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I/O + Chemotherapy in Treatment-Naive ES-SCLC

Panelists: Byoung Chul Cho, MD, PhD, Yonsei Cancer Center at Yonsei University College of Medicine; Pasi A. Janne, MD, PhD, Lowe Center for Thoracic Oncology, Belfer Center for Applied Cancer Science, Harvard University; Suresh S. Ramalingam, MD, FASCO, Winship Cancer Institute of Emory University; Johan F. Vansteenkiste, MD, PhD, Leuven University Hospital
Published: Wednesday, Nov 06, 2019



Transcript:

Suresh S. Ramalingam, MD, FASCO: Let’s now switch gears and talk about small cell lung cancer, where we have seen very little progress in more than 2 decades, but finally we may be turning the corner. Johan, talk to us about immune checkpoint inhibition in small cell lung cancer.

Johan F. Vansteenkiste, MD, PhD: What we learned from the trials in relapsed small cell lung cancer was rather disappointing, with median progression-free survival [PFS] of 1.5 months to 2 months. There were some patients who made a slight plateau, but overall, I felt the relapsed treatment data with immunotherapy were rather disappointing. We have 2 randomized-controlled trials in the first-line setting now, and that is adding either atezolizumab to platinum-etoposide or durvalumab to platinum-etoposide.

There’s a bit longer follow-up in the atezolizumab trial, which had its initial report in 2018, while the CASPIAN trial has its initial report in 2019. Actually, when you look at the trials, in my opinion, they are very similar. They’re very similar in populations, perhaps slightly more patients with metastatic, liver metastatic disease in the atezolizumab trial, but otherwise they’re very similar. They’re also very similar in outcome, and OS [overall survival], in PFS, in the response rate, and in tolerability profile. They’re both with anti–PD-L1 [anti–programmed death-ligand 1] antibodies as well. So I think the 2 trials really complement each other.

What do they tell us? Well, they tell us that even with chemoimmunotherapy, you lose a lot of small cell lung cancer patients during the first year of therapy. It’s better than it was before, but it’s only slightly better. The difference mainly comes in the interval between 1 and 2 years, where in both of these trials for long-term overall survival for small cell lung cancer, stage IV, there is a difference if you add atezolizumab or durvalumab to just platinum-etoposide. It means that many patients with small cell lung cancer will still fail our initial therapy.

In contrast with non–small cell lung cancer, we are not there yet at all. But there is a fraction of patients who benefit from adding immunotherapy. For that fraction of patients, the problem is it’s very difficult to define the fraction because of the data that we have seen until now. There are some new data here at the ESMO [European Society for Medical Oncology] meeting, but I can only comment on them very briefly. Both PD-L1 expression and tumor mutational burden, in tissue, or in plasma, seem to fail to predict which patients will benefit. It’s true progress, but we don’t really know which patients have the benefit, which is difficult, of course, because it’s not exactly cheap therapy.

Pasi A. Jänne, MD, PhD: I will say that despite that, it is really 1 of the first trials to move the needle even though it’s just a little bit, but at least it’s a little bit. I think we’ve certainly widely adopted using immunotherapy in combination with chemotherapy because of that in small cell lung cancer, because progress has otherwise been quite limited, unfortunately.

Johan F. Vansteenkiste, MD, PhD: It’s the first progress in 20 years.

Suresh S. Ramalingam, MD, FASCO: Cho, we were here 2 weeks ago at the World Conference on Lung Cancer, which was the first time we heard the CASPIAN trial results. Can you talk a little bit about your interpretation of the CASPIAN results, topline data, and what you took home with you?

Byoung Chul Cho, MD, PhD: As Johan already mentioned, in my mind, CASPIAN is a duplicate of IMpower133. The design of the study is adding durvalumab, another anti–PD-L1 inhibitor, to cytotoxic chemotherapy, etoposide-carboplatin. It slightly improved progression-free survival and slightly improved the overall survival. I do believe, as Dr Pasi Jänne already mentioned, this will be implemented in our routine practice in treatment naive extensive-stage or recurrent small cell lung cancer.

But I have question here that, as Johan already mentioned, why the Kaplan-Meier survival curve, by adding immunotherapy in extensive small cell lung cancer, is different from that in non–small cell lung cancer. We do see a quite early separation of the Kaplan-Meier survival curve by adding immunotherapy to cytotoxic chemotherapy in advanced-stage non–small cell lung cancer shown in the KEYNOTE-189 and 407 studies, but this study shows a very modest and nearly overlapping Kaplan-Meier survival curve in the initial 5 or 6 months of treatment. So again, the survival benefit, in my mind, is quite modest. But for the last 30 years, these are the first data demonstrating overall survival benefit in treatment naive extensive-stage small cell lung cancer, so we should adopt these data in our routine practice.

Pasi A. Jänne, MD, PhD: There’s at least 1 more trial coming. There is a pembro [pembrolizumab] trial that is completed, and we eagerly await those results to see if they again are similar to the other 2.

Johan F. Vansteenkiste, MD, PhD: I was also puzzled as to why the difference between non–small cell lung cancer and small cell lung cancer, but actually if you look to simple pathology slides, simple H&E [hemaotoxylin and eosin] staining, in non–small cell lung cancer, you see these tumor islands of adenocarcinoma and some mucus, and you see a lot of tumor microenvironment. In small cell lung cancer, you see these small cells, a little cytoplasm, very hard staining of the old cell carcinoma from the past. There’s nearly no tumor microenvironment. So probably my guess, I’m not extremely optimistic, it will remain a difficult thing to largely influence small cell lung cancer with just checkpoint inhibitors alone. Perhaps other things will be needed such as cellular therapies, adding vaccines, or whatever, I don’t know, bispecific antibodies. But just checkpoint alone won’t make the earth quake in small cell lung cancer as they have done in non–small cell lung cancer. I believe this is a reality we have to accept.

Transcript Edited for Clarity

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Transcript:

Suresh S. Ramalingam, MD, FASCO: Let’s now switch gears and talk about small cell lung cancer, where we have seen very little progress in more than 2 decades, but finally we may be turning the corner. Johan, talk to us about immune checkpoint inhibition in small cell lung cancer.

Johan F. Vansteenkiste, MD, PhD: What we learned from the trials in relapsed small cell lung cancer was rather disappointing, with median progression-free survival [PFS] of 1.5 months to 2 months. There were some patients who made a slight plateau, but overall, I felt the relapsed treatment data with immunotherapy were rather disappointing. We have 2 randomized-controlled trials in the first-line setting now, and that is adding either atezolizumab to platinum-etoposide or durvalumab to platinum-etoposide.

There’s a bit longer follow-up in the atezolizumab trial, which had its initial report in 2018, while the CASPIAN trial has its initial report in 2019. Actually, when you look at the trials, in my opinion, they are very similar. They’re very similar in populations, perhaps slightly more patients with metastatic, liver metastatic disease in the atezolizumab trial, but otherwise they’re very similar. They’re also very similar in outcome, and OS [overall survival], in PFS, in the response rate, and in tolerability profile. They’re both with anti–PD-L1 [anti–programmed death-ligand 1] antibodies as well. So I think the 2 trials really complement each other.

What do they tell us? Well, they tell us that even with chemoimmunotherapy, you lose a lot of small cell lung cancer patients during the first year of therapy. It’s better than it was before, but it’s only slightly better. The difference mainly comes in the interval between 1 and 2 years, where in both of these trials for long-term overall survival for small cell lung cancer, stage IV, there is a difference if you add atezolizumab or durvalumab to just platinum-etoposide. It means that many patients with small cell lung cancer will still fail our initial therapy.

In contrast with non–small cell lung cancer, we are not there yet at all. But there is a fraction of patients who benefit from adding immunotherapy. For that fraction of patients, the problem is it’s very difficult to define the fraction because of the data that we have seen until now. There are some new data here at the ESMO [European Society for Medical Oncology] meeting, but I can only comment on them very briefly. Both PD-L1 expression and tumor mutational burden, in tissue, or in plasma, seem to fail to predict which patients will benefit. It’s true progress, but we don’t really know which patients have the benefit, which is difficult, of course, because it’s not exactly cheap therapy.

Pasi A. Jänne, MD, PhD: I will say that despite that, it is really 1 of the first trials to move the needle even though it’s just a little bit, but at least it’s a little bit. I think we’ve certainly widely adopted using immunotherapy in combination with chemotherapy because of that in small cell lung cancer, because progress has otherwise been quite limited, unfortunately.

Johan F. Vansteenkiste, MD, PhD: It’s the first progress in 20 years.

Suresh S. Ramalingam, MD, FASCO: Cho, we were here 2 weeks ago at the World Conference on Lung Cancer, which was the first time we heard the CASPIAN trial results. Can you talk a little bit about your interpretation of the CASPIAN results, topline data, and what you took home with you?

Byoung Chul Cho, MD, PhD: As Johan already mentioned, in my mind, CASPIAN is a duplicate of IMpower133. The design of the study is adding durvalumab, another anti–PD-L1 inhibitor, to cytotoxic chemotherapy, etoposide-carboplatin. It slightly improved progression-free survival and slightly improved the overall survival. I do believe, as Dr Pasi Jänne already mentioned, this will be implemented in our routine practice in treatment naive extensive-stage or recurrent small cell lung cancer.

But I have question here that, as Johan already mentioned, why the Kaplan-Meier survival curve, by adding immunotherapy in extensive small cell lung cancer, is different from that in non–small cell lung cancer. We do see a quite early separation of the Kaplan-Meier survival curve by adding immunotherapy to cytotoxic chemotherapy in advanced-stage non–small cell lung cancer shown in the KEYNOTE-189 and 407 studies, but this study shows a very modest and nearly overlapping Kaplan-Meier survival curve in the initial 5 or 6 months of treatment. So again, the survival benefit, in my mind, is quite modest. But for the last 30 years, these are the first data demonstrating overall survival benefit in treatment naive extensive-stage small cell lung cancer, so we should adopt these data in our routine practice.

Pasi A. Jänne, MD, PhD: There’s at least 1 more trial coming. There is a pembro [pembrolizumab] trial that is completed, and we eagerly await those results to see if they again are similar to the other 2.

Johan F. Vansteenkiste, MD, PhD: I was also puzzled as to why the difference between non–small cell lung cancer and small cell lung cancer, but actually if you look to simple pathology slides, simple H&E [hemaotoxylin and eosin] staining, in non–small cell lung cancer, you see these tumor islands of adenocarcinoma and some mucus, and you see a lot of tumor microenvironment. In small cell lung cancer, you see these small cells, a little cytoplasm, very hard staining of the old cell carcinoma from the past. There’s nearly no tumor microenvironment. So probably my guess, I’m not extremely optimistic, it will remain a difficult thing to largely influence small cell lung cancer with just checkpoint inhibitors alone. Perhaps other things will be needed such as cellular therapies, adding vaccines, or whatever, I don’t know, bispecific antibodies. But just checkpoint alone won’t make the earth quake in small cell lung cancer as they have done in non–small cell lung cancer. I believe this is a reality we have to accept.

Transcript Edited for Clarity
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