine kinase inhibitors], and all I get is progression after progression. It gets to a point where the tumor burden is too much or the patient is symptomatic, and you want to get some disease reduction and reduction of the tumor burden.

So, clearly, I pull the trigger on chemotherapy. Again, this is another patient population that benefits from the platinum doublet, based on all of the data that we have using pemetrexed. So there is constant monitoring of the patient on TKIs to see whether they’re having responses or not, and, if they’re not and are getting into trouble, going to chemotherapy is the way I would normally do it. And, again, the whole issue with brain metastases becomes of paramount importance here and how you have to continue to monitor. If they’re progressing systemically and you’re going from one TKI to another, it’s likely that there could be brain progression, and you don’t want to miss that. So I think it just makes management of this patient population a little bit more challenging in the absence of clear data.

H. Jack West, MD: I think you raise a great point. We have reached a consensus, I think. For patients with brain metastases at the time of diagnoses, at least asymptomatic, if they have a driver mutation, and specifically are ALK-positive, we are increasingly confident that alectinib, brigatinib, and lorlatinib all have good CNS [central nervous system] activity, and we don’t need to rush them to the radiation oncologist. But how does having somebody with a history of controlled brain metastases who’s now progressing shape your choice of whether or if to move to chemotherapy, where you may not have that? Or are you inclined to try to give both concurrently for these patients with an intracranial component of disease that’s as much of a concern as the extracranial?

Charu Aggarwal, MD, MH: That’s a very good question. Fortunately, it hasn’t come up yet in my clinical practice, where I’ve had to think about continuing the TKI with chemotherapy. I think they’ve just had such florid progression. Either they’ve just had such florid progression that I’ve had to abandon one approach and go to the other, or they have not yet had such florid progression where I could just continue with the TKI and add in radiation, for example, for oligoprogression with the oligoprogression paradigm. If I were to be in that situation, I just don’t know whether I have the data to safely deliver both chemotherapy and, let’s say, alectinib or lorlatinib. I could presumably do it with very close follow-up, but that would be in a completely data-free zone.

H. Jack West, MD: Right, that’s true. It’s tough, and I think that having to worry a lot about intracranial disease would factor into our decisions about how long to stay in the EGFR-directed axis versus switching to chemotherapy. If we know that patients are at high risk for intracranial progression, we might linger longer with additional ALK inhibitor therapy. At least that’s my view on it.

There have been very little data on ALK-positive patients and their responsiveness to immunotherapy. Much of what scant information there is has been aggregating them with EGFR mutation–positive patients. I would say, though, that we’re getting a clearer sense that these are not the same population. They’re distinct, and the ALK-positive patients, even with high PD-L1, are especially unlikely to benefit from immunotherapy. So what’s your approach to how or whether to use immunotherapy for the ALK-positive patients?

Charu Aggarwal, MD, MH: So, again, I think we are blessed to have several different TKIs to choose from. With the recent approval of lorlatinib, that’s usually what we will go to in the second-line or third-line setting. I’m less inclined to use immunotherapy because of the paucity of data. I think if I were in a situation where I’ve gone through 2 or 3 TKIs and now I’m in a setting where I have to use systemic therapy, I would prefer to use chemotherapy over an I-O [immune-oncology] agent, even if their PD-L1 level is high.

H. Jack West, MD: Would you be inclined to do a chemotherapy/I-O or a chemotherapy/bevacizumab/I-O combination for the ALK-positives, based on the IMpower150 trial?

Charu Aggarwal, MD, MH: I think chemotherapy/bevacizumab/I-O would probably be a data-driven approach. I mean, it’s a subset analysis that included ALK- and EGFR-mutant patients. So I think that could be theoretically and practically delivered, and feasibly.

Hossein Borghaei, DO: Yeah, I think it’s pretty much the same discussion we have with the EGFR patient population, and I don’t feel comfortable with single-agent I-O. I would consider chemotherapy/I-O plus bevacizumab, possibly, as an option. I would also still argue that platinum doublet chemotherapy in this patient population, post multiple TKIs, is still a very good option. And, again, if there’s a trial that combines a couple of different I-O agents, I think that would be my preference if I’m going to go toward I-O.

H. Jack West, MD: We’ve mentioned lorlatinib, already now FDA approved and with good data, not just in the minimally treated patients but even in several patients who have had 2, 3, or more ALK inhibitors. Do you have experience using lorlatinib? And, if so, what’s been your experience in terms of tolerability issues? How broadly feasible is this, or are there toxicity concerns that community oncologists need to be aware of?

Charu Aggarwal, MD, MH: I’ve used it on a trial. So far, I have not used it since the FDA approval. And I have not really had major success with it, unfortunately, just because I think it was in a much later line of therapy. It was on a compassionate-use basis. And the patient was not on it long enough for me to really tease out the tolerability issues over time.

Hossein Borghaei, DO: We’ve had the study open also, but I didn’t really have a patient on this drug. I don’t have any personal experience in dealing with it, but I know through talking to my colleagues that it seems to be a very easy drug to tolerate. There are minimal toxicities. So, again, it looks like it’s a viable option.

H. Jack West, MD: Yeah, I’ve used it in a limited capacity. I would not say it’s nontoxic. There are different toxicities. We know of the lipids, weight gain, and sometimes there are mental status confusion issues. So nothing insurmountable, but there is a learning curve to it. So that will be a bit of a challenge, I think, especially in a setting where most oncologists are not going to see a lot of these patients and have much experience using this. It’s great to have another option available, especially one where you can see good activity even in such extensively treated patients.

This has been extremely informative. Before we end the discussion, I’d like to get closing thoughts from each of you. Dr Aggarwal?

Charu Aggarwal, MD, MH: I would just say that this is an exciting time to be a lung cancer oncologist. Every other week, every other month, we get another approval or we get another study that changes practice. I don’t think in the past 10 years this has ever happened before, so more to come.

H. Jack West, MD: Yep. Dr Borghaei?

Hossein Borghaei, DO: I agree. I think it’s a very exciting time to be a thoracic oncologist because of all of the options that we have. You really get the sense that you are beginning to help patients have a better quality of life, live a little bit longer, and, hopefully, advance the science. I do feel bad for our colleagues on the NCCN [National Comprehensive Cancer Network] guidelines. They have to update the data almost constantly, but that’s a great thing. That’s a great problem to have.

H. Jack West, MD: That is a real champagne problem there. I think it’s been amazing that in our time doing this, managing even metastatic non–small cell disease has gone from being an expectation of typically just months, and you take the gains where you get them, to now having the majority of our patients living beyond a year and thinking more about years of benefit, which is great, let alone the potential for curing more patients. As you bring up, we are having advances at such a terrific pace. It’s been dizzying, and it’s great, but it makes it even more of a challenge to get that information out to a broader population of general oncologists who are seeing 10 or 15 kinds of cancer a day. Very important, but it’s, again, a great challenge to have.

Thank you all for your contributions to the discussion. On behalf of our panel, we thank you for joining us, and we hope you found this OncLive Peer Exchange® to be useful and informative.

Transcript edited for clarity.

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Transcript:

H. Jack West, MD:
When do you turn from ALK-directed therapy to chemotherapy? Particularly, let’s dispense with crizotinib. The second-generation agents are more effective, but do you have any confidence that brigatinib after alectinib is a high-yield change, or would you go straight to lorlatinib? Or when do you stop going to the well, move to chemotherapy, and maybe come back to an ALK inhibitor therapy later?

Hossein Borghaei, DO: So that’s a difficult question you’re asking, again because we don’t really have clear data to guide us. I think if I’m done with alectinib and I don’t think we’re going to get any more clinical efficacy, my first choice would be to use lorlatinib because I think the data in that setting are much stronger with that particular agent. But, as far as when to go to chemotherapy and all of that, there are a couple of scenarios. (A) I’ve gone through 2 or 3 TKIs [tyrosine kinase inhibitors], and all I get is progression after progression. It gets to a point where the tumor burden is too much or the patient is symptomatic, and you want to get some disease reduction and reduction of the tumor burden.

So, clearly, I pull the trigger on chemotherapy. Again, this is another patient population that benefits from the platinum doublet, based on all of the data that we have using pemetrexed. So there is constant monitoring of the patient on TKIs to see whether they’re having responses or not, and, if they’re not and are getting into trouble, going to chemotherapy is the way I would normally do it. And, again, the whole issue with brain metastases becomes of paramount importance here and how you have to continue to monitor. If they’re progressing systemically and you’re going from one TKI to another, it’s likely that there could be brain progression, and you don’t want to miss that. So I think it just makes management of this patient population a little bit more challenging in the absence of clear data.

H. Jack West, MD: I think you raise a great point. We have reached a consensus, I think. For patients with brain metastases at the time of diagnoses, at least asymptomatic, if they have a driver mutation, and specifically are ALK-positive, we are increasingly confident that alectinib, brigatinib, and lorlatinib all have good CNS [central nervous system] activity, and we don’t need to rush them to the radiation oncologist. But how does having somebody with a history of controlled brain metastases who’s now progressing shape your choice of whether or if to move to chemotherapy, where you may not have that? Or are you inclined to try to give both concurrently for these patients with an intracranial component of disease that’s as much of a concern as the extracranial?

Charu Aggarwal, MD, MH: That’s a very good question. Fortunately, it hasn’t come up yet in my clinical practice, where I’ve had to think about continuing the TKI with chemotherapy. I think they’ve just had such florid progression. Either they’ve just had such florid progression that I’ve had to abandon one approach and go to the other, or they have not yet had such florid progression where I could just continue with the TKI and add in radiation, for example, for oligoprogression with the oligoprogression paradigm. If I were to be in that situation, I just don’t know whether I have the data to safely deliver both chemotherapy and, let’s say, alectinib or lorlatinib. I could presumably do it with very close follow-up, but that would be in a completely data-free zone.

H. Jack West, MD: Right, that’s true. It’s tough, and I think that having to worry a lot about intracranial disease would factor into our decisions about how long to stay in the EGFR-directed axis versus switching to chemotherapy. If we know that patients are at high risk for intracranial progression, we might linger longer with additional ALK inhibitor therapy. At least that’s my view on it.

There have been very little data on ALK-positive patients and their responsiveness to immunotherapy. Much of what scant information there is has been aggregating them with EGFR mutation–positive patients. I would say, though, that we’re getting a clearer sense that these are not the same population. They’re distinct, and the ALK-positive patients, even with high PD-L1, are especially unlikely to benefit from immunotherapy. So what’s your approach to how or whether to use immunotherapy for the ALK-positive patients?

Charu Aggarwal, MD, MH: So, again, I think we are blessed to have several different TKIs to choose from. With the recent approval of lorlatinib, that’s usually what we will go to in the second-line or third-line setting. I’m less inclined to use immunotherapy because of the paucity of data. I think if I were in a situation where I’ve gone through 2 or 3 TKIs and now I’m in a setting where I have to use systemic therapy, I would prefer to use chemotherapy over an I-O [immune-oncology] agent, even if their PD-L1 level is high.

H. Jack West, MD: Would you be inclined to do a chemotherapy/I-O or a chemotherapy/bevacizumab/I-O combination for the ALK-positives, based on the IMpower150 trial?

Charu Aggarwal, MD, MH: I think chemotherapy/bevacizumab/I-O would probably be a data-driven approach. I mean, it’s a subset analysis that included ALK- and EGFR-mutant patients. So I think that could be theoretically and practically delivered, and feasibly.

Hossein Borghaei, DO: Yeah, I think it’s pretty much the same discussion we have with the EGFR patient population, and I don’t feel comfortable with single-agent I-O. I would consider chemotherapy/I-O plus bevacizumab, possibly, as an option. I would also still argue that platinum doublet chemotherapy in this patient population, post multiple TKIs, is still a very good option. And, again, if there’s a trial that combines a couple of different I-O agents, I think that would be my preference if I’m going to go toward I-O.

H. Jack West, MD: We’ve mentioned lorlatinib, already now FDA approved and with good data, not just in the minimally treated patients but even in several patients who have had 2, 3, or more ALK inhibitors. Do you have experience using lorlatinib? And, if so, what’s been your experience in terms of tolerability issues? How broadly feasible is this, or are there toxicity concerns that community oncologists need to be aware of?

Charu Aggarwal, MD, MH: I’ve used it on a trial. So far, I have not used it since the FDA approval. And I have not really had major success with it, unfortunately, just because I think it was in a much later line of therapy. It was on a compassionate-use basis. And the patient was not on it long enough for me to really tease out the tolerability issues over time.

Hossein Borghaei, DO: We’ve had the study open also, but I didn’t really have a patient on this drug. I don’t have any personal experience in dealing with it, but I know through talking to my colleagues that it seems to be a very easy drug to tolerate. There are minimal toxicities. So, again, it looks like it’s a viable option.

H. Jack West, MD: Yeah, I’ve used it in a limited capacity. I would not say it’s nontoxic. There are different toxicities. We know of the lipids, weight gain, and sometimes there are mental status confusion issues. So nothing insurmountable, but there is a learning curve to it. So that will be a bit of a challenge, I think, especially in a setting where most oncologists are not going to see a lot of these patients and have much experience using this. It’s great to have another option available, especially one where you can see good activity even in such extensively treated patients.

This has been extremely informative. Before we end the discussion, I’d like to get closing thoughts from each of you. Dr Aggarwal?

Charu Aggarwal, MD, MH: I would just say that this is an exciting time to be a lung cancer oncologist. Every other week, every other month, we get another approval or we get another study that changes practice. I don’t think in the past 10 years this has ever happened before, so more to come.

H. Jack West, MD: Yep. Dr Borghaei?

Hossein Borghaei, DO: I agree. I think it’s a very exciting time to be a thoracic oncologist because of all of the options that we have. You really get the sense that you are beginning to help patients have a better quality of life, live a little bit longer, and, hopefully, advance the science. I do feel bad for our colleagues on the NCCN [National Comprehensive Cancer Network] guidelines. They have to update the data almost constantly, but that’s a great thing. That’s a great problem to have.

H. Jack West, MD: That is a real champagne problem there. I think it’s been amazing that in our time doing this, managing even metastatic non–small cell disease has gone from being an expectation of typically just months, and you take the gains where you get them, to now having the majority of our patients living beyond a year and thinking more about years of benefit, which is great, let alone the potential for curing more patients. As you bring up, we are having advances at such a terrific pace. It’s been dizzying, and it’s great, but it makes it even more of a challenge to get that information out to a broader population of general oncologists who are seeing 10 or 15 kinds of cancer a day. Very important, but it’s, again, a great challenge to have.

Thank you all for your contributions to the discussion. On behalf of our panel, we thank you for joining us, and we hope you found this OncLive Peer Exchange® to be useful and informative.

Transcript edited for clarity.
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