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Practical Considerations for Immunotherapy in Stage 3 NSCLC

Insights From: Suresh Senan, MD, VU University Medical Center; Solange Peters, MD, PhD, Centre Hospitalier Universitaire Vaudois
Published: Wednesday, Apr 04, 2018



Transcript: 

Suresh Senan, MRCP, FRCR, PhD: In locally advanced non–small cell lung cancer, the timing of immunotherapy in the PACIFIC trial was up to 42 days after chemoradiotherapy. So, one could ask whether this is really the optimal time because the selection of patients was those who did not progress after standard chemoradiotherapy. So, it begs the question: Would there have been a group of patients who could have benefited and not progressed had immunotherapy been administered earlier?

There are 2 other aspects to consider. There are trials ongoing to evaluate immune checkpoint inhibitors during concurrent chemoradiotherapy. Now, it may be beneficial, but we do not know for which patients it will be beneficial. So, it could be a question of in some subgroups of patients that it may be beneficial to start concurrent, but we are not yet informed as to which group that is. For patients who get immunotherapy only after, what’s not clear to us is, should we have to wait until the performance status is improved to 0 or 1 before getting it? We do not know. We do know that there was no increase in esophagitis in the patients who received durvalumab after completing chemoradiotherapy. So, is it necessary to wait until the acute toxicity is fully subsided before starting immunotherapy, particularly if there’s no enhancement of that toxicity?

The PACIFIC trial also showed that in the first 6 to 8 weeks, there was quite a big increase in the percentage of patients who got progressive disease, which begs the question, can this problem be limited by starting immunotherapy early, directly after chemoradiotherapy? I think we need a bit of safety data to show that the esophagitis is not going to be prolonged and that when we’re thinking about cure, we should be a little bit more flexible. If the patient’s fit when they come in, we should not really wait for them to be totally fit before administering immunotherapy, because it seems to be a window in the first 6 weeks or so where a lot of the events are taking place, which we would like to prevent.

And finally, we shouldn’t forget that 30% of patients in the durvalumab arm had disease progression in the first 12 months. So, perhaps if we knew which subgroup they were, perhaps this is a group where early administration, or even concurrent administration, may play a role because we’ve addressed part of the problem but we have not solved it totally. The problem of disease recurrence is in the first 12 months.

My center participated in the PACIFIC trial. At this point, we have 2 other trials: the one other trial of immuno-oncology in locally advanced non–small cell lung cancer and another on limited non–small cell lung cancer. So, we are comfortable with the combinations. We are comfortable with the toxicity profiles. But of course, in the other 2 trials, we have to wait for it to be reported because the drugs are different, the patient populations are different, and the sequencing is different. So, I think careful assessment and follow-up of data, of toxicity information, is necessary to help us feel more comfortable with this combination therapy. But the initial results are quite positive.

One other point to note is that we do not know, because there’s no registration before starting chemoradiotherapy, too much about the patients who dropped out. So, are we just seeing the results in a very select fit cohort of patients with small tumors, for example? Although the study gives us information about stages 3A and 3B, as a radiation oncologist, one needs to know about tumor volume, amount of esophagitis, number of nodes, because these are things we need to factor in. We would be a lot more comfortable if we had that information as well before implementing immunotherapy for chemotherapy-radiated therapy.

Solange Peters, MD, PhD: Well, based on the data given by PACIFIC, at the time being there’s no need to test for PD-L1 in that disease. And in particular in the disease, having tissue is difficult because very often you just have a small biopsy, you have a cytology sample for these patients provided or found in a bronchoscopy or something like that. So, you shouldn’t make the effort to try to have a biopsy and test for PD-L1 because it doesn’t impact your treatment at all. And if you have a relapse afterwards, you can still biopsy the relapse. But I think you shouldn’t insist on doing that.

If I were an investigator in a trial, the PACIFIC couldn’t do that, I would question other biomarkers beyond PD-L1 because there is a whole landscape of biomarkers. And the one I prefer, or we prefer in the field, is to look at the mutation burden, how many mutations are to be found in the tumor. We call it tumor mutation burden. But for that, you need quite a lot of tissue. So, this maybe could not be done in real life. At the time being, you need to know what tumor you have, to be sure you have lung cancer, and then you have to proceed with a treatment.

Marina Chiara Garassino, MD: The PACIFIC trial is really important because we have the information that continuing with durvalumab after chemoradiation can increase the progression-free survival. However, this is a very selected population because patients were treated with concurrent chemoradiation, which is not the treatment for all the patients. Sometimes, for example, you can decide to go with the sequential treatment, go before with chemotherapy and then with the radiation therapy. So, we have no information if the durvalumab works or so in the sequential therapy. We think yes, but it must be proven. For example, we have an expanded access program, which allows you to also treat patients in the sequential treatment. And this can be important to have information about the safety and also on the efficacy of this kind of strategy.

The optimal point to start immunotherapy is as soon as you can. Because we know that there is an important rationale behind the use of radiotherapy and also chemotherapy before the immunotherapy, which is the activation of the T cells, the decrease of the myeloid suppressor cells, but importantly, the increase of the immunogenic death of the tumor, which can increase the number of neoantigens.

So, potentially as soon as you can, you must start with the immunotherapy to exploit all the benefits of chemotherapy in the use of immunotherapy. In fact, if you look at the subgroup analysis of the PACIFIC trial, you can observe that the most benefit is for patients who started immediately with the immunotherapy. However, in some cases, you have to wait because maybe the patient still has some toxicity from the previous treatment. What we know from the PACIFIC is that you can do it because the benefit is everywhere, is longer for the subgroups. But potentially, if you want to exploit the rationale of the combination, I think that you can start as soon as possible.

Potentially, all of the patients with a stage 3 locally advanced non–small cell lung cancer can benefit from this kind of treatment. We have to just exclude the patients with the stronger contraindications for immunotherapy, such as active immune disease, or for whom we do not have information about the patients who develop, for example, lung toxicity after the radiation. So, now we must be very careful with these kinds of patients. But what we know from the PACIFIC is that there is not an increase of their toxicity in the lung toxicity for this kind of patient. However, in my opinion, we must be very careful with the treatment with this patient. But potentially considering that the progression-free survival is 11 months for this kind of patient, for which there was nothing until 6 months ago, I think that potentially this can be an option for all of the patients with stage 3 non–small cell lung cancer.

Transcript Edited for Clarity 
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Transcript: 

Suresh Senan, MRCP, FRCR, PhD: In locally advanced non–small cell lung cancer, the timing of immunotherapy in the PACIFIC trial was up to 42 days after chemoradiotherapy. So, one could ask whether this is really the optimal time because the selection of patients was those who did not progress after standard chemoradiotherapy. So, it begs the question: Would there have been a group of patients who could have benefited and not progressed had immunotherapy been administered earlier?

There are 2 other aspects to consider. There are trials ongoing to evaluate immune checkpoint inhibitors during concurrent chemoradiotherapy. Now, it may be beneficial, but we do not know for which patients it will be beneficial. So, it could be a question of in some subgroups of patients that it may be beneficial to start concurrent, but we are not yet informed as to which group that is. For patients who get immunotherapy only after, what’s not clear to us is, should we have to wait until the performance status is improved to 0 or 1 before getting it? We do not know. We do know that there was no increase in esophagitis in the patients who received durvalumab after completing chemoradiotherapy. So, is it necessary to wait until the acute toxicity is fully subsided before starting immunotherapy, particularly if there’s no enhancement of that toxicity?

The PACIFIC trial also showed that in the first 6 to 8 weeks, there was quite a big increase in the percentage of patients who got progressive disease, which begs the question, can this problem be limited by starting immunotherapy early, directly after chemoradiotherapy? I think we need a bit of safety data to show that the esophagitis is not going to be prolonged and that when we’re thinking about cure, we should be a little bit more flexible. If the patient’s fit when they come in, we should not really wait for them to be totally fit before administering immunotherapy, because it seems to be a window in the first 6 weeks or so where a lot of the events are taking place, which we would like to prevent.

And finally, we shouldn’t forget that 30% of patients in the durvalumab arm had disease progression in the first 12 months. So, perhaps if we knew which subgroup they were, perhaps this is a group where early administration, or even concurrent administration, may play a role because we’ve addressed part of the problem but we have not solved it totally. The problem of disease recurrence is in the first 12 months.

My center participated in the PACIFIC trial. At this point, we have 2 other trials: the one other trial of immuno-oncology in locally advanced non–small cell lung cancer and another on limited non–small cell lung cancer. So, we are comfortable with the combinations. We are comfortable with the toxicity profiles. But of course, in the other 2 trials, we have to wait for it to be reported because the drugs are different, the patient populations are different, and the sequencing is different. So, I think careful assessment and follow-up of data, of toxicity information, is necessary to help us feel more comfortable with this combination therapy. But the initial results are quite positive.

One other point to note is that we do not know, because there’s no registration before starting chemoradiotherapy, too much about the patients who dropped out. So, are we just seeing the results in a very select fit cohort of patients with small tumors, for example? Although the study gives us information about stages 3A and 3B, as a radiation oncologist, one needs to know about tumor volume, amount of esophagitis, number of nodes, because these are things we need to factor in. We would be a lot more comfortable if we had that information as well before implementing immunotherapy for chemotherapy-radiated therapy.

Solange Peters, MD, PhD: Well, based on the data given by PACIFIC, at the time being there’s no need to test for PD-L1 in that disease. And in particular in the disease, having tissue is difficult because very often you just have a small biopsy, you have a cytology sample for these patients provided or found in a bronchoscopy or something like that. So, you shouldn’t make the effort to try to have a biopsy and test for PD-L1 because it doesn’t impact your treatment at all. And if you have a relapse afterwards, you can still biopsy the relapse. But I think you shouldn’t insist on doing that.

If I were an investigator in a trial, the PACIFIC couldn’t do that, I would question other biomarkers beyond PD-L1 because there is a whole landscape of biomarkers. And the one I prefer, or we prefer in the field, is to look at the mutation burden, how many mutations are to be found in the tumor. We call it tumor mutation burden. But for that, you need quite a lot of tissue. So, this maybe could not be done in real life. At the time being, you need to know what tumor you have, to be sure you have lung cancer, and then you have to proceed with a treatment.

Marina Chiara Garassino, MD: The PACIFIC trial is really important because we have the information that continuing with durvalumab after chemoradiation can increase the progression-free survival. However, this is a very selected population because patients were treated with concurrent chemoradiation, which is not the treatment for all the patients. Sometimes, for example, you can decide to go with the sequential treatment, go before with chemotherapy and then with the radiation therapy. So, we have no information if the durvalumab works or so in the sequential therapy. We think yes, but it must be proven. For example, we have an expanded access program, which allows you to also treat patients in the sequential treatment. And this can be important to have information about the safety and also on the efficacy of this kind of strategy.

The optimal point to start immunotherapy is as soon as you can. Because we know that there is an important rationale behind the use of radiotherapy and also chemotherapy before the immunotherapy, which is the activation of the T cells, the decrease of the myeloid suppressor cells, but importantly, the increase of the immunogenic death of the tumor, which can increase the number of neoantigens.

So, potentially as soon as you can, you must start with the immunotherapy to exploit all the benefits of chemotherapy in the use of immunotherapy. In fact, if you look at the subgroup analysis of the PACIFIC trial, you can observe that the most benefit is for patients who started immediately with the immunotherapy. However, in some cases, you have to wait because maybe the patient still has some toxicity from the previous treatment. What we know from the PACIFIC is that you can do it because the benefit is everywhere, is longer for the subgroups. But potentially, if you want to exploit the rationale of the combination, I think that you can start as soon as possible.

Potentially, all of the patients with a stage 3 locally advanced non–small cell lung cancer can benefit from this kind of treatment. We have to just exclude the patients with the stronger contraindications for immunotherapy, such as active immune disease, or for whom we do not have information about the patients who develop, for example, lung toxicity after the radiation. So, now we must be very careful with these kinds of patients. But what we know from the PACIFIC is that there is not an increase of their toxicity in the lung toxicity for this kind of patient. However, in my opinion, we must be very careful with the treatment with this patient. But potentially considering that the progression-free survival is 11 months for this kind of patient, for which there was nothing until 6 months ago, I think that potentially this can be an option for all of the patients with stage 3 non–small cell lung cancer.

Transcript Edited for Clarity 
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