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Emerging Immunotherapy Options for Metastatic NSCLC

Insights From: Suresh Senan, MD, VU University Medical Center; Solange Peters, MD, PhD, Centre Hospitalier Universitaire Vaudois
Published: Thursday, Apr 26, 2018



Transcript: 

Solange Peters, MD, PhD: The most interesting setting now for advanced metastatic disease is, again, the frontline treatment. We have been seeing the evidence in late lines, but now we’d like to give immunotherapy to start, probably also because the immune system is stronger in the beginning of the disease than later on, when the patient and the T cells are completely exhausted. There are many, many trials ongoing. I cannot even count them—20, 30, 40. But what is interesting is how to categorize them. I think we have been looking at what we have to look at in term of monotherapy, just giving pembrolizumab in high PD-L1. I’m not sure we will reach really better data giving only immunotherapy checkpoint inhibitors. But then you have combination of checkpoints plus chemotherapy, and you have the combination of checkpoint and checkpoint, so CTLA-4 and anti-PD-1 or anti-PD-L1. But there will be the new checkpoints—TIM3, LAG3, IDO. So, probably in these multimodality immunotherapy combinations, we will see some new partners coming. They are being studied now in phase I trials in late lines, but the good ones will probably come also for frontline. So, the main question will be, will we be seduced, or will the results look better by having chemoimmunotherapy or by just sparing chemotherapy for later on and starting with immuno/immuno combinations?

If I had to prefer a strategy, I would choose immunotherapy combinations, because I like the idea that our patients can spend 1 year, 2 years, 3 years without having chemotherapy, because we don’t like chemotherapy so much. It’s toxic, it’s difficult, and it’s really not personalized. So, this will be good, but we need to have some positive results to do that. So, these data are awaited, probably the most important ones to come in the next months—there are 3 of them. One of these trials is MYSTIC. MYSTIC is anti-CTLA-4 and anti-PD-L1 versus chemotherapy. We know that PFS is negative, but wait for the OS. So, this would be good, because it’s CTLA-4 and anti-PD-L1 as potential standard frontline therapy. Second is KEYNOTE-189, which is the second arm of the IMpower. It’s chemotherapy plus pembrolizumab versus chemotherapy. It’s interesting—no bevacizumab, just chemotherapy/pembrolizumab versus chemotherapy, so it’s interesting. It should read out also early next year, I guess. And the last one is CheckMate-227. It’s nivolumab, which is being combined in a very complex manner, broken down by PD-L1–positive or PD-L1–negative into various strategies. And nivolumab plus ipilimumab, so anti-PD-L1/CTLA-4, or nivolumab plus chemotherapy in the negative ones…all this landscape will let us know what’s probably the best treatment in these patients for the future. I’m sure there’s going to be lots of debate.

I remember when I started, it was in the early 2000s, maybe at the end of ’90s. Nobody wanted to do this job because lung cancer was chemotherapy versus chemotherapy versus chemotherapy. We made many choices. Do a better chemotherapy and it failed. And it was less than a year survival—less than a year, 9 months—at the time. Then came the molecular characterization, so we knew EGFR…There was some targeted therapy, but it was for a small proportion of patients—but there was some, so this became a bit more exciting. And suddenly comes immunotherapy. When you can tell your patients that you have a new class of drug that is well tolerated, you keep your hair, and you can continue to go to work—amazing, right? And we’re just at the beginning, so we’ll probably improve the strategy. But even at the beginning, some patients are still alive at 5 years—a small proportion, but between 15% and 20% of these patients are here at 5 years. The 5-year survival with chemotherapy, it’s not complex, it’s not a difficult number, it’s zero. It doesn’t exist. So, you really completely change the fact that when you see a patient, you have some unknowns. You don’t know who are the patients who will respond, so you say to the patient, “Maybe it’s going to be you.” You have to know that some of the patients do not benefit, but some do. And if the patient responds or has a benefit, you don’t know how long it’s going to last. So, I like the unknowns, because it’s also about having hopes for your patients and creating hope for the patients, allowing them to have some hope in life. It’s a new paradigm. There are lots of things we don’t know, but it’s also kind of a new opportunity to try to—we shouldn’t say these kinds of words—have long-term benefit. My colleagues will say “cure” cancer. I think that’s a vision of tomorrow, trying to cure cancer, and that’s something we didn’t discuss in lung cancer when I was starting in this discipline.

Suresh Senan, MRCP, FRCR, PhD: One area of interest besides locally advanced non–small cell lung cancer is patients with a limited number of metastases, the so-called oligometastases. So, the oligometastasis paradigm deals with patients who have not a very extensive disease but a limited number of metastatic sites, between 3 and a maximum of 5, in which we could think of potential cure for a small number of these patients.

A previous meta-analysis suggested that if patients have no mediastinal nodal disease and a limited number of metastases, they do better. But the interest has really been raised by 2 trials that closed prematurely in the United States, which suggested that in patients with a limited number of metastases, there’s a big difference in progression-free survival in 1 study between about 3 1/2 months and nearly 11 months, by administering what they call local consolidation therapy—radiotherapy to the chest and stereotactic radiotherapy to the other side. So, there are 2 randomized trials that are close and 1 nonrandomized trial reporting that this strategy is a feasible one to be exploited. If you add to that, in selected patients, immune chemoradiotherapy may improve long-term survival. Plus, given the fact that stereotactic radiotherapy may activate the immune system, you can appreciate why there’s a lot of interest in designing these trials, comparing the best of immune chemoradiotherapy with immune-activating radiotherapy in a patient population with a limited number of metastases. I think that’s where we think that we could just make a big enough impact to show improvement in survival.

So, that’s a fascinating area for research. There are many independent investigator-initiated trials under way to see whether we could translate the gains in advanced disease and in locally advanced disease to oligometastatic disease. And that’s the so-called abscopal effect of focal radiation: enhancing the immune system in the whole body to also attack other sites that are not irradiated. I think we need to understand it a lot better, but the idea is very appealing for us.

Transcript Edited for Clarity
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Transcript: 

Solange Peters, MD, PhD: The most interesting setting now for advanced metastatic disease is, again, the frontline treatment. We have been seeing the evidence in late lines, but now we’d like to give immunotherapy to start, probably also because the immune system is stronger in the beginning of the disease than later on, when the patient and the T cells are completely exhausted. There are many, many trials ongoing. I cannot even count them—20, 30, 40. But what is interesting is how to categorize them. I think we have been looking at what we have to look at in term of monotherapy, just giving pembrolizumab in high PD-L1. I’m not sure we will reach really better data giving only immunotherapy checkpoint inhibitors. But then you have combination of checkpoints plus chemotherapy, and you have the combination of checkpoint and checkpoint, so CTLA-4 and anti-PD-1 or anti-PD-L1. But there will be the new checkpoints—TIM3, LAG3, IDO. So, probably in these multimodality immunotherapy combinations, we will see some new partners coming. They are being studied now in phase I trials in late lines, but the good ones will probably come also for frontline. So, the main question will be, will we be seduced, or will the results look better by having chemoimmunotherapy or by just sparing chemotherapy for later on and starting with immuno/immuno combinations?

If I had to prefer a strategy, I would choose immunotherapy combinations, because I like the idea that our patients can spend 1 year, 2 years, 3 years without having chemotherapy, because we don’t like chemotherapy so much. It’s toxic, it’s difficult, and it’s really not personalized. So, this will be good, but we need to have some positive results to do that. So, these data are awaited, probably the most important ones to come in the next months—there are 3 of them. One of these trials is MYSTIC. MYSTIC is anti-CTLA-4 and anti-PD-L1 versus chemotherapy. We know that PFS is negative, but wait for the OS. So, this would be good, because it’s CTLA-4 and anti-PD-L1 as potential standard frontline therapy. Second is KEYNOTE-189, which is the second arm of the IMpower. It’s chemotherapy plus pembrolizumab versus chemotherapy. It’s interesting—no bevacizumab, just chemotherapy/pembrolizumab versus chemotherapy, so it’s interesting. It should read out also early next year, I guess. And the last one is CheckMate-227. It’s nivolumab, which is being combined in a very complex manner, broken down by PD-L1–positive or PD-L1–negative into various strategies. And nivolumab plus ipilimumab, so anti-PD-L1/CTLA-4, or nivolumab plus chemotherapy in the negative ones…all this landscape will let us know what’s probably the best treatment in these patients for the future. I’m sure there’s going to be lots of debate.

I remember when I started, it was in the early 2000s, maybe at the end of ’90s. Nobody wanted to do this job because lung cancer was chemotherapy versus chemotherapy versus chemotherapy. We made many choices. Do a better chemotherapy and it failed. And it was less than a year survival—less than a year, 9 months—at the time. Then came the molecular characterization, so we knew EGFR…There was some targeted therapy, but it was for a small proportion of patients—but there was some, so this became a bit more exciting. And suddenly comes immunotherapy. When you can tell your patients that you have a new class of drug that is well tolerated, you keep your hair, and you can continue to go to work—amazing, right? And we’re just at the beginning, so we’ll probably improve the strategy. But even at the beginning, some patients are still alive at 5 years—a small proportion, but between 15% and 20% of these patients are here at 5 years. The 5-year survival with chemotherapy, it’s not complex, it’s not a difficult number, it’s zero. It doesn’t exist. So, you really completely change the fact that when you see a patient, you have some unknowns. You don’t know who are the patients who will respond, so you say to the patient, “Maybe it’s going to be you.” You have to know that some of the patients do not benefit, but some do. And if the patient responds or has a benefit, you don’t know how long it’s going to last. So, I like the unknowns, because it’s also about having hopes for your patients and creating hope for the patients, allowing them to have some hope in life. It’s a new paradigm. There are lots of things we don’t know, but it’s also kind of a new opportunity to try to—we shouldn’t say these kinds of words—have long-term benefit. My colleagues will say “cure” cancer. I think that’s a vision of tomorrow, trying to cure cancer, and that’s something we didn’t discuss in lung cancer when I was starting in this discipline.

Suresh Senan, MRCP, FRCR, PhD: One area of interest besides locally advanced non–small cell lung cancer is patients with a limited number of metastases, the so-called oligometastases. So, the oligometastasis paradigm deals with patients who have not a very extensive disease but a limited number of metastatic sites, between 3 and a maximum of 5, in which we could think of potential cure for a small number of these patients.

A previous meta-analysis suggested that if patients have no mediastinal nodal disease and a limited number of metastases, they do better. But the interest has really been raised by 2 trials that closed prematurely in the United States, which suggested that in patients with a limited number of metastases, there’s a big difference in progression-free survival in 1 study between about 3 1/2 months and nearly 11 months, by administering what they call local consolidation therapy—radiotherapy to the chest and stereotactic radiotherapy to the other side. So, there are 2 randomized trials that are close and 1 nonrandomized trial reporting that this strategy is a feasible one to be exploited. If you add to that, in selected patients, immune chemoradiotherapy may improve long-term survival. Plus, given the fact that stereotactic radiotherapy may activate the immune system, you can appreciate why there’s a lot of interest in designing these trials, comparing the best of immune chemoradiotherapy with immune-activating radiotherapy in a patient population with a limited number of metastases. I think that’s where we think that we could just make a big enough impact to show improvement in survival.

So, that’s a fascinating area for research. There are many independent investigator-initiated trials under way to see whether we could translate the gains in advanced disease and in locally advanced disease to oligometastatic disease. And that’s the so-called abscopal effect of focal radiation: enhancing the immune system in the whole body to also attack other sites that are not irradiated. I think we need to understand it a lot better, but the idea is very appealing for us.

Transcript Edited for Clarity
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Online CME Activities
TitleExpiration DateCME Credits
Medical Crossfire®: Key Questions for the Use of Immunotherapy Throughout the Disease Continuum for NSCLC in an Era of Rapid DevelopmentSep 29, 20181.5
Community Practice Connections™: 18th Annual International Lung Cancer Congress®Oct 31, 20181.5
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