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Evolving Strategies for Locally Advanced NSCLC

Insights From: Suresh Senan, MD, VU University Medical Center; Solange Peters, MD, PhD, Centre Hospitalier Universitaire Vaudois
Published: Monday, Apr 09, 2018



Transcript: 

Solange Peters, MD, PhD: Moving from PACIFIC to this unresectable stage 3 disease setting is a matter of debate at the time being. Because there are trials being developed to try to improve what has been shown with PACIFIC, to even do better, right? What can you do? There are many questions. We discussed the fact that the duration of 1 year of durvalumab might be questioned. Maybe you needed a longer period of time. But you can also imagine trying to be even more multimodal, but it’s not without consequence. And the best way to envisage a kind of immunogenic cell death or vaccination process would be to give everything at the same time. So, in an ideal world, you would give chemotherapy, radiation, and immunotherapy altogether in order to be sure that the immune system is activated at the time. So, the most important number of cancer cells are dying during radiochemotherapy. But, of course, we need some safety data before. I have never really had, in hand, enough safety data published or shown in public to allow you to start immediately with this randomized phase III trial. So, establish the safety and this would be a very good strategy.

In preclinical models, a mice model, it works better to give everything together rather than sequentially. So, that’s probably the rule. Then you can play with the chemotherapy. You can change the chemotherapy because some have more immunogenic effect than other ones. So, you could probably replace one drug with another one. We know that etoposide is a good treatment to induce immune response; it helps the immune system. Some are less so.

There’s a lot of literature about the best compound to use to activate the immune system, mainly coming from colleagues in Gustave Roussy in Paris. So, there might be somewhere to play there. Of course, you could always imagine trying to start to boost your immune system before starting radiochemotherapy. It puts, again, the idea of induction—induction chemotherapy/immunotherapy, induction immunotherapy—so all of these things have to be tested. It opens a huge field of before, during, or after treatment. But to me, the most important question is, can you give radiotherapy with a background of immunotherapy? If you start before, if you’re giving the same time, it’s the same thing, because for microkinetic, it is very flat. So, are you able to deliver 60 gray when you have nivolumab, durvalumab, pembrolizumab on board, without taking any risk? And if you know that, then you can start to randomize patients.

Marina Chiara Garassino, MD: I think that the most important thing to treating patients with locally advanced disease is a good staging from the beginning, because you have to decide whether to go with surgery or go with a chemoradiation. And what can be the new scenario is that maybe we will have neoadjuvant treatment with immune checkpoint inhibitors work in the neoadjuvant setting, helping more and cause shrinkage of the disease, which can be very helpful for the surgeon later. Or maybe the scenario will change again because we will have to wait for the adjuvant results. So, I think that the scenario will be challenging because we are sure that, in a certain way, we will have immunotherapy in the armamentarium of the treatment of non–small cell lung cancer. And we will have to work maybe also at the academic level to put the immunotherapy immediately or to put it at the end of the program or to use the synergistic effect with chemotherapy or radiotherapy or radiotherapy alone, for example. In some cases, you can go to radiotherapy alone and immunotherapy can be a feasible option, also for patients with palliative intent. So, I think that now we have a lot of drugs and we have to work on how to combine all of the drugs in a rational way and not just to put everything, like we say in Italy, in minestrone.

Solange Peters, MD, PhD: After PACIFIC, I think we have started to revise our challenges, our debate and controversies, I would say. What we have provocatively written in the editorial of the New England Journal of Medicine, it was not to provoke the community. But we have been discussing, in stage 3A, the N2 disease for decades—surgery, no surgery, surgery, no surgery. And I would do surgery. In New York, I would do radiotherapy. So, really kind of expert opinion management. We have such good results with durvalumab after radiochemotherapy. There is this question still serving a debate: Do we still have to discuss again and again about the role of surgery? PACIFIC definitely decided for radiochemotherapy followed by durvalumab in all stage 3 patients. So, of course, we don’t have the answer because we haven’t randomized these patients. But based on an improvement of 10 months’ PFS, probably there will be more and more patients who will not receive surgery but will receive radiochemotherapy followed by durvalumab. In particular, when you question this in the little bit older patients, the little bit fragile patients, when you don’t really know what to choose, this will push investigators or physicians to have radiochemotherapy delivered.

So, change a little bit the balance between surgery and radiotherapy in favor of radiotherapy. But the next trials are coming, right? Maybe the next trials will tell us that surgery is still very important. The other thing, which is also probably of great interest in the field, is, are we able to predict after radiochemotherapy who are the patients who really need durvalumab? We discussed together before this, there’s no subgroup of patients benefitting more than the other ones. But the UK colleagues, in particular, are developing tests to detect minimal residual disease. So, in the blood, you can test. If some very personalized mutations can still be found after you have completed your curative intent treatment, it means the disease will relapse at some point. So, if you’re sensitive enough to identify the patient at risk of relapse and the patient not at risk of relapse, it would be good for the society because you could only give durvalumab to the patients who are at risk. But we’re still not there. I think we should move this way, also for sustainability, over time.

Transcript Edited for Clarity 
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Transcript: 

Solange Peters, MD, PhD: Moving from PACIFIC to this unresectable stage 3 disease setting is a matter of debate at the time being. Because there are trials being developed to try to improve what has been shown with PACIFIC, to even do better, right? What can you do? There are many questions. We discussed the fact that the duration of 1 year of durvalumab might be questioned. Maybe you needed a longer period of time. But you can also imagine trying to be even more multimodal, but it’s not without consequence. And the best way to envisage a kind of immunogenic cell death or vaccination process would be to give everything at the same time. So, in an ideal world, you would give chemotherapy, radiation, and immunotherapy altogether in order to be sure that the immune system is activated at the time. So, the most important number of cancer cells are dying during radiochemotherapy. But, of course, we need some safety data before. I have never really had, in hand, enough safety data published or shown in public to allow you to start immediately with this randomized phase III trial. So, establish the safety and this would be a very good strategy.

In preclinical models, a mice model, it works better to give everything together rather than sequentially. So, that’s probably the rule. Then you can play with the chemotherapy. You can change the chemotherapy because some have more immunogenic effect than other ones. So, you could probably replace one drug with another one. We know that etoposide is a good treatment to induce immune response; it helps the immune system. Some are less so.

There’s a lot of literature about the best compound to use to activate the immune system, mainly coming from colleagues in Gustave Roussy in Paris. So, there might be somewhere to play there. Of course, you could always imagine trying to start to boost your immune system before starting radiochemotherapy. It puts, again, the idea of induction—induction chemotherapy/immunotherapy, induction immunotherapy—so all of these things have to be tested. It opens a huge field of before, during, or after treatment. But to me, the most important question is, can you give radiotherapy with a background of immunotherapy? If you start before, if you’re giving the same time, it’s the same thing, because for microkinetic, it is very flat. So, are you able to deliver 60 gray when you have nivolumab, durvalumab, pembrolizumab on board, without taking any risk? And if you know that, then you can start to randomize patients.

Marina Chiara Garassino, MD: I think that the most important thing to treating patients with locally advanced disease is a good staging from the beginning, because you have to decide whether to go with surgery or go with a chemoradiation. And what can be the new scenario is that maybe we will have neoadjuvant treatment with immune checkpoint inhibitors work in the neoadjuvant setting, helping more and cause shrinkage of the disease, which can be very helpful for the surgeon later. Or maybe the scenario will change again because we will have to wait for the adjuvant results. So, I think that the scenario will be challenging because we are sure that, in a certain way, we will have immunotherapy in the armamentarium of the treatment of non–small cell lung cancer. And we will have to work maybe also at the academic level to put the immunotherapy immediately or to put it at the end of the program or to use the synergistic effect with chemotherapy or radiotherapy or radiotherapy alone, for example. In some cases, you can go to radiotherapy alone and immunotherapy can be a feasible option, also for patients with palliative intent. So, I think that now we have a lot of drugs and we have to work on how to combine all of the drugs in a rational way and not just to put everything, like we say in Italy, in minestrone.

Solange Peters, MD, PhD: After PACIFIC, I think we have started to revise our challenges, our debate and controversies, I would say. What we have provocatively written in the editorial of the New England Journal of Medicine, it was not to provoke the community. But we have been discussing, in stage 3A, the N2 disease for decades—surgery, no surgery, surgery, no surgery. And I would do surgery. In New York, I would do radiotherapy. So, really kind of expert opinion management. We have such good results with durvalumab after radiochemotherapy. There is this question still serving a debate: Do we still have to discuss again and again about the role of surgery? PACIFIC definitely decided for radiochemotherapy followed by durvalumab in all stage 3 patients. So, of course, we don’t have the answer because we haven’t randomized these patients. But based on an improvement of 10 months’ PFS, probably there will be more and more patients who will not receive surgery but will receive radiochemotherapy followed by durvalumab. In particular, when you question this in the little bit older patients, the little bit fragile patients, when you don’t really know what to choose, this will push investigators or physicians to have radiochemotherapy delivered.

So, change a little bit the balance between surgery and radiotherapy in favor of radiotherapy. But the next trials are coming, right? Maybe the next trials will tell us that surgery is still very important. The other thing, which is also probably of great interest in the field, is, are we able to predict after radiochemotherapy who are the patients who really need durvalumab? We discussed together before this, there’s no subgroup of patients benefitting more than the other ones. But the UK colleagues, in particular, are developing tests to detect minimal residual disease. So, in the blood, you can test. If some very personalized mutations can still be found after you have completed your curative intent treatment, it means the disease will relapse at some point. So, if you’re sensitive enough to identify the patient at risk of relapse and the patient not at risk of relapse, it would be good for the society because you could only give durvalumab to the patients who are at risk. But we’re still not there. I think we should move this way, also for sustainability, over time.

Transcript Edited for Clarity 
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