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Potential for Use of Checkpoint Inhibitors in Early-Stage NSCLC

Panelists: Benjamin P. Levy, MD, Johns Hopkins Sidney Kimmel Cancer Center; Hossein Borghaei, DO, MS, Fox Chase Cancer Center; Roy S. Herbst, MD, PhD, Yale Cancer Center; Suresh S. Ramalingam, MD, Emory University School of Medicine; Naiyer A. Rizvi, MD, Columbia University Medical Center; Thomas E. Stinchcombe, MD, Duke Cancer Institute
Published: Wednesday, Feb 28, 2018



Transcript: 

Benjamin P. Levy, MD: Let’s finish off this section going back to points that Suresh mentioned about the role of checkpoint inhibitors in early-stage disease and where we’re heading. Just to go back a couple points here. We’ve got a couple of different data sets coming out sooner rather than later. The ANVIL study, as you mentioned. The LCMC (Lung Cancer Mutation Consortium) is doing a neoadjuvant trial with atezolizumab. BMS (Bristol-Myers Squibb) is doing a neoadjuvant trial with nivolumab. Is this where the field is heading? Do you think this is where we’re going to be applying these drugs, and do we need a different endpoint for these neoadjuvant studies rather than overall survival, a surrogate endpoint that may be quicker to achieve?

Suresh S. Ramalingam, MD: The exciting data with immune checkpoint inhibition in stage 4 and now in unresectable stage 3B clearly lead us to a possible scenario where these drugs can be used to cure patients even more effectively than what we’re doing right now. So, that’s the excitement of our integration of checkpoint inhibition in early-stage disease. And if what we’ve seen so far holds true, I think we should be able to cure more patients with these agents. And the question will be, what markers can we use to select those patients who benefit? So, that’s where the ANVIL, which is the ECOG-ACRIN–led NCTN trial, and some of the other pharma-led trials will all answer the question. The neoadjuvant approach is also very exciting. We have not shown in lung cancer, so far, that the neoadjuvant approach is better than the adjuvant approach in any trial.

Benjamin P. Levy, MD: Good point.

Suresh S. Ramalingam, MD: So, if we can take a group of patients, induce major pathologic or complete pathologic responses with relatively brief duration of immune checkpoint inhibition, either by itself or with chemotherapy or as a combination of checkpoint inhibitors, I think that will be a major advance in our ability to improve outcomes for our patients. With regard to endpoints, I think for the curative setting, survival will continue to be the main endpoint we look at. We can certainly use some intermediate endpoints to get a signal for early-phase clinical trials to see if a regimen looks promising enough or not. And that’s where the major pathologic response comes in. Complete pathologic response is another such endpoint. But, ultimately, our conviction to use this across a patient population would depend on if there is an impact on survival.

Benjamin P. Levy, MD: Any other points regarding the neoadjuvant/adjuvant approach? I think the data, obviously, we still need to wait and see. I think some of these surrogate endpoints may be important, but overall survival is still what we look for in these trials.

Roy S. Herbst, MD, PhD: Two things. The neoadjuvant approach certainly has great scientific merits but we have to, of course, make sure we don’t compromise, in any way, patient care. But if history is any guide here, all of the therapies in lung cancer always have had better activity as they moved up—chemotherapy in the metastatic setting moved to the earlier stage, chemoradiation, adjuvant therapy. So, if these drugs really work, the earlier we can get them to patients, the better. I think that’s going to be the trend, and we’ll do it through clinical trials.

Benjamin P. Levy, MD: Naiyer, you and I were having a conversation before the panel about how earlier-stage disease may be more immunogenic or immune therapies may work in earlier-stage disease better than they work in advanced-stage disease. Do you think that’s going to bear out?

Naiyer A. Rizvi, MD: It’s possible. We know from the metastatic disease setting that we commonly are starting to see more failures in one location, one area of metastases. It can be a subclone, which is ultimately resistant. But if it’s for earlier stage disease—maybe there is less tumor heterogeneity, a smaller subclone fraction—maybe you can do a better job of eradicating cancer.

Benjamin P. Levy, MD: OK.

Roy S. Herbst, MD, PhD: The whole idea of immuno-prevention now has come to pass. Just a couple of Stand Up To Cancer Dream Teams were funded, and they’re looking at early disease, and they’re looking at MHC (major histocompatibility complex) and antigen presentation in these tumors. So, it might be that we start using, someday, immunotherapy in preneoplastic lesions or in patients who have smoking-induced damage who have stopped smoking, for example.

Benjamin P. Levy, MD: The future is rich for these drugs.

Roy S. Herbst, MD, PhD: Absolutely.

Transcript Edited for Clarity 

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Transcript: 

Benjamin P. Levy, MD: Let’s finish off this section going back to points that Suresh mentioned about the role of checkpoint inhibitors in early-stage disease and where we’re heading. Just to go back a couple points here. We’ve got a couple of different data sets coming out sooner rather than later. The ANVIL study, as you mentioned. The LCMC (Lung Cancer Mutation Consortium) is doing a neoadjuvant trial with atezolizumab. BMS (Bristol-Myers Squibb) is doing a neoadjuvant trial with nivolumab. Is this where the field is heading? Do you think this is where we’re going to be applying these drugs, and do we need a different endpoint for these neoadjuvant studies rather than overall survival, a surrogate endpoint that may be quicker to achieve?

Suresh S. Ramalingam, MD: The exciting data with immune checkpoint inhibition in stage 4 and now in unresectable stage 3B clearly lead us to a possible scenario where these drugs can be used to cure patients even more effectively than what we’re doing right now. So, that’s the excitement of our integration of checkpoint inhibition in early-stage disease. And if what we’ve seen so far holds true, I think we should be able to cure more patients with these agents. And the question will be, what markers can we use to select those patients who benefit? So, that’s where the ANVIL, which is the ECOG-ACRIN–led NCTN trial, and some of the other pharma-led trials will all answer the question. The neoadjuvant approach is also very exciting. We have not shown in lung cancer, so far, that the neoadjuvant approach is better than the adjuvant approach in any trial.

Benjamin P. Levy, MD: Good point.

Suresh S. Ramalingam, MD: So, if we can take a group of patients, induce major pathologic or complete pathologic responses with relatively brief duration of immune checkpoint inhibition, either by itself or with chemotherapy or as a combination of checkpoint inhibitors, I think that will be a major advance in our ability to improve outcomes for our patients. With regard to endpoints, I think for the curative setting, survival will continue to be the main endpoint we look at. We can certainly use some intermediate endpoints to get a signal for early-phase clinical trials to see if a regimen looks promising enough or not. And that’s where the major pathologic response comes in. Complete pathologic response is another such endpoint. But, ultimately, our conviction to use this across a patient population would depend on if there is an impact on survival.

Benjamin P. Levy, MD: Any other points regarding the neoadjuvant/adjuvant approach? I think the data, obviously, we still need to wait and see. I think some of these surrogate endpoints may be important, but overall survival is still what we look for in these trials.

Roy S. Herbst, MD, PhD: Two things. The neoadjuvant approach certainly has great scientific merits but we have to, of course, make sure we don’t compromise, in any way, patient care. But if history is any guide here, all of the therapies in lung cancer always have had better activity as they moved up—chemotherapy in the metastatic setting moved to the earlier stage, chemoradiation, adjuvant therapy. So, if these drugs really work, the earlier we can get them to patients, the better. I think that’s going to be the trend, and we’ll do it through clinical trials.

Benjamin P. Levy, MD: Naiyer, you and I were having a conversation before the panel about how earlier-stage disease may be more immunogenic or immune therapies may work in earlier-stage disease better than they work in advanced-stage disease. Do you think that’s going to bear out?

Naiyer A. Rizvi, MD: It’s possible. We know from the metastatic disease setting that we commonly are starting to see more failures in one location, one area of metastases. It can be a subclone, which is ultimately resistant. But if it’s for earlier stage disease—maybe there is less tumor heterogeneity, a smaller subclone fraction—maybe you can do a better job of eradicating cancer.

Benjamin P. Levy, MD: OK.

Roy S. Herbst, MD, PhD: The whole idea of immuno-prevention now has come to pass. Just a couple of Stand Up To Cancer Dream Teams were funded, and they’re looking at early disease, and they’re looking at MHC (major histocompatibility complex) and antigen presentation in these tumors. So, it might be that we start using, someday, immunotherapy in preneoplastic lesions or in patients who have smoking-induced damage who have stopped smoking, for example.

Benjamin P. Levy, MD: The future is rich for these drugs.

Roy S. Herbst, MD, PhD: Absolutely.

Transcript Edited for Clarity 
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