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Future Directions for Treatment of Lung Adenocarcinoma

Panelists: Mark A. Socinski, MD, Florida Hospital Cancer Institute; Mark Kris, MD, Memorial Sloan-Kettering; Jared Weiss, MD, UNC Lineberger Comprehensive Cancer Center; Ross Camidge, MD, PhD, University of Colorado Cancer Center; David R. Spigel, MD, Sarah Cannon Research Institute
Published: Thursday, Aug 03, 2017



Transcript:

Mark A. Socinski, MD: Is there anything to be gained? In the EGFR space, we looked for T790M. Is there anything to be gained in this space looking for the various secondary mutations? Here, they occur with greater frequency after crizotinib. Is it informative? If you’ve got 2 or 3 drugs, are you likely to use one based upon the information you learn on retesting?

Ross Camidge, MD, PhD: I think the jury is still out on this. I think there’s some very nice preclinical work where you can get a table saying, with the IC50 or the IC90, I can color-code by boxes. But it’s somewhat misleading. If you look at some of these figures, it’s completely arbitrary: Why is this number, 49.9, green, where this number is 50.1 and it’s orange? In an individual patient—to go back to the take-home message you’ve been hammering—it depends on what their exposure is, because they’re not a petri dish. The other thing is that in an individual patient, you may have multiple mutations. So, this isn’t T790M. This is a much more complex situation. Multiple mutations can coexist in the same patient and may even coexist in the same gene. I think that’s still being researched—the so-called ALK master protocol is attempting to address that. But I think at the moment there is no call at all for somebody in the community to rebiopsy and say, “You’ve got this, therefore you need that.”

David R. Spigel, MD: We just had a patient who had been on ceritinib for 3 years, and when we originally biopsied her, all we knew was that she was ALK-positive by FISH. But I rebiopsied her recently, and we found a BRAF-activating mutation and no ALK.

Mark A. Socinski, MD: What did you do?

David R. Spigel, MD: We’re working on trying to get her vemurafenib and cobimetinib, but my registrar in Tennessee probably won’t be able to pull that off.

Mark A. Socinski, MD: Obviously, when most of us trained, we did a single biopsy at the time of diagnosis. If we’ve learned anything, it’s that this is an incredibly heterogeneous group of patients. When you start to do these rebiopsies and you find something like this, it almost makes you afraid of how much you don’t know, you don’t rebiopsy, and these sorts of things. So, it’s a complicated time.

Ross Camidge, MD, PhD: I’d like rein in my definitive “You should never do a biopsy,” because I think if you put somebody on a drug and they’re doing well, you save them a biopsy. But if you put somebody on a drug and they’re just blowing through it or not doing what you think, then you should go find something.

Mark G. Kris, MD: Then you should look for something else.

David R. Spigel, MD: Have you used brigatinib in the ROS setting at all?

Ross Camidge, MD, PhD: In the original phase I, but the numbers were very small.

Mark G. Kris, MD: Yes. Can I just make a comment about biopsies? One thing about the immunotherapy trials, they’ve totally changed the environment on biopsies. This idea that you can’t get a biopsy or a rebiopsy—there must be 5 to 10,000 biopsies done in those trials, yes? So, it’s over. I must say that they’re a lot safer, quicker to get, and, when in doubt, I would biopsy.

David R. Spigel, MD: Not to get too far into that, what used to be really all cores for us—guided cores and interventional—are now this navigational bronchoscopy using a corelike needle. It’s so much easier, and we’re getting everything we need to know to interrogate the tumor.

Mark A. Socinski, MD: So, Ross, you mentioned lorlatinib. Are there other agents on the horizon?

Ross Camidge, MD, PhD: There’s another so-called next-generation inhibitor, which is a much smaller molecule that’s supposed to fit into the kinase better, made by a company called Turning Point—TPX-0005. There’s also ensartinib, which came out of the same team that designed crizotinib. And they actually are, along with brigatinib and lorlatinib, doing head-to-heads against crizotinib in the first-line setting.

Mark A. Socinski, MD: We’re almost out of time. I think this has been extremely informative. Before we end this discussion, I’d like to get final thoughts from each of our panelists. I’ll start with Dr Camidge—what are your final thoughts?

Ross Camidge, MD, PhD: It is a changing field, and it’s very exciting. It’s slightly exhausting, but it’s all for the benefit of the patients.

Mark A. Socinski, MD: Mark?

Mark G. Kris, MD: I just encourage people to sit down when you’re making a decision, with every patient, and look at every single modality available, and see with all of those modalities, which ones are best for that patient on that day. Even consider things that are outside the box, like radiation, surgery—things that we would never have done 10 years ago, we’re doing now, and they can help individual patients. So, just make sure you think of everything. Don’t do everything, but at least think about it.

Mark A. Socinski, MD: Dr. Spigel?

David R. Spigel, MD: I just echo this excitement, not only for us in research but also for patients and families. It’s just a tremendous time to be able to help people and know that there are many options, not just immunotherapy or targeted therapy, but also the diagnostics have improved tremendously in even our radiation therapy and surgical approaches. So, there are a lot of reasons to be hopeful.

Mark A. Socinski, MD: And last but not least…

Jared Weiss, MD: We’ve had a very informative conversation today about some very advanced new treatments that are biomarker dependent. So, I’ll end with a final thought: You don’t know if you don’t test. We still have very high rates of nontesting in this country, even for EGFR. And so, I would end with a final thought to do all appropriate testing—meaning PD-L1 on all patients in the frontline setting and comprehensive molecular testing for all nonsquamous patients.

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

Transcript Edited for Clarity

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Transcript:

Mark A. Socinski, MD: Is there anything to be gained? In the EGFR space, we looked for T790M. Is there anything to be gained in this space looking for the various secondary mutations? Here, they occur with greater frequency after crizotinib. Is it informative? If you’ve got 2 or 3 drugs, are you likely to use one based upon the information you learn on retesting?

Ross Camidge, MD, PhD: I think the jury is still out on this. I think there’s some very nice preclinical work where you can get a table saying, with the IC50 or the IC90, I can color-code by boxes. But it’s somewhat misleading. If you look at some of these figures, it’s completely arbitrary: Why is this number, 49.9, green, where this number is 50.1 and it’s orange? In an individual patient—to go back to the take-home message you’ve been hammering—it depends on what their exposure is, because they’re not a petri dish. The other thing is that in an individual patient, you may have multiple mutations. So, this isn’t T790M. This is a much more complex situation. Multiple mutations can coexist in the same patient and may even coexist in the same gene. I think that’s still being researched—the so-called ALK master protocol is attempting to address that. But I think at the moment there is no call at all for somebody in the community to rebiopsy and say, “You’ve got this, therefore you need that.”

David R. Spigel, MD: We just had a patient who had been on ceritinib for 3 years, and when we originally biopsied her, all we knew was that she was ALK-positive by FISH. But I rebiopsied her recently, and we found a BRAF-activating mutation and no ALK.

Mark A. Socinski, MD: What did you do?

David R. Spigel, MD: We’re working on trying to get her vemurafenib and cobimetinib, but my registrar in Tennessee probably won’t be able to pull that off.

Mark A. Socinski, MD: Obviously, when most of us trained, we did a single biopsy at the time of diagnosis. If we’ve learned anything, it’s that this is an incredibly heterogeneous group of patients. When you start to do these rebiopsies and you find something like this, it almost makes you afraid of how much you don’t know, you don’t rebiopsy, and these sorts of things. So, it’s a complicated time.

Ross Camidge, MD, PhD: I’d like rein in my definitive “You should never do a biopsy,” because I think if you put somebody on a drug and they’re doing well, you save them a biopsy. But if you put somebody on a drug and they’re just blowing through it or not doing what you think, then you should go find something.

Mark G. Kris, MD: Then you should look for something else.

David R. Spigel, MD: Have you used brigatinib in the ROS setting at all?

Ross Camidge, MD, PhD: In the original phase I, but the numbers were very small.

Mark G. Kris, MD: Yes. Can I just make a comment about biopsies? One thing about the immunotherapy trials, they’ve totally changed the environment on biopsies. This idea that you can’t get a biopsy or a rebiopsy—there must be 5 to 10,000 biopsies done in those trials, yes? So, it’s over. I must say that they’re a lot safer, quicker to get, and, when in doubt, I would biopsy.

David R. Spigel, MD: Not to get too far into that, what used to be really all cores for us—guided cores and interventional—are now this navigational bronchoscopy using a corelike needle. It’s so much easier, and we’re getting everything we need to know to interrogate the tumor.

Mark A. Socinski, MD: So, Ross, you mentioned lorlatinib. Are there other agents on the horizon?

Ross Camidge, MD, PhD: There’s another so-called next-generation inhibitor, which is a much smaller molecule that’s supposed to fit into the kinase better, made by a company called Turning Point—TPX-0005. There’s also ensartinib, which came out of the same team that designed crizotinib. And they actually are, along with brigatinib and lorlatinib, doing head-to-heads against crizotinib in the first-line setting.

Mark A. Socinski, MD: We’re almost out of time. I think this has been extremely informative. Before we end this discussion, I’d like to get final thoughts from each of our panelists. I’ll start with Dr Camidge—what are your final thoughts?

Ross Camidge, MD, PhD: It is a changing field, and it’s very exciting. It’s slightly exhausting, but it’s all for the benefit of the patients.

Mark A. Socinski, MD: Mark?

Mark G. Kris, MD: I just encourage people to sit down when you’re making a decision, with every patient, and look at every single modality available, and see with all of those modalities, which ones are best for that patient on that day. Even consider things that are outside the box, like radiation, surgery—things that we would never have done 10 years ago, we’re doing now, and they can help individual patients. So, just make sure you think of everything. Don’t do everything, but at least think about it.

Mark A. Socinski, MD: Dr. Spigel?

David R. Spigel, MD: I just echo this excitement, not only for us in research but also for patients and families. It’s just a tremendous time to be able to help people and know that there are many options, not just immunotherapy or targeted therapy, but also the diagnostics have improved tremendously in even our radiation therapy and surgical approaches. So, there are a lot of reasons to be hopeful.

Mark A. Socinski, MD: And last but not least…

Jared Weiss, MD: We’ve had a very informative conversation today about some very advanced new treatments that are biomarker dependent. So, I’ll end with a final thought: You don’t know if you don’t test. We still have very high rates of nontesting in this country, even for EGFR. And so, I would end with a final thought to do all appropriate testing—meaning PD-L1 on all patients in the frontline setting and comprehensive molecular testing for all nonsquamous patients.

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

Transcript Edited for Clarity
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