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Locally Advanced NSCLC: Audience Q&A

Panelists:Walter Curran, JR., MD, FACR, Winship Cancer Institute of Emory University; Mark G. Kris, MD, Memorial Sloan Kettering Cancer Center; Jyoti D. Patel, MD, University of Chicago
Published: Tuesday, Apr 03, 2018



Transcript:

Mark Kris, MD:
Let’s go, now, to some of the questions that have come in. We’ll do our best to answer them. Are patients really cured by this? Walter?

Walter J. Curran Jr., MD: Chemoradiation cures people. We often use the 5-year survival benchmark as an important benchmark, and we’re now seeing over 20% of these selected patients who are alive at 5 years. Some of them will be cured. Cure is a tough word, but if you’re without evidence of progression of disease and are living a good life after 5 years, I’m happy that the therapy has done its job.

Mark Kris, MD: I trust the data will bear this out. I know the surgical data better than the data on chemoradiation, but there are very few recurrences after the third year, frankly.

Walter J. Curran Jr., MD: Yes.

Jyoti D. Patel, MD: Right.

Mark Kris, MD: The other thing to remember is that we have these long-term survivors. They’re also at risk for second primary lung cancers. So, that tumor nodule that pops up 5 years afterward, under surveillance, is more likely to be another primary lung cancer that needs another primary therapy approach.

Walter J. Curran Jr., MD: Yes.

Mark Kris, MD: Jyoti, as the medical oncologist, is there a role for bevacizumab in patients who are receiving radiation?

Jyoti D. Patel, MD: It’s been a checkered past, certainly. Initially, some studies looked at radiation to sort of palliate local symptoms, normalize blood supply, and give bevacizumab to patients with squamous cancer. That failed, with a high degree of pulmonary hemorrhage. In patients who were getting chemoradiation, who were nonsquamous, there were higher rates of fistulas and, again, more toxicities. So, at this juncture, I think most of us have abandoned any idea of bringing bevacizumab into the chemoradiation space. But we are now looking at checkpoint inhibitors with anti-VEGF. There may be a role for these, and that may be investigated in the future.

Mark Kris, MD: What about ramucirumab?

Jyoti D. Patel, MD: Certainly, ramucirumab has efficacy with these checkpoint inhibitors. Ramucirumab with radiation—I would be pretty nervous about that. We’re seeing higher rates of fistula formation and esophagitis.

Mark Kris, MD: Is that across all cancers? Or, in lung, particularly?

Jyoti D. Patel, MD: In lung, particularly. I don’t know about esophageal cancer.

Walter J. Curran Jr., MD: I don’t know the data. Bevacizumab issues were seen across many disease sites.

Mark Kris, MD: People thought that if you gave some radiation, it would be safe to give bevacizumab. But, that really didn’t pan out in the few trials that were done. Do you ask for, as you would, in a stage 4 patient, up-front complete genotyping on a multiplex panel? Do you ask for that in a stage 3B patient, who is inoperable and unresectable?

Jyoti D. Patel, MD: I think it’s based on institutional practice. Certainly, at my institution, we do reflex testing in all patients who are diagnosed as part of an institutional research effort. Practically speaking, for patients with potentially curative therapy, from stage 1 to stage 3, it should not influence your decision making. Sometimes, you may get it, early on, as part of the diagnostic workup. Then, lo and behold, the PET looks better than you thought, or the axillary lymph node ends up being reactive and benign. And so, you may have that information. At this juncture, I don’t think we know how tumor mutation burden, for example, fits in for these patients. Are there patients who will benefit more with checkpoint inhibitors after radiation? I don’t know. At this juncture, probably not. It doesn’t fit in to my treatment paradigm.

Mark Kris, MD: If a patient was referred to you from another institution, and they did not have adequate tissue for multiplex testing, would you do a rebiopsy at this point?

Jyoti D. Patel, MD: No, not if I was planning to treat them with curative intent.

Mark Kris, MD: Walter, what’s the paradigm at Emory University?

Walter J. Curran Jr., MD: It’s similar. We do a 20-gene panel on all patients, regardless of stage. We use that as a reference. It’s been challenging to do trials, even on a national basis, that involve any kind of molecular testing for stage 3 patients. NRG Oncology and Alliance came together to do a randomized phase II trial, which only looked at those with EGFR or ALK mutations. We looked at an ALK inhibitor or an EGFR inhibitor in addition to chemoradiation. We did not complete enrollment. The main reasons were the lack of testing of those patients at the institution, or the perception that there were fewer mutated patients in the stage 3 than the stage 4 cohort. I think it’s actually a combination of both reasons. We’re seeing that in the ALCHEMIST trial with the ALK mutations.

Jyoti D. Patel, MD: It’s tough. All we do is spend all day telling people to get mutation testing. “Know before you treat.” In this setting—that’s 3B, as close as you can get—we’re backing away from it. So, it’s tough.

Mark Kris, MD: I have to say, Walter, I share your experience here. The only time, in my medical career, that I had to send back a grant was for giving afatinib with concurrent chemotherapy and radiation. That said, though, this paradigm is changing quickly.

Walter J. Curran Jr., MD: Yes, I agree.

Mark Kris, MD: More and more, as part of the initial biopsy, people are getting a next-generation panel. I think all of the panelists are doing this at their institutions. But blood-based testing has changed that as well. So, if you wanted to do that trial, now, when you had blood-based testing, you could.

Walter J. Curran Jr., MD: I agree.

Mark Kris, MD: The other thing is, our pathologists routinely do immunohistochemistry studies for EGFR, L858R, and ALK. Every time they get a diagnosis of lung cancer, give it to them. It’s reflexively reported. And PD-L1. So, within 48 hours, we have that data. We could refer somebody for that kind of trial.

Walter J. Curran Jr., MD: Yes, right.

Mark Kris, MD: What about giving an immune checkpoint blocker with SBRT?

Walter J. Curran Jr., MD: The answer to this question is being determined as part of trials at several centers, including our own. I suggest to proceed with caution, outside of trial. There are people with metastatic disease, be it melanoma, lung, or some other disease, who are going to be on a checkpoint inhibitor and are going to need SBRT. I like to be careful, but, based on what I’ve seen clinically, and what I’ve read, I have not seen undue toxicity. There is the opportunity for synergism.

Mark Kris, MD: Can I make a comment on that report, in JAMA Oncology, about the increased risk of radionecrosis in people getting SBRT for CNS lesions?

Walter J. Curran Jr., MD: Yes, that’s interesting. We haven’t seen that, but it’s something we need to watch for. The reality is, radiation necrosis inside a lesion is really what you’re after with stereotactic radiation. What you don’t want is necrosis outside of the lesion. You’re probably learning that the kind of doses we give with brain radiosurgery and in a patient who has immune checkpoint inhibitor response is probably more therapy than they need to kill the lesion. So, we have to kind of back down on something.

Jyoti D. Patel, MD: Another piece that I think is interesting is using SBRT in patients with metastatic disease and immunotherapy. Often, SBRT is utilized for patients with oligometastatic disease.

Walter J. Curran Jr., MD: Correct.

Jyoti D. Patel, MD: Those patients seem to have a higher PD-L1. They may be analogous to those early stage patients that you’re talking about. There may be something that the immune system is doing to keep the cancer in check. Clinically, they seem to have a higher response. Again, proceed with caution in nonclinical trials. But there may be something there.

Walter J. Curran Jr., MD: I agree.

Mark Kris, MD: One critique I had, of that paper, is they focused on radionecrosis. But they didn’t talk about the long-term outcome of those patients.

Walter J. Curran Jr., MD: Which could have been great.

Mark Kris, MD: Perhaps when they get into these solitary metastasis scenarios, these patients can sometimes be cured?

Jyoti D. Patel, MD: There’s your use of bevacizumab.

Mark Kris, MD: That’s my use of bevacizumab. I’d be very, very careful with that. Jyoti, what do you do with a patient who progresses while they’re on durvalumab? Let’s say it’s a new liver metastasis. Let’s make it clear-cut.

Jyoti D. Patel, MD: This would bring us back to the drawing board. Again, going back to what we know, we’d do a biopsy of that lesion. If that tumor revealed high PD-L1, I would treat that patient with chemotherapy if they progressed.

Mark Kris, MD: What about while they’re on durvalumab?

Jyoti D. Patel, MD: On durvalumab, I would re-biopsy, if there was evidence of progression. Reflexively, we would get the PD-L1 test, at out institution. But, if they progressed on durvalumab, I would go to chemotherapy or clinical trial.

Mark Kris, MD: What about after that?

Jyoti D. Patel, MD: At the duration of 12 months? I don’t know how long is the right amount.

Mark Kris, MD: Let me pick a number. A year after stopping the durvalumab, you have the liver metastasis.

Jyoti D. Patel, MD: Then, I would re-biopsy. If a high PD-L1 is detected, I’d absolutely treat.

Mark Kris, MD: So, you treat them like a newly diagnosed stage 4 patient?

Jyoti D. Patel, MD: De novo, exactly.

Mark Kris, MD: I think that makes sense. I think most people would do that.

Jyoti D. Patel, MD: If they progress 2 months after stopping, would I restart? Probably.

Mark Kris, MD: What is your routine for re-scanning these patients? Your patient completes chemoradiation. How quickly after the end of the completion of chemotherapy and radiation do you normally re-scan in the absence of symptoms?

Walter J. Curran Jr., MD: My practice would be to scan the patient 6 to 8 weeks after chemoradiation. That gives me the best window to look at imaging response to the chemoradiation. It’s given them time to respond, before we start seeing some significant scarring in the radiation field.

Mark Kris, MD: OK. Jyoti, what about you?

Jyoti D. Patel, MD: I don’t think that we really have good guidance. It tends to be sort of institutionally directed. Traditionally, I’ve looked at patients between 4 and 6 weeks after. That will likely change as more and more patients are treated on durvalumab. But, again, this is where that clinical hat really comes into play. You have to be comfortable in knowing that your patients have recovered from all toxicity before you initiate therapy. And then, you really need to be tuned in with your advanced care providers, your nurses, with your entire clinical staff when you’re treating these patients every 2 weeks for a year. You need to be doing a thorough review of systems, looking for the weird toxicities that can happen.

Mark Kris, MD: Yes. Our institution generally does not do another imaging study in the absence of durvalumab for 3 to 4 months after the conclusion of radiation in the asymptomatic patient. That is largely done to get away from the process of recovery (the scarring that follows). In someone who is fit, if she or he has done well, you would need to consider doing an imaging study much sooner.

We’ve had a lot of new issues to deal with, but I hope everybody will agree that they’ve been the kind of things that we want to deal with. We’re trying to find a way to deliver an important therapy to more patients. The estimation is that almost 50,000 people a year, in the United States, could benefit from this therapy. So, it’s a great opportunity for thoracic surgeons, medical oncologists, and radiation oncologists to really make a huge difference. We’re very proud of what’s happened in people with more advanced disease, and we’ve led to a lot of longer and better lives. This is a step even beyond that—longer, better, and maybe even cured.

It’s just amazing to me that I’ve cared for people long enough that they have gotten second primary cancers. I’ve got a chance to cure them again. This is something that I never thought would have been possible.
This has been a great discussion. Thank you. Thank you for your candor on your experience. I think people really want to know what you do, and you were very, very clear about that. We hope that you’ve all found this information valuable to you and valuable to the care of your patients. Hopefully, you’ll be able to put some of this into practice later this week. Thank you for watching OncLive® NewsNetwork.

Transcript Edited for Clarity 
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Slider Right


Transcript:

Mark Kris, MD:
Let’s go, now, to some of the questions that have come in. We’ll do our best to answer them. Are patients really cured by this? Walter?

Walter J. Curran Jr., MD: Chemoradiation cures people. We often use the 5-year survival benchmark as an important benchmark, and we’re now seeing over 20% of these selected patients who are alive at 5 years. Some of them will be cured. Cure is a tough word, but if you’re without evidence of progression of disease and are living a good life after 5 years, I’m happy that the therapy has done its job.

Mark Kris, MD: I trust the data will bear this out. I know the surgical data better than the data on chemoradiation, but there are very few recurrences after the third year, frankly.

Walter J. Curran Jr., MD: Yes.

Jyoti D. Patel, MD: Right.

Mark Kris, MD: The other thing to remember is that we have these long-term survivors. They’re also at risk for second primary lung cancers. So, that tumor nodule that pops up 5 years afterward, under surveillance, is more likely to be another primary lung cancer that needs another primary therapy approach.

Walter J. Curran Jr., MD: Yes.

Mark Kris, MD: Jyoti, as the medical oncologist, is there a role for bevacizumab in patients who are receiving radiation?

Jyoti D. Patel, MD: It’s been a checkered past, certainly. Initially, some studies looked at radiation to sort of palliate local symptoms, normalize blood supply, and give bevacizumab to patients with squamous cancer. That failed, with a high degree of pulmonary hemorrhage. In patients who were getting chemoradiation, who were nonsquamous, there were higher rates of fistulas and, again, more toxicities. So, at this juncture, I think most of us have abandoned any idea of bringing bevacizumab into the chemoradiation space. But we are now looking at checkpoint inhibitors with anti-VEGF. There may be a role for these, and that may be investigated in the future.

Mark Kris, MD: What about ramucirumab?

Jyoti D. Patel, MD: Certainly, ramucirumab has efficacy with these checkpoint inhibitors. Ramucirumab with radiation—I would be pretty nervous about that. We’re seeing higher rates of fistula formation and esophagitis.

Mark Kris, MD: Is that across all cancers? Or, in lung, particularly?

Jyoti D. Patel, MD: In lung, particularly. I don’t know about esophageal cancer.

Walter J. Curran Jr., MD: I don’t know the data. Bevacizumab issues were seen across many disease sites.

Mark Kris, MD: People thought that if you gave some radiation, it would be safe to give bevacizumab. But, that really didn’t pan out in the few trials that were done. Do you ask for, as you would, in a stage 4 patient, up-front complete genotyping on a multiplex panel? Do you ask for that in a stage 3B patient, who is inoperable and unresectable?

Jyoti D. Patel, MD: I think it’s based on institutional practice. Certainly, at my institution, we do reflex testing in all patients who are diagnosed as part of an institutional research effort. Practically speaking, for patients with potentially curative therapy, from stage 1 to stage 3, it should not influence your decision making. Sometimes, you may get it, early on, as part of the diagnostic workup. Then, lo and behold, the PET looks better than you thought, or the axillary lymph node ends up being reactive and benign. And so, you may have that information. At this juncture, I don’t think we know how tumor mutation burden, for example, fits in for these patients. Are there patients who will benefit more with checkpoint inhibitors after radiation? I don’t know. At this juncture, probably not. It doesn’t fit in to my treatment paradigm.

Mark Kris, MD: If a patient was referred to you from another institution, and they did not have adequate tissue for multiplex testing, would you do a rebiopsy at this point?

Jyoti D. Patel, MD: No, not if I was planning to treat them with curative intent.

Mark Kris, MD: Walter, what’s the paradigm at Emory University?

Walter J. Curran Jr., MD: It’s similar. We do a 20-gene panel on all patients, regardless of stage. We use that as a reference. It’s been challenging to do trials, even on a national basis, that involve any kind of molecular testing for stage 3 patients. NRG Oncology and Alliance came together to do a randomized phase II trial, which only looked at those with EGFR or ALK mutations. We looked at an ALK inhibitor or an EGFR inhibitor in addition to chemoradiation. We did not complete enrollment. The main reasons were the lack of testing of those patients at the institution, or the perception that there were fewer mutated patients in the stage 3 than the stage 4 cohort. I think it’s actually a combination of both reasons. We’re seeing that in the ALCHEMIST trial with the ALK mutations.

Jyoti D. Patel, MD: It’s tough. All we do is spend all day telling people to get mutation testing. “Know before you treat.” In this setting—that’s 3B, as close as you can get—we’re backing away from it. So, it’s tough.

Mark Kris, MD: I have to say, Walter, I share your experience here. The only time, in my medical career, that I had to send back a grant was for giving afatinib with concurrent chemotherapy and radiation. That said, though, this paradigm is changing quickly.

Walter J. Curran Jr., MD: Yes, I agree.

Mark Kris, MD: More and more, as part of the initial biopsy, people are getting a next-generation panel. I think all of the panelists are doing this at their institutions. But blood-based testing has changed that as well. So, if you wanted to do that trial, now, when you had blood-based testing, you could.

Walter J. Curran Jr., MD: I agree.

Mark Kris, MD: The other thing is, our pathologists routinely do immunohistochemistry studies for EGFR, L858R, and ALK. Every time they get a diagnosis of lung cancer, give it to them. It’s reflexively reported. And PD-L1. So, within 48 hours, we have that data. We could refer somebody for that kind of trial.

Walter J. Curran Jr., MD: Yes, right.

Mark Kris, MD: What about giving an immune checkpoint blocker with SBRT?

Walter J. Curran Jr., MD: The answer to this question is being determined as part of trials at several centers, including our own. I suggest to proceed with caution, outside of trial. There are people with metastatic disease, be it melanoma, lung, or some other disease, who are going to be on a checkpoint inhibitor and are going to need SBRT. I like to be careful, but, based on what I’ve seen clinically, and what I’ve read, I have not seen undue toxicity. There is the opportunity for synergism.

Mark Kris, MD: Can I make a comment on that report, in JAMA Oncology, about the increased risk of radionecrosis in people getting SBRT for CNS lesions?

Walter J. Curran Jr., MD: Yes, that’s interesting. We haven’t seen that, but it’s something we need to watch for. The reality is, radiation necrosis inside a lesion is really what you’re after with stereotactic radiation. What you don’t want is necrosis outside of the lesion. You’re probably learning that the kind of doses we give with brain radiosurgery and in a patient who has immune checkpoint inhibitor response is probably more therapy than they need to kill the lesion. So, we have to kind of back down on something.

Jyoti D. Patel, MD: Another piece that I think is interesting is using SBRT in patients with metastatic disease and immunotherapy. Often, SBRT is utilized for patients with oligometastatic disease.

Walter J. Curran Jr., MD: Correct.

Jyoti D. Patel, MD: Those patients seem to have a higher PD-L1. They may be analogous to those early stage patients that you’re talking about. There may be something that the immune system is doing to keep the cancer in check. Clinically, they seem to have a higher response. Again, proceed with caution in nonclinical trials. But there may be something there.

Walter J. Curran Jr., MD: I agree.

Mark Kris, MD: One critique I had, of that paper, is they focused on radionecrosis. But they didn’t talk about the long-term outcome of those patients.

Walter J. Curran Jr., MD: Which could have been great.

Mark Kris, MD: Perhaps when they get into these solitary metastasis scenarios, these patients can sometimes be cured?

Jyoti D. Patel, MD: There’s your use of bevacizumab.

Mark Kris, MD: That’s my use of bevacizumab. I’d be very, very careful with that. Jyoti, what do you do with a patient who progresses while they’re on durvalumab? Let’s say it’s a new liver metastasis. Let’s make it clear-cut.

Jyoti D. Patel, MD: This would bring us back to the drawing board. Again, going back to what we know, we’d do a biopsy of that lesion. If that tumor revealed high PD-L1, I would treat that patient with chemotherapy if they progressed.

Mark Kris, MD: What about while they’re on durvalumab?

Jyoti D. Patel, MD: On durvalumab, I would re-biopsy, if there was evidence of progression. Reflexively, we would get the PD-L1 test, at out institution. But, if they progressed on durvalumab, I would go to chemotherapy or clinical trial.

Mark Kris, MD: What about after that?

Jyoti D. Patel, MD: At the duration of 12 months? I don’t know how long is the right amount.

Mark Kris, MD: Let me pick a number. A year after stopping the durvalumab, you have the liver metastasis.

Jyoti D. Patel, MD: Then, I would re-biopsy. If a high PD-L1 is detected, I’d absolutely treat.

Mark Kris, MD: So, you treat them like a newly diagnosed stage 4 patient?

Jyoti D. Patel, MD: De novo, exactly.

Mark Kris, MD: I think that makes sense. I think most people would do that.

Jyoti D. Patel, MD: If they progress 2 months after stopping, would I restart? Probably.

Mark Kris, MD: What is your routine for re-scanning these patients? Your patient completes chemoradiation. How quickly after the end of the completion of chemotherapy and radiation do you normally re-scan in the absence of symptoms?

Walter J. Curran Jr., MD: My practice would be to scan the patient 6 to 8 weeks after chemoradiation. That gives me the best window to look at imaging response to the chemoradiation. It’s given them time to respond, before we start seeing some significant scarring in the radiation field.

Mark Kris, MD: OK. Jyoti, what about you?

Jyoti D. Patel, MD: I don’t think that we really have good guidance. It tends to be sort of institutionally directed. Traditionally, I’ve looked at patients between 4 and 6 weeks after. That will likely change as more and more patients are treated on durvalumab. But, again, this is where that clinical hat really comes into play. You have to be comfortable in knowing that your patients have recovered from all toxicity before you initiate therapy. And then, you really need to be tuned in with your advanced care providers, your nurses, with your entire clinical staff when you’re treating these patients every 2 weeks for a year. You need to be doing a thorough review of systems, looking for the weird toxicities that can happen.

Mark Kris, MD: Yes. Our institution generally does not do another imaging study in the absence of durvalumab for 3 to 4 months after the conclusion of radiation in the asymptomatic patient. That is largely done to get away from the process of recovery (the scarring that follows). In someone who is fit, if she or he has done well, you would need to consider doing an imaging study much sooner.

We’ve had a lot of new issues to deal with, but I hope everybody will agree that they’ve been the kind of things that we want to deal with. We’re trying to find a way to deliver an important therapy to more patients. The estimation is that almost 50,000 people a year, in the United States, could benefit from this therapy. So, it’s a great opportunity for thoracic surgeons, medical oncologists, and radiation oncologists to really make a huge difference. We’re very proud of what’s happened in people with more advanced disease, and we’ve led to a lot of longer and better lives. This is a step even beyond that—longer, better, and maybe even cured.

It’s just amazing to me that I’ve cared for people long enough that they have gotten second primary cancers. I’ve got a chance to cure them again. This is something that I never thought would have been possible.
This has been a great discussion. Thank you. Thank you for your candor on your experience. I think people really want to know what you do, and you were very, very clear about that. We hope that you’ve all found this information valuable to you and valuable to the care of your patients. Hopefully, you’ll be able to put some of this into practice later this week. Thank you for watching OncLive® NewsNetwork.

Transcript Edited for Clarity 
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