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Immunotherapy for Brain Metastases

Panelists:Benjamin P. Levy, MD, Mount Sinai Health Systems;Chandra P. Belani, MD, Penn State Cancer Institute;Marina Garassino, MD, National Cancer Institute Milan, Italy;Sarah B. Goldberg, MD, MPH, Yale Cancer Center;Ramaswamy Govindan, MD, Washington University School of Medicine;Mark G. Kris, MD, Memorial Sloan-Kettering Cancer Center
Published: Monday, Oct 03, 2016


Transcript:

Benjamin P. Levy, MD:
Talk a little bit about your data looking at these drugs in terms of their ability to cross the blood-brain barrier, elicit response rates in the brain. You’ve had some data that was presented, I think, at the World Conference on Lung Cancer, showing that there is the potential for them to treat brain metastases.

Sarah B. Goldberg, MD, MPH: Several years ago when these drugs were first starting to show activity, we decided that we really wanted to look at how they worked in the brain. When a drug works elsewhere, it can work in the brain as well. We think a lot about, do drugs cross the blood-brain barrier? I think to a large degree they do. One question with immune therapy is, will the antibodies cross? One interesting point is the antibodies don’t necessarily have to get in, right? You can activate T cells and they can get in. So, it doesn’t have to be that the drug is getting there, but the question is, is something getting there? The idea is, can you use a systemic therapy instead of or in addition to local therapy, like surgery or radiation, or even avoid those local therapies?

We performed this trial, and it’s still actually ongoing, but we do have some data now that we just published recently that shows that these drugs work specifically with our trial. Pembrolizumab does work in the brain. So, in patients with brain metastases that have not been radiated, or those who have been radiated and then have progression, using pembrolizumab instead of another local therapy can be effective in the brain. The response rate is no higher than the systemic response rate. You can’t imagine it would be more, but it does look to be the same. The study we did was in melanoma and in lung cancer. It looks like it can be effective in the brain. I think it’s really exciting for patients who have, in our study at least, smaller asymptomatic brain metastases. You can use immune therapy and get a good response in the brain.

Benjamin P. Levy, MD: Circumventing the need for radiation if a patient progresses in the brain using these drugs, is that something that we should be thinking about for these patients outside of a clinical trial right now?

Sarah B. Goldberg, MD, MPH: Our trial is small and it’s the first experience doing this. So far we’ve published data on 18 patients with lung cancer and 18 with melanoma. We have to take that with what it is. We have seen several fantastic responses. We had four complete responses in the brain. They were small metastases, but really they’re now gone. And the data we published showed several months of durable benefit. But, now it’s been over a year in some patients. So, we’ve seen some really fantastic durable responses in the brain, and those patients have now been able to avoid radiation. Some of those patients have had prior radiation, so it really is nice that they’re able to get benefit, systemically and in the brain. Should it be done outside of a trial? Sometimes patients are stuck. They already have had radiation and they can’t get more, or there’s concern for toxicity, so I think it’s a consideration. You have to be cautious because we have seen some issues in the brain. And so, we monitor those patients really closely. And, we’re always doing it in consultation with a neurosurgeon that we work very closely with, and radiation oncologists, to talk about the pros and the cons of each strategy. We’ve actually created a tumor board around really discussing these patients. They can be complicated, but I think it’s a potential strategy you can consider.

Benjamin P. Levy, MD: Is there a patient outside of a patient who may have autoimmune diseases that you wouldn’t give these drugs to? There’s been some hints from CheckMate studies and from the KEYNOTE-001 study that molecular subsets, particularly EGFR-positive patients, may not be the right patient for these types of drugs. Has that been your experience? We were giving these drugs to EGFR-positive patients before the data came out that said, “This may not be the best options for these patients.” Any thoughts on that?

Sarah B. Goldberg, MD, MPH: So, some of the trials that have looked at this have treated all-comers, and then looked at the subsets of KRAS-positive and EGFR-positive patients. And it does look like the EGFR-mutation–positive patients don’t benefit as much from immune therapy compared to chemotherapy. I’m curious how other people interpret the data. I think it’s become clear that there probably is less activity in patients with EGFR than without, but we clearly have seen very significant benefit in patients with an EGFR mutation on immune therapy. I would not say that it’s something to avoid. It may be something that you want to sequence a bit differently than you would in other patients, so these drugs are now approved in second-line setting for patients with non-small cell lung cancer. But, I would say maybe in patients with EGFR, maybe you can extrapolate to ALK and other diseases that tend to be in never- or light-smokers. Maybe in those diseases you want to use other things first. But, I, in no way, would say that those patients should not get immune therapy.

Benjamin P. Levy, MD: Mark, your thoughts on this.

Mark G. Kris, MD: I totally agree with that. I think I’ve shocked even some of my partners that I would offer somebody with EGFR-mutant or an ALK-positive cancer nivolumab in the first-line setting, or nivolumab/ipilimumab. And the reason for that is, I’ve not been able to get a cure in any patient with those drugs.

Benjamin P. Levy, MD: You’d offer them first-line treatment in combination or just first-line treatment?

Mark G. Kris, MD: First-line treatment. Because if you’ve seen these patients that have had these multi-year, disease-free outcomes, there is no other therapy in stage IV disease that can offer that. And, in the right patient with careful supervision, stopping the drug is totally reasonable in somebody who wants that approach. And I would do that, and table the TKI. Sadly, it’s not a curative regimen. And in the places it could be curative, like in the adjuvant setting, I can’t seem to get anybody interested in it. I’m the only one who gives that, too. But, I do think it’s a totally reasonable thing. And your point about it being less effective is correct, but in the right patient with that explanation, I think it can happen. There isn’t another treatment that we have as medical oncologists that can give that long of a remission with that few side effects.

Benjamin P. Levy, MD: You mentioned adjuvant, neoadjuvant. Want to put a plug in the for ALCHEMIST study and what are the efforts you’re doing?

Mark G. Kris, MD: Again, we’re trying to use these drugs in a curative setting and to try to use them to enhance a cure. Do we know how to do that? Of course not. And there are a whole range of clinical trials initiating now, giving these agents in the neoadjuvant setting; both the single-agent PD-L1 and PD-1 drugs and also giving combinations. And in the adjuvant setting, just a couple of weeks ago, there’s been initiation of a clinical trial to give nivolumab to patients on the ALCHEMIST study that do not have an ALK rearrangement or EGFR mutation.

Benjamin P. Levy, MD: I don’t know if I would agree with the combination strategy with nivolumab and ipilimumab with the EGFR-positive patients, only based on my own anecdotal experience of these drugs. At least in the resistance setting, they have not worked. I do think that there is a place for these drugs that needs to be exploited and explored in the neoadjuvant and the adjuvant setting. We need to learn more about how these drugs work. We need pre-tissue and post-tissue after drug delivery to see the dynamic changes elicited by these agents. But, point well taken that these drugs are providing the most durable responses we’ve seen to date.

Mark G. Kris, MD: All three of us are part of the Lung Cancer Mutation Consortium and all have ALCHEMIST running, too. So, I think our three institutions support those trials both neoadjuvantly and adjuvantly.

Benjamin P. Levy, MD: Govindan, your thoughts on where we sit currently, not future, with the checkpoint inhibitors?

Ramaswamy Govindan, MD: I agree with all the points made. The second-line setting is very clear. I think, at the moment, we are trying to decide how to move them forward in the frontline setting, and how to combine them with other drugs to enhance activity on this. I’m not so sure I would offer nivolumab to EGFR-mutant patients in the frontline setting, but definitely in the second- or third-line setting, I would consider that.

Transcript Edited for Clarity
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Transcript:

Benjamin P. Levy, MD:
Talk a little bit about your data looking at these drugs in terms of their ability to cross the blood-brain barrier, elicit response rates in the brain. You’ve had some data that was presented, I think, at the World Conference on Lung Cancer, showing that there is the potential for them to treat brain metastases.

Sarah B. Goldberg, MD, MPH: Several years ago when these drugs were first starting to show activity, we decided that we really wanted to look at how they worked in the brain. When a drug works elsewhere, it can work in the brain as well. We think a lot about, do drugs cross the blood-brain barrier? I think to a large degree they do. One question with immune therapy is, will the antibodies cross? One interesting point is the antibodies don’t necessarily have to get in, right? You can activate T cells and they can get in. So, it doesn’t have to be that the drug is getting there, but the question is, is something getting there? The idea is, can you use a systemic therapy instead of or in addition to local therapy, like surgery or radiation, or even avoid those local therapies?

We performed this trial, and it’s still actually ongoing, but we do have some data now that we just published recently that shows that these drugs work specifically with our trial. Pembrolizumab does work in the brain. So, in patients with brain metastases that have not been radiated, or those who have been radiated and then have progression, using pembrolizumab instead of another local therapy can be effective in the brain. The response rate is no higher than the systemic response rate. You can’t imagine it would be more, but it does look to be the same. The study we did was in melanoma and in lung cancer. It looks like it can be effective in the brain. I think it’s really exciting for patients who have, in our study at least, smaller asymptomatic brain metastases. You can use immune therapy and get a good response in the brain.

Benjamin P. Levy, MD: Circumventing the need for radiation if a patient progresses in the brain using these drugs, is that something that we should be thinking about for these patients outside of a clinical trial right now?

Sarah B. Goldberg, MD, MPH: Our trial is small and it’s the first experience doing this. So far we’ve published data on 18 patients with lung cancer and 18 with melanoma. We have to take that with what it is. We have seen several fantastic responses. We had four complete responses in the brain. They were small metastases, but really they’re now gone. And the data we published showed several months of durable benefit. But, now it’s been over a year in some patients. So, we’ve seen some really fantastic durable responses in the brain, and those patients have now been able to avoid radiation. Some of those patients have had prior radiation, so it really is nice that they’re able to get benefit, systemically and in the brain. Should it be done outside of a trial? Sometimes patients are stuck. They already have had radiation and they can’t get more, or there’s concern for toxicity, so I think it’s a consideration. You have to be cautious because we have seen some issues in the brain. And so, we monitor those patients really closely. And, we’re always doing it in consultation with a neurosurgeon that we work very closely with, and radiation oncologists, to talk about the pros and the cons of each strategy. We’ve actually created a tumor board around really discussing these patients. They can be complicated, but I think it’s a potential strategy you can consider.

Benjamin P. Levy, MD: Is there a patient outside of a patient who may have autoimmune diseases that you wouldn’t give these drugs to? There’s been some hints from CheckMate studies and from the KEYNOTE-001 study that molecular subsets, particularly EGFR-positive patients, may not be the right patient for these types of drugs. Has that been your experience? We were giving these drugs to EGFR-positive patients before the data came out that said, “This may not be the best options for these patients.” Any thoughts on that?

Sarah B. Goldberg, MD, MPH: So, some of the trials that have looked at this have treated all-comers, and then looked at the subsets of KRAS-positive and EGFR-positive patients. And it does look like the EGFR-mutation–positive patients don’t benefit as much from immune therapy compared to chemotherapy. I’m curious how other people interpret the data. I think it’s become clear that there probably is less activity in patients with EGFR than without, but we clearly have seen very significant benefit in patients with an EGFR mutation on immune therapy. I would not say that it’s something to avoid. It may be something that you want to sequence a bit differently than you would in other patients, so these drugs are now approved in second-line setting for patients with non-small cell lung cancer. But, I would say maybe in patients with EGFR, maybe you can extrapolate to ALK and other diseases that tend to be in never- or light-smokers. Maybe in those diseases you want to use other things first. But, I, in no way, would say that those patients should not get immune therapy.

Benjamin P. Levy, MD: Mark, your thoughts on this.

Mark G. Kris, MD: I totally agree with that. I think I’ve shocked even some of my partners that I would offer somebody with EGFR-mutant or an ALK-positive cancer nivolumab in the first-line setting, or nivolumab/ipilimumab. And the reason for that is, I’ve not been able to get a cure in any patient with those drugs.

Benjamin P. Levy, MD: You’d offer them first-line treatment in combination or just first-line treatment?

Mark G. Kris, MD: First-line treatment. Because if you’ve seen these patients that have had these multi-year, disease-free outcomes, there is no other therapy in stage IV disease that can offer that. And, in the right patient with careful supervision, stopping the drug is totally reasonable in somebody who wants that approach. And I would do that, and table the TKI. Sadly, it’s not a curative regimen. And in the places it could be curative, like in the adjuvant setting, I can’t seem to get anybody interested in it. I’m the only one who gives that, too. But, I do think it’s a totally reasonable thing. And your point about it being less effective is correct, but in the right patient with that explanation, I think it can happen. There isn’t another treatment that we have as medical oncologists that can give that long of a remission with that few side effects.

Benjamin P. Levy, MD: You mentioned adjuvant, neoadjuvant. Want to put a plug in the for ALCHEMIST study and what are the efforts you’re doing?

Mark G. Kris, MD: Again, we’re trying to use these drugs in a curative setting and to try to use them to enhance a cure. Do we know how to do that? Of course not. And there are a whole range of clinical trials initiating now, giving these agents in the neoadjuvant setting; both the single-agent PD-L1 and PD-1 drugs and also giving combinations. And in the adjuvant setting, just a couple of weeks ago, there’s been initiation of a clinical trial to give nivolumab to patients on the ALCHEMIST study that do not have an ALK rearrangement or EGFR mutation.

Benjamin P. Levy, MD: I don’t know if I would agree with the combination strategy with nivolumab and ipilimumab with the EGFR-positive patients, only based on my own anecdotal experience of these drugs. At least in the resistance setting, they have not worked. I do think that there is a place for these drugs that needs to be exploited and explored in the neoadjuvant and the adjuvant setting. We need to learn more about how these drugs work. We need pre-tissue and post-tissue after drug delivery to see the dynamic changes elicited by these agents. But, point well taken that these drugs are providing the most durable responses we’ve seen to date.

Mark G. Kris, MD: All three of us are part of the Lung Cancer Mutation Consortium and all have ALCHEMIST running, too. So, I think our three institutions support those trials both neoadjuvantly and adjuvantly.

Benjamin P. Levy, MD: Govindan, your thoughts on where we sit currently, not future, with the checkpoint inhibitors?

Ramaswamy Govindan, MD: I agree with all the points made. The second-line setting is very clear. I think, at the moment, we are trying to decide how to move them forward in the frontline setting, and how to combine them with other drugs to enhance activity on this. I’m not so sure I would offer nivolumab to EGFR-mutant patients in the frontline setting, but definitely in the second- or third-line setting, I would consider that.

Transcript Edited for Clarity
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