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NSCLC: Immunotherapy Beyond Progression

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: Tuesday, Oct 31, 2017



Transcript: 

Suresh S. Ramalingam, MD: A related issue is treatment beyond progression, which is when you started patients on a checkpoint inhibitor, they got the scan, and patients have progression right off the bat. Or, some initially benefit and then have progression. There’s this notion that if you give the drug and continue after progression, there might still be some benefit. What are your thoughts on that issue?

Benjamin Besse, MD, PhD: I think treatment beyond progression is not an issue of immunotherapy, it’s a general concern. It may be a good strategy with some TKIs, sometimes with chemotherapy, and with immunotherapy. It’s always the same. There is not 1 kind of progression, there are different kinds. When it’s, for example, metastatic progression with just 1 or 2 lesions and all the rest of the disease, that can be treated with chemotherapy, immunotherapy, or a TKI. Our strategy is always to try to give a local treatment to the progressive site and then go on with immunotherapy. I have to say, in some patients, it’s a very successful approach.

Suresh S. Ramalingam, MD: It’s a patient-to-patient decision. If you have progression at multiple sites, and it’s clear that the patient is not benefiting, you stop treatment. If there is local progression or some slight increase in tumor size, you may want to give benefit of the doubt and continue the checkpoint inhibitor. Is that how you treat?

Giorgio Scagliotti, MD, PhD: Yes. Well, it’s a customized approach. As you said, this is a patient-by-patient approach. This concept of treatment beyond progression came mainly from the field of the oncogenetic tumors. That is a different type of tumor. We are dealing with a series of drugs that are working on the immune system. As you said, when there is systemic progression in multiple sites, you can go at it for another cycle. But then, you need to make a therapeutic decision, because it doesn’t make any sense to hope that 3 or 4 months later the patients will be in remission, because this is against the biology of the disease.

Suresh S. Ramalingam, MD: As we wrap up this discussion on immune checkpoint inhibition, Marina, I want to come back to you about some of the emerging biomarkers. At this meeting, we saw assessment of mutation burden, particularly using peripheral blood. Give us your thoughts on mutation burden as is measured in the tissue or in the blood. What other markers are you looking out for?

Marina Garassino, MD: Thank you for the question, because it’s another important issue. We know that, in principle, mutational burden is important, because you have the creation of new proteins, new antitoxins, so you can have more of an immunity against the cancer. And we also have the results from CheckMate-026 suggesting that when you have a high mutational burden, nivolumab performs better than chemotherapy. But on the contrary, when the mutational burden is low, chemotherapy is much better than nivolumab.

So, the situation is quite complex, because that study was done with the FoundationOne test, which is a good approximation of the whole exome, and it is quite a reliable test. But at the same time, we know that across the labs—and, of course, also the same lab—you can have very different results, and the interpretation of the mutational burden is quite difficult in every center. So, I think that we are far from the clinical use of the mutational burden.

This is much more complex if we talk about the mutational burden on the blood. For the EGFR tyrosine kinase inhibitor, it is wonderful to use the mutational burden for the drug and not on the tissue, and we have a good concordance. But I would suggest not going with a homemade mutational burden test, because they can be not so concordant with, for example, FoundationOne or Whole Exome Sequencing.

Another point that I would like to make is that high mutational burden is an independent factor from PD-L1 expression. So, maybe by combining PD-L1 and mutational burden, we can select better patients. But in my opinion, this is far from the daily practice of tomorrow morning.

Suresh S. Ramalingam, MD: Thank you, that was a very nice overview on biomarkers.

Giorgio Scagliotti, MD, PhD: Can I jump in for just a quick point? Up until now, we were concentrating most of our research on the tumor. When we are trying to emulate the immune system, in principle we are looking to the tumor microenvironment. And we are always forgetting to address, to check, the role of the immune system itself. So, I saw up until now little research on immune infiltrates. And I would like to remind you that also in the context of melanoma, immuno-checkpoints are the standard of care in addition to other agents. They are really game changers.

The tumor shrinkage has been absurd only in those patients in whom there is the expression of immune checkpoints, the expression of PD-L1, and the expression of immune infiltrates. That is a paper that has already been published 4 years ago. And there will be less research on the tumor microenvironment after now. We probably need to work around that, because it’s quite unlikely that we will find 1 single marker to address the issue of immunotherapy, to identify the subgroup. It’s a combination of factors, looking to the tumor and looking to the tumor microenvironment. This is my expectation for the near future in terms of research.

Suresh S. Ramalingam, MD: It is clear that a lot more work remains to be done in this space in terms of the upcoming months. I am eagerly awaiting the phase III trials of chemotherapy plus checkpoint inhibition to understand where that combination fits in. It’s clearly an important clinical question. We only have partial answers.

Transcript Edited for Clarity 

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Transcript: 

Suresh S. Ramalingam, MD: A related issue is treatment beyond progression, which is when you started patients on a checkpoint inhibitor, they got the scan, and patients have progression right off the bat. Or, some initially benefit and then have progression. There’s this notion that if you give the drug and continue after progression, there might still be some benefit. What are your thoughts on that issue?

Benjamin Besse, MD, PhD: I think treatment beyond progression is not an issue of immunotherapy, it’s a general concern. It may be a good strategy with some TKIs, sometimes with chemotherapy, and with immunotherapy. It’s always the same. There is not 1 kind of progression, there are different kinds. When it’s, for example, metastatic progression with just 1 or 2 lesions and all the rest of the disease, that can be treated with chemotherapy, immunotherapy, or a TKI. Our strategy is always to try to give a local treatment to the progressive site and then go on with immunotherapy. I have to say, in some patients, it’s a very successful approach.

Suresh S. Ramalingam, MD: It’s a patient-to-patient decision. If you have progression at multiple sites, and it’s clear that the patient is not benefiting, you stop treatment. If there is local progression or some slight increase in tumor size, you may want to give benefit of the doubt and continue the checkpoint inhibitor. Is that how you treat?

Giorgio Scagliotti, MD, PhD: Yes. Well, it’s a customized approach. As you said, this is a patient-by-patient approach. This concept of treatment beyond progression came mainly from the field of the oncogenetic tumors. That is a different type of tumor. We are dealing with a series of drugs that are working on the immune system. As you said, when there is systemic progression in multiple sites, you can go at it for another cycle. But then, you need to make a therapeutic decision, because it doesn’t make any sense to hope that 3 or 4 months later the patients will be in remission, because this is against the biology of the disease.

Suresh S. Ramalingam, MD: As we wrap up this discussion on immune checkpoint inhibition, Marina, I want to come back to you about some of the emerging biomarkers. At this meeting, we saw assessment of mutation burden, particularly using peripheral blood. Give us your thoughts on mutation burden as is measured in the tissue or in the blood. What other markers are you looking out for?

Marina Garassino, MD: Thank you for the question, because it’s another important issue. We know that, in principle, mutational burden is important, because you have the creation of new proteins, new antitoxins, so you can have more of an immunity against the cancer. And we also have the results from CheckMate-026 suggesting that when you have a high mutational burden, nivolumab performs better than chemotherapy. But on the contrary, when the mutational burden is low, chemotherapy is much better than nivolumab.

So, the situation is quite complex, because that study was done with the FoundationOne test, which is a good approximation of the whole exome, and it is quite a reliable test. But at the same time, we know that across the labs—and, of course, also the same lab—you can have very different results, and the interpretation of the mutational burden is quite difficult in every center. So, I think that we are far from the clinical use of the mutational burden.

This is much more complex if we talk about the mutational burden on the blood. For the EGFR tyrosine kinase inhibitor, it is wonderful to use the mutational burden for the drug and not on the tissue, and we have a good concordance. But I would suggest not going with a homemade mutational burden test, because they can be not so concordant with, for example, FoundationOne or Whole Exome Sequencing.

Another point that I would like to make is that high mutational burden is an independent factor from PD-L1 expression. So, maybe by combining PD-L1 and mutational burden, we can select better patients. But in my opinion, this is far from the daily practice of tomorrow morning.

Suresh S. Ramalingam, MD: Thank you, that was a very nice overview on biomarkers.

Giorgio Scagliotti, MD, PhD: Can I jump in for just a quick point? Up until now, we were concentrating most of our research on the tumor. When we are trying to emulate the immune system, in principle we are looking to the tumor microenvironment. And we are always forgetting to address, to check, the role of the immune system itself. So, I saw up until now little research on immune infiltrates. And I would like to remind you that also in the context of melanoma, immuno-checkpoints are the standard of care in addition to other agents. They are really game changers.

The tumor shrinkage has been absurd only in those patients in whom there is the expression of immune checkpoints, the expression of PD-L1, and the expression of immune infiltrates. That is a paper that has already been published 4 years ago. And there will be less research on the tumor microenvironment after now. We probably need to work around that, because it’s quite unlikely that we will find 1 single marker to address the issue of immunotherapy, to identify the subgroup. It’s a combination of factors, looking to the tumor and looking to the tumor microenvironment. This is my expectation for the near future in terms of research.

Suresh S. Ramalingam, MD: It is clear that a lot more work remains to be done in this space in terms of the upcoming months. I am eagerly awaiting the phase III trials of chemotherapy plus checkpoint inhibition to understand where that combination fits in. It’s clearly an important clinical question. We only have partial answers.

Transcript Edited for Clarity 
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