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Consolidation Immunotherapy for Locally Advanced NSCLC

Panelists: Suresh S. Ramalingam, MD, Emory University School of Medicine; Benjamin Besse, MD, PhD, Gustave Roussy; Marina Garassino, MD National Cancer Institute; Giorgio Scagliotti, MD, PhD, University of Turin
Published Online: Friday, Dec 01, 2017



Transcript: 

Suresh S. Ramalingam, MD: Now, as we wrap up this conversation, I want to take advantage of this opportunity with the experts here to talk about another exciting development that was reported at ESMO this year. It is not in metastatic disease, but in early-stage disease, stage 3 unresectable non–small cell lung cancer. These are patients who are treated with concurrent chemotherapy and radiation. We’ve seen that with such an approach, the 5-year survival rate is in the order of about 20%. There was not much progress in 15, 20 years. But now we learned that durvalumab, a PD-L1 inhibitor, was tested in that setting and has shown activity. A paper will be out in the New England Journal of Medicine this week. So, Benjamin, let me ask you to describe that study to the audience, and then we’ll get Giorgio and Marina to comment on how they view these data as applicable to their patients.

Benjamin Besse, MD, PhD: The PACIFIC study is a very simple study. It’s designed for patients with locally advanced, stage 3 non–small cell lung cancer. They all received definitive chemoradiation, and they were randomized up to 42 days after the end of the chemoradiation between placebo or durvalumab for 1 year. The results are quite impressive, because the PFS of the control arm is 5 months and it’s 16 months in the durvalumab arm. There were, at the press release, a lot of comments on the positivity of the PFS, but it’s a curative setting, a curative intent. What we want to see is more patients cured, so a benefit in terms of overall survival. And we don’t have, though, those data yet. But it’s true that the magnitude of the benefit is so impressive that we all think there will be some improvement in the OS. There is a curve in the time to event or the time to death that also suggests the OS curves should be good. Let’s see the rate of crossover, when the patients will recur in the control arm, if patients receive immunotherapy. But it can be considered today as a new standard of care in this indication.

Suresh S. Ramalingam, MD: Giorgio?

Giorgio Scagliotti, MD, PhD: I fully agree. I fully agree because for the last 20 years, we didn’t progress. The PACIFIC study is filling the gap in a segment of treatment for non–small cell lung cancer that was totally empty for 20 years. Even today—and I’m speaking to my European colleagues—not every patient with locally advanced non–small cell lung cancer is treated universally with concurrent chemotherapy and radiotherapy. If we go, for instance, to the United Kingdom, there is still a significant proportion of patients who are treated with sequential chemotherapy and radiotherapy. Independently from that type of approach that is not a matter of discussion today, there was nothing. So, at the end of chemotherapy and radiotherapy, it was just adopting a wait-and-see policy until progression. That is true. Again, the scientific data tell you that you are prolonging PFS, but that is coming with another notion that, at least for me, is becoming every day more important. It was already mentioned before.

Any type of maintenance is becoming an option, and not only for chemotherapy. That was just an initial approach. It’s true that we are ontogenetically treating tumors until progression and maintaining the treatment. We are also trying to do the same in second-line and in front-line metastatic non–small cell lung cancer with immunotherapy. That is another way to deliver maintenance therapy in an effective way, because the PFS was significantly improved. Again, it’s moving along the line. Obviously, it’s still a dream: to step-by-step make lung cancer a type of chronic disease. That is my simple take from the study.

Suresh S. Ramalingam, MD: One of the things I found particularly important from the study, in addition to what has been discussed so far, was the tolerability profile. We did not see any excessive toxicity. Concerns about pneumonitis were reassuringly not a problem here. The second observation I thought was interesting was that the PD-L1 expression didn’t seem to matter, because this is a different situation where you have given chemotherapy and radiation to the tumor. It’s already inflamed, so the PD-L1 expression didn’t seem to make a big impact on the tumor. What are your observations, Marina? What do you think?

Marina Garassino, MD: I fully agree with all of the panel, because this is really a clear practice-changing study. Just to comment on something different, this study considered only concomitant chemotherapy, and maybe we have to also work on sequential chemoradiation. It’s not always an option for all of the patients with stage 3 unresectable disease, having concomitant therapy from the beginning. So, I think that at the academic level, maybe we can work to collect these data for the other strategies with maintenance with durvalumab.

Suresh S. Ramalingam, MD: So, there are exciting developments in stage 3 disease. Do you see anything on the horizon for patients with resected non–small cell lung cancer, stage 1, 2, or 3A? I know there are a lot of adjuvant therapy trials with checkpoint inhibitors. Is there anything you see as what people should keep their eye out for?

Benjamin Besse, MD, PhD: Well, immunotherapy works in resected melanoma, so a lot of trials are ongoing with PD-1 of a PD-L1 agent in the adjuvant setting. It’s 1 year of treatment. Considering the positivity of durvalumab, that is also curative intent. We are really waiting for these data that could be practice changing. Let’s not forget that in these studies, patients did receive chemotherapy. It’s an additional treatment. If they are eligible for chemotherapy, they receive chemotherapy, and then they’re randomized between immunotherapy and placebo. Let’s wait for the results. One concern that I have is that each time you play with the immune system, you can have a bad surprise, a long-term bad surprise. So, for all of these trial that are in the curative setting, we should have very long follow-up, probably up to 10 years, to be sure that this modulation of the immune system did not impact either side effects or secondary cancer.

Suresh S. Ramalingam, MD: Great.

Transcript Edited for Clarity 

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Transcript: 

Suresh S. Ramalingam, MD: Now, as we wrap up this conversation, I want to take advantage of this opportunity with the experts here to talk about another exciting development that was reported at ESMO this year. It is not in metastatic disease, but in early-stage disease, stage 3 unresectable non–small cell lung cancer. These are patients who are treated with concurrent chemotherapy and radiation. We’ve seen that with such an approach, the 5-year survival rate is in the order of about 20%. There was not much progress in 15, 20 years. But now we learned that durvalumab, a PD-L1 inhibitor, was tested in that setting and has shown activity. A paper will be out in the New England Journal of Medicine this week. So, Benjamin, let me ask you to describe that study to the audience, and then we’ll get Giorgio and Marina to comment on how they view these data as applicable to their patients.

Benjamin Besse, MD, PhD: The PACIFIC study is a very simple study. It’s designed for patients with locally advanced, stage 3 non–small cell lung cancer. They all received definitive chemoradiation, and they were randomized up to 42 days after the end of the chemoradiation between placebo or durvalumab for 1 year. The results are quite impressive, because the PFS of the control arm is 5 months and it’s 16 months in the durvalumab arm. There were, at the press release, a lot of comments on the positivity of the PFS, but it’s a curative setting, a curative intent. What we want to see is more patients cured, so a benefit in terms of overall survival. And we don’t have, though, those data yet. But it’s true that the magnitude of the benefit is so impressive that we all think there will be some improvement in the OS. There is a curve in the time to event or the time to death that also suggests the OS curves should be good. Let’s see the rate of crossover, when the patients will recur in the control arm, if patients receive immunotherapy. But it can be considered today as a new standard of care in this indication.

Suresh S. Ramalingam, MD: Giorgio?

Giorgio Scagliotti, MD, PhD: I fully agree. I fully agree because for the last 20 years, we didn’t progress. The PACIFIC study is filling the gap in a segment of treatment for non–small cell lung cancer that was totally empty for 20 years. Even today—and I’m speaking to my European colleagues—not every patient with locally advanced non–small cell lung cancer is treated universally with concurrent chemotherapy and radiotherapy. If we go, for instance, to the United Kingdom, there is still a significant proportion of patients who are treated with sequential chemotherapy and radiotherapy. Independently from that type of approach that is not a matter of discussion today, there was nothing. So, at the end of chemotherapy and radiotherapy, it was just adopting a wait-and-see policy until progression. That is true. Again, the scientific data tell you that you are prolonging PFS, but that is coming with another notion that, at least for me, is becoming every day more important. It was already mentioned before.

Any type of maintenance is becoming an option, and not only for chemotherapy. That was just an initial approach. It’s true that we are ontogenetically treating tumors until progression and maintaining the treatment. We are also trying to do the same in second-line and in front-line metastatic non–small cell lung cancer with immunotherapy. That is another way to deliver maintenance therapy in an effective way, because the PFS was significantly improved. Again, it’s moving along the line. Obviously, it’s still a dream: to step-by-step make lung cancer a type of chronic disease. That is my simple take from the study.

Suresh S. Ramalingam, MD: One of the things I found particularly important from the study, in addition to what has been discussed so far, was the tolerability profile. We did not see any excessive toxicity. Concerns about pneumonitis were reassuringly not a problem here. The second observation I thought was interesting was that the PD-L1 expression didn’t seem to matter, because this is a different situation where you have given chemotherapy and radiation to the tumor. It’s already inflamed, so the PD-L1 expression didn’t seem to make a big impact on the tumor. What are your observations, Marina? What do you think?

Marina Garassino, MD: I fully agree with all of the panel, because this is really a clear practice-changing study. Just to comment on something different, this study considered only concomitant chemotherapy, and maybe we have to also work on sequential chemoradiation. It’s not always an option for all of the patients with stage 3 unresectable disease, having concomitant therapy from the beginning. So, I think that at the academic level, maybe we can work to collect these data for the other strategies with maintenance with durvalumab.

Suresh S. Ramalingam, MD: So, there are exciting developments in stage 3 disease. Do you see anything on the horizon for patients with resected non–small cell lung cancer, stage 1, 2, or 3A? I know there are a lot of adjuvant therapy trials with checkpoint inhibitors. Is there anything you see as what people should keep their eye out for?

Benjamin Besse, MD, PhD: Well, immunotherapy works in resected melanoma, so a lot of trials are ongoing with PD-1 of a PD-L1 agent in the adjuvant setting. It’s 1 year of treatment. Considering the positivity of durvalumab, that is also curative intent. We are really waiting for these data that could be practice changing. Let’s not forget that in these studies, patients did receive chemotherapy. It’s an additional treatment. If they are eligible for chemotherapy, they receive chemotherapy, and then they’re randomized between immunotherapy and placebo. Let’s wait for the results. One concern that I have is that each time you play with the immune system, you can have a bad surprise, a long-term bad surprise. So, for all of these trial that are in the curative setting, we should have very long follow-up, probably up to 10 years, to be sure that this modulation of the immune system did not impact either side effects or secondary cancer.

Suresh S. Ramalingam, MD: Great.

Transcript Edited for Clarity 
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