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CASPIAN Trial: Durvalumab and Chemotherapy in 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: Thursday, Nov 14, 2019



Transcript:

Suresh S. Ramalingam, MD, FASCO: Johan, at this meeting, Luis Paz-Ares, MD, PhD, presented some data from the CASPIAN study further providing clarification on patterns of progression, biomarker evaluation. Can you walk us through those data?

Johan F. Vansteenkiste, MD, PhD: Yes. Well, what was presented was, of course, a repeat of the output of the CASPIAN data. In the CASPIAN data, pre-treatment biopsies were not mandatory, but they were more frequent than they were in IMpower133, where it was about one-third of the patients. Here, if I remember, there were tissue samples in 55% of the patients. The authors looked at the PD-L1 [programmed death-ligand 1] expression on tumor cells and on immune cells, and what they found was that even if you use the 1% cutoff, the PD-L1 expression on tumor cells of small cell lung cancer was very low.

The PD-L1 expression on immune cells was present in a more substantial degree in only 20% of the patients. It’s again relating to what I just said about tumor microenvironment. You don’t have to detect much, unfortunately. They used the SP263 antibody, and they used it in that trial as a continuous variable. They found some relationships, but if you put them together in a forest plot, again there was no biomarker on tissue that could predict which patient is the one who really has the benefit from adding durvalumab to the platinum-etoposide.

Suresh S. Ramalingam, MD, FASCO: Do we use PD-L1 expression to select therapy for small cell lung cancer patients?

Pasi A. Jänne, MD, PhD: Not at the moment. Expression levels tend to be fairly low, and there was a single-agent pembro [pembrolizumab] trial that did that, and I believe it was around 20% or so who had some degree of expression. The majority of patients don’t. But it’s not routinely used, at least not in our practice.

Suresh S. Ramalingam, MD, FASCO: You mentioned single-agent pembrolizumab, Pasi. It has an FDA approval in the United States for third-line therapy. Is that something you routinely use in your patient population?

Pasi A. Jänne, MD, PhD: Typically in that setting we do use it. There’s obviously been exploration of other immune checkpoint inhibitors there as single agents. But with the approval of pembrolizumab, we do end up using that. Sometimes you do see the remarkable responses like you see in non–small cell lung cancer, but I tend to think they’re a little bit less common.

Suresh S. Ramalingam, MD, FASCO: Now, when we use chemotherapy plus PD-L1 inhibition in the frontline setting, is there a role for immunotherapy in the second-line setting?

Johan F. Vansteenkiste, MD, PhD: In small cell lung cancer?

Suresh S. Ramalingam, MD, FASCO: In small cell lung cancer.

Johan F. Vansteenkiste, MD, PhD: At this time, there could be a role for combined immunotherapy, so combining anti–PD-1 [anti-programmed cell death protein 1]/PD-L1 with anti–CTLA-4 [anti–cytotoxic T-lymphocyte–associated protein 4]. But it’s still a field that is pretty much in exploration. The reality is that after first-line failure in small cell lung cancer, stage IV, there is no real good treatment. In general, these patients are better off if you have the opportunity to include them in a clinical trial—that’s probably the best that you can do. But of course, there is work ongoing with new immunotherapies, especially cellular therapies or bispecific antibodies that together with checkpoint inhibitors may have an effect on that aspect. But clearly that is way too early for clinical practice.

Suresh S. Ramalingam, MD, FASCO: What salvage therapy options are you excited about, Cho, as you see all the presentations at the ESMO [European Society for Medical Oncology] and World Conference on Lung Cancer annual meetings?

Byoung Chul Cho, MD, PhD: Except for immunotherapy…?

Suresh S. Ramalingam, MD, FASCO: Besides immunotherapy, do you see anything coming down the road? I’ve heard some data about lurbinectedin, which is reading out hopefully in the next year or so. They had about 100 patients treated with monotherapy, and the response rates were about 45% in the sensitive small cell lung cancer patient population.

Pasi A. Jänne, MD, PhD: That is pretty good, and as the only approved therapy there is topotecan, which can be a tough treatment, especially if that regimen is administered for the 5 days in a row. So again, having alternative strategies in that scenario would be great. But I agree with Johan, that is definitely an area of absolute need for clinical trials and in new drug development. But it’s good to know they’re coming.

Johan F. Vansteenkiste, MD, PhD: We will hear a little bit more about lurbinectedin in the future. But for me a bit unfortunately, the phase III trial will compare the standard, which is topotecan, and this is not a gold standard, not with lurbinectedin but with doxorubicin plus lurbinectedin. It will not be a full or pure picture, but it’s nice to look forward to these results anyway.

Suresh S. Ramalingam, MD, FASCO: To sum up this part of the conversation, in small cell lung cancer we finally see some improvement. We know that atezo [atezolizumab] plus chemotherapy is already approved by the FDA and is used in clinical practice in the United States. The CASPIAN data clearly showed that durva [durvalumab] also belongs in that space with very comparable improvement in overall survival and PFS [progression-free survival], as with atezolizumab. We look forward to having durvalumab as another immune checkpoint inhibitor in the frontline space for small cell lung cancer.

Johan F. Vansteenkiste, MD, PhD: Just to add, just a few weeks ago, the EMA [European Medicines Agency] also approved platinum-etoposide-atezolizumab.

Suresh S. Ramalingam, MD, FASCO: So clearly, the use of these agents is going to expand to other parts of the world as well, which will be good news for our patients with small cell lung cancer. As the panel clearly pointed out, biomarkers for these patients and options beyond first-line chemoimmunotherapy are all going to be important research questions moving forward.

Transcript Edited for Clarity

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Transcript:

Suresh S. Ramalingam, MD, FASCO: Johan, at this meeting, Luis Paz-Ares, MD, PhD, presented some data from the CASPIAN study further providing clarification on patterns of progression, biomarker evaluation. Can you walk us through those data?

Johan F. Vansteenkiste, MD, PhD: Yes. Well, what was presented was, of course, a repeat of the output of the CASPIAN data. In the CASPIAN data, pre-treatment biopsies were not mandatory, but they were more frequent than they were in IMpower133, where it was about one-third of the patients. Here, if I remember, there were tissue samples in 55% of the patients. The authors looked at the PD-L1 [programmed death-ligand 1] expression on tumor cells and on immune cells, and what they found was that even if you use the 1% cutoff, the PD-L1 expression on tumor cells of small cell lung cancer was very low.

The PD-L1 expression on immune cells was present in a more substantial degree in only 20% of the patients. It’s again relating to what I just said about tumor microenvironment. You don’t have to detect much, unfortunately. They used the SP263 antibody, and they used it in that trial as a continuous variable. They found some relationships, but if you put them together in a forest plot, again there was no biomarker on tissue that could predict which patient is the one who really has the benefit from adding durvalumab to the platinum-etoposide.

Suresh S. Ramalingam, MD, FASCO: Do we use PD-L1 expression to select therapy for small cell lung cancer patients?

Pasi A. Jänne, MD, PhD: Not at the moment. Expression levels tend to be fairly low, and there was a single-agent pembro [pembrolizumab] trial that did that, and I believe it was around 20% or so who had some degree of expression. The majority of patients don’t. But it’s not routinely used, at least not in our practice.

Suresh S. Ramalingam, MD, FASCO: You mentioned single-agent pembrolizumab, Pasi. It has an FDA approval in the United States for third-line therapy. Is that something you routinely use in your patient population?

Pasi A. Jänne, MD, PhD: Typically in that setting we do use it. There’s obviously been exploration of other immune checkpoint inhibitors there as single agents. But with the approval of pembrolizumab, we do end up using that. Sometimes you do see the remarkable responses like you see in non–small cell lung cancer, but I tend to think they’re a little bit less common.

Suresh S. Ramalingam, MD, FASCO: Now, when we use chemotherapy plus PD-L1 inhibition in the frontline setting, is there a role for immunotherapy in the second-line setting?

Johan F. Vansteenkiste, MD, PhD: In small cell lung cancer?

Suresh S. Ramalingam, MD, FASCO: In small cell lung cancer.

Johan F. Vansteenkiste, MD, PhD: At this time, there could be a role for combined immunotherapy, so combining anti–PD-1 [anti-programmed cell death protein 1]/PD-L1 with anti–CTLA-4 [anti–cytotoxic T-lymphocyte–associated protein 4]. But it’s still a field that is pretty much in exploration. The reality is that after first-line failure in small cell lung cancer, stage IV, there is no real good treatment. In general, these patients are better off if you have the opportunity to include them in a clinical trial—that’s probably the best that you can do. But of course, there is work ongoing with new immunotherapies, especially cellular therapies or bispecific antibodies that together with checkpoint inhibitors may have an effect on that aspect. But clearly that is way too early for clinical practice.

Suresh S. Ramalingam, MD, FASCO: What salvage therapy options are you excited about, Cho, as you see all the presentations at the ESMO [European Society for Medical Oncology] and World Conference on Lung Cancer annual meetings?

Byoung Chul Cho, MD, PhD: Except for immunotherapy…?

Suresh S. Ramalingam, MD, FASCO: Besides immunotherapy, do you see anything coming down the road? I’ve heard some data about lurbinectedin, which is reading out hopefully in the next year or so. They had about 100 patients treated with monotherapy, and the response rates were about 45% in the sensitive small cell lung cancer patient population.

Pasi A. Jänne, MD, PhD: That is pretty good, and as the only approved therapy there is topotecan, which can be a tough treatment, especially if that regimen is administered for the 5 days in a row. So again, having alternative strategies in that scenario would be great. But I agree with Johan, that is definitely an area of absolute need for clinical trials and in new drug development. But it’s good to know they’re coming.

Johan F. Vansteenkiste, MD, PhD: We will hear a little bit more about lurbinectedin in the future. But for me a bit unfortunately, the phase III trial will compare the standard, which is topotecan, and this is not a gold standard, not with lurbinectedin but with doxorubicin plus lurbinectedin. It will not be a full or pure picture, but it’s nice to look forward to these results anyway.

Suresh S. Ramalingam, MD, FASCO: To sum up this part of the conversation, in small cell lung cancer we finally see some improvement. We know that atezo [atezolizumab] plus chemotherapy is already approved by the FDA and is used in clinical practice in the United States. The CASPIAN data clearly showed that durva [durvalumab] also belongs in that space with very comparable improvement in overall survival and PFS [progression-free survival], as with atezolizumab. We look forward to having durvalumab as another immune checkpoint inhibitor in the frontline space for small cell lung cancer.

Johan F. Vansteenkiste, MD, PhD: Just to add, just a few weeks ago, the EMA [European Medicines Agency] also approved platinum-etoposide-atezolizumab.

Suresh S. Ramalingam, MD, FASCO: So clearly, the use of these agents is going to expand to other parts of the world as well, which will be good news for our patients with small cell lung cancer. As the panel clearly pointed out, biomarkers for these patients and options beyond first-line chemoimmunotherapy are all going to be important research questions moving forward.

Transcript Edited for Clarity
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