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I/O Combination Regimens & the Importance of Biomarkers

Panelists: Naiyer A. Rizvi, MD, NewYork-Presbyterian Hospital; Taofeek K. Owonikoko, MD, PhD, Winship Cancer Institute of Emory University; Ticiana Leal, MD, University of Wisconsin-Madison; Jamie E. Chaft, MD, Memorial Sloan Kettering Cancer Center
Published: Wednesday, Oct 23, 2019



Transcript: 

Naiyer A. Rizvi, MD: Another curveball for Taofeek. There are data that show that for many years, cyclophosphamide is very good at depleting T-regs [regulatory T cells], and doxorubicin is a very immunogenic chemotherapy. You see where I’m going here. We switched from CAP [capecitabine], Cytoxan-Adriamycin-platinum to etoposide largely for tolerance reasons. Maybe we should be revisiting the CAP [capecitabine] regimen with immunotherapy.

Taofeek K. Owonikoko, MD, PhD: I would not disagree with that. I believe that as we understand more and more about the biology of this disease—now that we’re also recognizing that different subset of small cell will respond to different regimens—it would be good to let the biology drive what we do for the patient. We still know that 30% of our patients would not respond to platinum-based doublet chemotherapy. Whether that is the platinum component or the topoisomerase inhibitor component, we don’t know for certain.

But whichever one it is we know that 1/3 of them will not respond. And the question is, is there a subset that we can identify who will respond to the anthracycline-based strategy where we can then offer the CAV [cyclophosphamide-Adriamycin-vincristine] as the chemotherapy of choice. That would be a very difficult study to conduct now, given where we’ve gone with platinum doublet plus immunotherapy. But I think the salvage setting actually gives us the opportunity to answer that question, because now if we go forward and move away from topotecan, that gives us the opportunity to look at those patients who are very poorly responsive to chemotherapy and immunotherapy. And then maybe in salvaging, we could go back if they have the right organ requirement and performance status, and see whether they will be the ones to respond to CAV [cyclophosphamide-Adriamycin-vincristine]. And at the International Association for the Study of Lung Cancer 2019 World Conference on Lung Cancer, they showed some of our data showing that different subtypes of small cell will respond to different classes of agents, although she did not look specifically at anthracyclines.

Naiyer A. Rizvi, MD: I think she looked at gemcitabine.

Taofeek K. Owonikoko, MD, PhD: Yeah, that’s the direction I think the field should move.

Naiyer A. Rizvi, MD: If you look at the IMpower133 data patients cohort, there’s about 40% of patients who had liver metastases. Both arms did fairly poorly and the hazard ratio was still favorable, but the outcomes for those with liver metastases were uniformly worse. Whereas if you didn’t have liver metastases you seem to benefit from immunotherapy more, and the hazard ratio was far more favorable. Maybe we need to think about that subset of liver metastases and figure out a way to do better for those patients as well.
One of the challenges with small cell is we don’t really know which patients are going to have that durable benefit and which aren’t. We talked a little about liver metastases. But in practice I think it’s challenging. Does anyone use PD-L1 [programmed death-ligand 1] expression or TMB [tumor mutational burden], or ctDNA [circulating tumor DNA] to see what’s going on with the patients at all? Jamie? No?

Jamie E. Chaft, MD: The data to date have not shown us a great signal. It’s been conflicting, particularly the plasma data. And I don’t think we have the luxury of time in this patient population to make that differentiation based on biomarker.

Taofeek K. Owonikoko, MD, PhD: Yeah, I think the TMB appeared very promising to start with from the CheckMate 032 trial. With that 1-year overall survival, it was 62%. But then when we went back to the frontline from the IMpower133 study and the blood-based TMB did not seem to predict benefit. It became a little more confusing. But I’m hopeful that we don’t abandon the attempt to develop biomarkers for immunotherapy in this just because it will help the field as a whole. More importantly, I think it will help us have those patients who don’t benefit from the current strategy, so we can figure out what we need to do to make immunotherapy be beneficial to them.

Transcript Edited for Clarity

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Transcript: 

Naiyer A. Rizvi, MD: Another curveball for Taofeek. There are data that show that for many years, cyclophosphamide is very good at depleting T-regs [regulatory T cells], and doxorubicin is a very immunogenic chemotherapy. You see where I’m going here. We switched from CAP [capecitabine], Cytoxan-Adriamycin-platinum to etoposide largely for tolerance reasons. Maybe we should be revisiting the CAP [capecitabine] regimen with immunotherapy.

Taofeek K. Owonikoko, MD, PhD: I would not disagree with that. I believe that as we understand more and more about the biology of this disease—now that we’re also recognizing that different subset of small cell will respond to different regimens—it would be good to let the biology drive what we do for the patient. We still know that 30% of our patients would not respond to platinum-based doublet chemotherapy. Whether that is the platinum component or the topoisomerase inhibitor component, we don’t know for certain.

But whichever one it is we know that 1/3 of them will not respond. And the question is, is there a subset that we can identify who will respond to the anthracycline-based strategy where we can then offer the CAV [cyclophosphamide-Adriamycin-vincristine] as the chemotherapy of choice. That would be a very difficult study to conduct now, given where we’ve gone with platinum doublet plus immunotherapy. But I think the salvage setting actually gives us the opportunity to answer that question, because now if we go forward and move away from topotecan, that gives us the opportunity to look at those patients who are very poorly responsive to chemotherapy and immunotherapy. And then maybe in salvaging, we could go back if they have the right organ requirement and performance status, and see whether they will be the ones to respond to CAV [cyclophosphamide-Adriamycin-vincristine]. And at the International Association for the Study of Lung Cancer 2019 World Conference on Lung Cancer, they showed some of our data showing that different subtypes of small cell will respond to different classes of agents, although she did not look specifically at anthracyclines.

Naiyer A. Rizvi, MD: I think she looked at gemcitabine.

Taofeek K. Owonikoko, MD, PhD: Yeah, that’s the direction I think the field should move.

Naiyer A. Rizvi, MD: If you look at the IMpower133 data patients cohort, there’s about 40% of patients who had liver metastases. Both arms did fairly poorly and the hazard ratio was still favorable, but the outcomes for those with liver metastases were uniformly worse. Whereas if you didn’t have liver metastases you seem to benefit from immunotherapy more, and the hazard ratio was far more favorable. Maybe we need to think about that subset of liver metastases and figure out a way to do better for those patients as well.
One of the challenges with small cell is we don’t really know which patients are going to have that durable benefit and which aren’t. We talked a little about liver metastases. But in practice I think it’s challenging. Does anyone use PD-L1 [programmed death-ligand 1] expression or TMB [tumor mutational burden], or ctDNA [circulating tumor DNA] to see what’s going on with the patients at all? Jamie? No?

Jamie E. Chaft, MD: The data to date have not shown us a great signal. It’s been conflicting, particularly the plasma data. And I don’t think we have the luxury of time in this patient population to make that differentiation based on biomarker.

Taofeek K. Owonikoko, MD, PhD: Yeah, I think the TMB appeared very promising to start with from the CheckMate 032 trial. With that 1-year overall survival, it was 62%. But then when we went back to the frontline from the IMpower133 study and the blood-based TMB did not seem to predict benefit. It became a little more confusing. But I’m hopeful that we don’t abandon the attempt to develop biomarkers for immunotherapy in this just because it will help the field as a whole. More importantly, I think it will help us have those patients who don’t benefit from the current strategy, so we can figure out what we need to do to make immunotherapy be beneficial to them.

Transcript Edited for Clarity
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