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Emerging Therapies for Nonsquamous 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: Wednesday, Dec 06, 2017



Transcript: 

Suresh S. Ramalingam, MD: I want to ask the last question to our panel. As we look at what the next frontier is for immunotherapy in lung cancer, everybody agrees that we’re going to start seeing combinations of checkpoint inhibitors with other agents. Maybe I can start with Giorgio. What are the combinations that you’re excited by?

Giorgio Scagliotti, MD, PhD: The easy answer is to follow the mainstream and say that the I-O/I-O combination that we are currently looking at is the combination of an immune checkpoint inhibitor plus an anti-CTLA4. There are also other agents in the immunity cycles that are currently under investigation in combination with PD-1 inhibitors. My personal take is that we still need to learn a lot about PD-L1 inhibition before moving forward, because in this kind of cross contamination, melanoma is not lung cancer and lung cancer is not melanoma. So, we cannot easily translate what we saw in melanoma to the field of non–small cell lung cancer. We can’t say, “Well, the I-O/I-O combination is definitely the answer.” Because I can easily reply that the role of KRAS in colorectal cancer is not the role of KRAS in lung cancer. The role of BRAF mutations in melanoma is not the role of BRAF mutations in colorectal cancer.

I still believe that the tissue context makes a difference and we need to avoid, as Benjamin said before, to rush to believe that 2 drugs are better than 1 and 3 drugs are better than 2. It is true for targeted therapies, because the biology is different. In this context, it is true that with 1 single inhibitor, it is not easy to manipulate the immune system because the immune system is highly regulated. Every system in the body is intensely regulated, and it’s not easy to manipulate it with 1 single inhibitor. But it’s true that we need to learn. We have successes. We’ve got therapeutic successes. Before moving forward, it is reasonable to explore the combinations, but we need to learn how to best position the PD-L1 and PD-1 inhibitors.

Suresh S. Ramalingam, MD: Marina?

Marina Garassino, MD: I substantially agree with Giorgio, but I am quite impressed by some results coming from IDO1 inhibition, while I’m less confident with the combinations with anti-CTLA4. I also think that the metabolism together with the immune checkpoint inhibitors can be another way to go, so I think that we have a lot of things to learn about. There are a lot of combinations to explore.

Suresh S. Ramalingam, MD: Benjamin?

Benjamin Besse, MD, PhD: I’m very excited by the studies in the refractory setting. You just start the immunotherapy, it doesn't work, and you make a biopsy. There are very nicely designed trials in which you do the biopsy, get a large molecular profile, and then go in with an immunotherapy plus something that is customized based on the molecular profile. I like this idea that immunotherapy is not just a drug you prescribe second-line, but a drug you can play with and with nice combinations. Let’s see the results.

Suresh S. Ramalingam, MD: Excellent. I want to say that this has been a fascinating discussion. There are a lot of exciting developments in lung cancer. We covered the key studies presented at ESMO 2017: the PACIFIC trial in stage 3 disease, where durvalumab comes into the space as maintenance therapy; the FLAURA study, where osimertinib entered the first-line space; some key data with ALK inhibition, crizotinib being the first-line option and now alectinib and ceritinib moving into the first-line space; and BRAF inhibition, which is a new targeted therapy approach for that subset of patients, with dabrafenib/trametinib. It’s a very exciting time. I want to thank all of you for participating in this panel discussion, and to our viewers, on behalf of our panel, we thank you for joining us.

Transcript Edited for Clarity 
 

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Transcript: 

Suresh S. Ramalingam, MD: I want to ask the last question to our panel. As we look at what the next frontier is for immunotherapy in lung cancer, everybody agrees that we’re going to start seeing combinations of checkpoint inhibitors with other agents. Maybe I can start with Giorgio. What are the combinations that you’re excited by?

Giorgio Scagliotti, MD, PhD: The easy answer is to follow the mainstream and say that the I-O/I-O combination that we are currently looking at is the combination of an immune checkpoint inhibitor plus an anti-CTLA4. There are also other agents in the immunity cycles that are currently under investigation in combination with PD-1 inhibitors. My personal take is that we still need to learn a lot about PD-L1 inhibition before moving forward, because in this kind of cross contamination, melanoma is not lung cancer and lung cancer is not melanoma. So, we cannot easily translate what we saw in melanoma to the field of non–small cell lung cancer. We can’t say, “Well, the I-O/I-O combination is definitely the answer.” Because I can easily reply that the role of KRAS in colorectal cancer is not the role of KRAS in lung cancer. The role of BRAF mutations in melanoma is not the role of BRAF mutations in colorectal cancer.

I still believe that the tissue context makes a difference and we need to avoid, as Benjamin said before, to rush to believe that 2 drugs are better than 1 and 3 drugs are better than 2. It is true for targeted therapies, because the biology is different. In this context, it is true that with 1 single inhibitor, it is not easy to manipulate the immune system because the immune system is highly regulated. Every system in the body is intensely regulated, and it’s not easy to manipulate it with 1 single inhibitor. But it’s true that we need to learn. We have successes. We’ve got therapeutic successes. Before moving forward, it is reasonable to explore the combinations, but we need to learn how to best position the PD-L1 and PD-1 inhibitors.

Suresh S. Ramalingam, MD: Marina?

Marina Garassino, MD: I substantially agree with Giorgio, but I am quite impressed by some results coming from IDO1 inhibition, while I’m less confident with the combinations with anti-CTLA4. I also think that the metabolism together with the immune checkpoint inhibitors can be another way to go, so I think that we have a lot of things to learn about. There are a lot of combinations to explore.

Suresh S. Ramalingam, MD: Benjamin?

Benjamin Besse, MD, PhD: I’m very excited by the studies in the refractory setting. You just start the immunotherapy, it doesn't work, and you make a biopsy. There are very nicely designed trials in which you do the biopsy, get a large molecular profile, and then go in with an immunotherapy plus something that is customized based on the molecular profile. I like this idea that immunotherapy is not just a drug you prescribe second-line, but a drug you can play with and with nice combinations. Let’s see the results.

Suresh S. Ramalingam, MD: Excellent. I want to say that this has been a fascinating discussion. There are a lot of exciting developments in lung cancer. We covered the key studies presented at ESMO 2017: the PACIFIC trial in stage 3 disease, where durvalumab comes into the space as maintenance therapy; the FLAURA study, where osimertinib entered the first-line space; some key data with ALK inhibition, crizotinib being the first-line option and now alectinib and ceritinib moving into the first-line space; and BRAF inhibition, which is a new targeted therapy approach for that subset of patients, with dabrafenib/trametinib. It’s a very exciting time. I want to thank all of you for participating in this panel discussion, and to our viewers, on behalf of our panel, we thank you for joining us.

Transcript Edited for Clarity 
 
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