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Emerging Trends and Combination Therapies for ALK+ NSCLC

Insights From: Robert C. Doebele, MD, PhD, University of Colorado School of Medicine; Thomas E. Stinchcombe, MD, Duke Cancer Center; David Spigel, MD, Sarah Cannon Research Institute
Published: Tuesday, Aug 13, 2019



Transcript: 

David Spigel, MD: The natural evolution of cancer drug development is to take great drugs and see if you can put them together. We see that all the time with chemotherapies. We see that now with immunotherapeutics, and chemotherapy, or I/O-I/O [immuno-oncology]. It’s natural to wonder what to do with folks who are on ALK-directed therapies. Should we use them as single agents? Should we combine them with chemotherapies? I mentioned that some of my colleagues like to keep the ALK therapy going even after progression, and then add in chemotherapy. Should immunotherapy play a role in any of these strategies?

This is all being actively investigated, and it’s easier to tell you about what not to do than what to do. For example, we know from an early work with crizotinib and nivolumab that you can get hepatic toxicity quickly. We know that some immunotherapies and ALK inhibitors can result in pneumonitis. I don’t think it’s as easy as we thought it would be to combine an ALK TKI [tyrosine kinase inhibitor] with some of the newer strategies that we have available. Chemotherapy seems to work OK and seems to be safe to do. We just don’t know if you should do it.

The data we have from IMPRESS in the EGFR setting [tell] us that if you progress on a drug like an EGFR TKI, you should stop it and move on to, in this case, chemotherapy, not continue it and add chemotherapy. Yet we’re asking those same questions right now in the ALK setting. We just don’t have data to tell us what to do. I do think there will be some combination strategies in the future. Chemotherapy seems to be the 1 that’s likely—the soonest strategy I think we would see. But I imagine there will be some other novel targeted therapy, perhaps an immunotherapy strategy at some point with 1 of these ALK inhibitors. But it is hard to see that happening easily right now because of toxicity concerns.

Robert C. Doebele, MD, PhD: It’s important to consider whether there are other strategies to better treat our ALK-positive patients now that we’re seeing significant activity with alectinib, brigatinib, and lorlatinib. One question that arises is whether we’re getting diminishing returns with multiple sequential ALK TKIs and whether we should consider combination strategies. One way to consider this would be an ALK TKI plus an immune checkpoint inhibitor. Studies presented last year demonstrate perhaps no better efficacy and some concerns about toxicity in term; for example, crizotinib plus a checkpoint inhibitor demonstrated significant hepatotoxicity. I think that gives us pause. I think it’s still meaningful to evaluate these combinations.

The other reason it’s important to consider combinations is that we’ve discussed that 1 of the key mechanisms of resistance to these drugs outside ALK kinase immune mutations is bypass signaling. And we think that the most effective way to treat bypass signaling is to treat both the ALK signaling component, as well as the new bypass signaling component, and trying to understand what are the dominant resistance pathways that emerge and what drugs we may use to combine in the future. I think that will be an emerging area of study.

Thomas E. Stinchcombe, MD: As the field moves forward, 1 of the questions is which subset of patients are going to have really remarkable durable benefit from the ALK TKIs alone. We’re talking, 3 or 4 years of progression-free survival benefit, or is there a subset of patients who are more prone to early disease progression. And those patients may be better candidates for maybe dual therapy. And I think the question really is, which group of patients are going to be candidates for dual-drug therapy at this point?

I think the goal is that we’ll have around 100% testing in the nonsquamous patient population. I think the methods may vary in terms of different practice locations, practice patterns, tissue availability. And I think we really want to improve our testing compliance at this point. I say that, but I also recognize [that] at times patients may not be a candidate for treatment of any sort; therefore, we’ll never reach that goal of 100% compliance. But we really would like to see most patients tested, not just for the ALK-rearrangement but for other targeted therapies, such as EGFR mutation. I think we’re really looking for more comprehensive testing and higher compliance.

David Spigel, MD: My best advice for my colleagues in the community for treating ALK-positive lung cancer is to pick up the phone and ask a question. I do it for questions all the time in areas that I’m not familiar with. I think you might have some familiarity, but it’s OK to pick up the phone and reach out and get a question answered in 5 seconds rather than just trying to figure it out through an article or reading UpToDate. I mean, you should do those things and you should be as knowledgeable as you can be. But I guess what I’m saying is you should feel comfortable to ask questions. There’s going to be somebody at your center, your region, or heck, across the world who would be happy to help answer an e-mail or a text or a quick phone call about, “Should I do this? Should I start this? How would you handle this problem?” That can save you a lot of grief and anguish, and get an answer from somebody who perhaps has been there already.

Robert C. Doebele, MD, PhD: Perhaps the most important impact we can have on our ALK-positive patients is to identify them. I think testing is the most critical thing. We know that ALK-positive patients come in all shapes, sizes, age, and so forth. And so we really need to be testing all our non–small cell lung cancer patients, particularly those with nonsquamous histology for ALK, because we really want to have that treatment available for those patients, and the only way to do that is to identify them.

Transcript Edited for Clarity
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Transcript: 

David Spigel, MD: The natural evolution of cancer drug development is to take great drugs and see if you can put them together. We see that all the time with chemotherapies. We see that now with immunotherapeutics, and chemotherapy, or I/O-I/O [immuno-oncology]. It’s natural to wonder what to do with folks who are on ALK-directed therapies. Should we use them as single agents? Should we combine them with chemotherapies? I mentioned that some of my colleagues like to keep the ALK therapy going even after progression, and then add in chemotherapy. Should immunotherapy play a role in any of these strategies?

This is all being actively investigated, and it’s easier to tell you about what not to do than what to do. For example, we know from an early work with crizotinib and nivolumab that you can get hepatic toxicity quickly. We know that some immunotherapies and ALK inhibitors can result in pneumonitis. I don’t think it’s as easy as we thought it would be to combine an ALK TKI [tyrosine kinase inhibitor] with some of the newer strategies that we have available. Chemotherapy seems to work OK and seems to be safe to do. We just don’t know if you should do it.

The data we have from IMPRESS in the EGFR setting [tell] us that if you progress on a drug like an EGFR TKI, you should stop it and move on to, in this case, chemotherapy, not continue it and add chemotherapy. Yet we’re asking those same questions right now in the ALK setting. We just don’t have data to tell us what to do. I do think there will be some combination strategies in the future. Chemotherapy seems to be the 1 that’s likely—the soonest strategy I think we would see. But I imagine there will be some other novel targeted therapy, perhaps an immunotherapy strategy at some point with 1 of these ALK inhibitors. But it is hard to see that happening easily right now because of toxicity concerns.

Robert C. Doebele, MD, PhD: It’s important to consider whether there are other strategies to better treat our ALK-positive patients now that we’re seeing significant activity with alectinib, brigatinib, and lorlatinib. One question that arises is whether we’re getting diminishing returns with multiple sequential ALK TKIs and whether we should consider combination strategies. One way to consider this would be an ALK TKI plus an immune checkpoint inhibitor. Studies presented last year demonstrate perhaps no better efficacy and some concerns about toxicity in term; for example, crizotinib plus a checkpoint inhibitor demonstrated significant hepatotoxicity. I think that gives us pause. I think it’s still meaningful to evaluate these combinations.

The other reason it’s important to consider combinations is that we’ve discussed that 1 of the key mechanisms of resistance to these drugs outside ALK kinase immune mutations is bypass signaling. And we think that the most effective way to treat bypass signaling is to treat both the ALK signaling component, as well as the new bypass signaling component, and trying to understand what are the dominant resistance pathways that emerge and what drugs we may use to combine in the future. I think that will be an emerging area of study.

Thomas E. Stinchcombe, MD: As the field moves forward, 1 of the questions is which subset of patients are going to have really remarkable durable benefit from the ALK TKIs alone. We’re talking, 3 or 4 years of progression-free survival benefit, or is there a subset of patients who are more prone to early disease progression. And those patients may be better candidates for maybe dual therapy. And I think the question really is, which group of patients are going to be candidates for dual-drug therapy at this point?

I think the goal is that we’ll have around 100% testing in the nonsquamous patient population. I think the methods may vary in terms of different practice locations, practice patterns, tissue availability. And I think we really want to improve our testing compliance at this point. I say that, but I also recognize [that] at times patients may not be a candidate for treatment of any sort; therefore, we’ll never reach that goal of 100% compliance. But we really would like to see most patients tested, not just for the ALK-rearrangement but for other targeted therapies, such as EGFR mutation. I think we’re really looking for more comprehensive testing and higher compliance.

David Spigel, MD: My best advice for my colleagues in the community for treating ALK-positive lung cancer is to pick up the phone and ask a question. I do it for questions all the time in areas that I’m not familiar with. I think you might have some familiarity, but it’s OK to pick up the phone and reach out and get a question answered in 5 seconds rather than just trying to figure it out through an article or reading UpToDate. I mean, you should do those things and you should be as knowledgeable as you can be. But I guess what I’m saying is you should feel comfortable to ask questions. There’s going to be somebody at your center, your region, or heck, across the world who would be happy to help answer an e-mail or a text or a quick phone call about, “Should I do this? Should I start this? How would you handle this problem?” That can save you a lot of grief and anguish, and get an answer from somebody who perhaps has been there already.

Robert C. Doebele, MD, PhD: Perhaps the most important impact we can have on our ALK-positive patients is to identify them. I think testing is the most critical thing. We know that ALK-positive patients come in all shapes, sizes, age, and so forth. And so we really need to be testing all our non–small cell lung cancer patients, particularly those with nonsquamous histology for ALK, because we really want to have that treatment available for those patients, and the only way to do that is to identify them.

Transcript Edited for Clarity
View Conference Coverage
Online CME Activities
TitleExpiration DateCME Credits
Advances in™ Therapies for Patients With ALK-Positive Lung Cancers: More Options…More Decisions…Better OutcomesAug 30, 20191.5
Oncology Briefings™: Treating Advanced NSCLC Without Actionable MutationsAug 30, 20191.0
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