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Immunotherapy in Early Stage NSCLC

Panelists: Mark A. Socinski, MD, AdventHealth Cancer Institute; Paul K. Paik, MD, Memorial Sloan Kettering Cancer Center; Kristin Higgins, MD, Emory Healthcare; Corey J. Langer, MD, Hospital of the University of Pennsylvania; Heather A. Wakelee, MD, Stanford University Medical Center; Ticiana A. Leal, MD, University of Wisconsin School of Medicine and Public Health
Published: Friday, Jul 12, 2019



Transcript: 

Mark A. Socinski, MD:  At our site, we have it seems like an increasing number of patients who get SBRT [stereotactic body radiation therapy], for one reason or another. Some are medically inoperable. Some prefer not to be operated on. I think this PACIFIC data do open the door to exploring this approach in earlier-stage disease, and I just wanted to get your comments on PACIFIC-4, specifically.

Kristin Higgins, MD: Yes. So we have an RTOG Foundation trial that is now active, PACIFIC-4, and it’s testing durvalumab following SBRT for patients with stage I, medically inoperable or high-risk early stage lung cancer. The patients will get SBRT, standard of care, fractionated based on the treating radiation oncologist. They then get registered to the trial, and they will get durvalumab every 4 weeks for 24 months.

Mark A. Socinski, MD: A little more convenient.

Kristin Higgins, MD: It is, but it does extend for 24 months. And the primary endpoint is PFS [progression-free survival] with OS [overall survival] as a secondary endpoint. So we’re very excited, and I think it’s a great opportunity for these early stage patients to be able to receive immunotherapy. Certainly after SBRT, distant failure is the dominant pattern of failure. So we need to do something else for these patients.

Mark A. Socinski, MD: Paul, I want to get your thoughts. We’ve seen some early data in the surgical setting, the neoadjuvant setting, with a number of different approaches.

Paul K. Paik, MD: Right. And Jamie Chaft, MD, and Patrick Forde, MBBCh, have been instrumental in releasing that initial data presented at ASCO [the American Society of Clinical Oncology] and published in the New England Journal of Medicine, which was quite compelling because we were seeing really major pathologic responses. So these are responses in the site of tumor upon resection. It may not have been evident radiographically, telling us that this does have activity. In my mind, this was great information. It certainly is sort of hypothesis generating, insofar as the great bulk of the work now is in trying to figure out what the ideal way to use this, probably in combination, is in the early stage setting.

Some of the newer data that will be presented and that are present in abstract form, in terms of induction or neoadjuvant, atezolizumab as a single-agent immune checkpoint inhibitor, and some data on ipilimumab and nivolumab as an induction regimen prior to surgery, again show activity that sort of ranges in spectrum, in terms of how promising induction atezolizumab is. The major pathologic response is varied from about 8% in PD-L1 [programmed death-ligand 1]–negative patients to maybe 25% in PD-L1–positive patients.

Again, radiographic response rate was not that great. It was about 7%. Ipilimumab/nivolumab was a little bit higher in that arm. It was about 25%, 29% for major pathologic response. But I think the issue is that for chemotherapy alone, we know from a couple of studies that the major pathologic response rate is about 22%. Again, that’s the context in which we’re operating. So I do think that this is very promising. But kind of like what we’ve seen in stage IV disease, I think the combination is where it’s going to be.

Mark A. Socinski, MD:  When you say combination, you mean chemoimmunotherapy?

Paul K. Paik, MD: Yes, that’s right.

Mark A. Socinski, MD:  Corey?

Corey J. Langer, MD: That’s been borne out. At World Conference on Lung Cancer last year, there was a small study. This was phase II, stage IIIa patients, with a neoadjuvant combination of nivolumab with [paclitaxel/carboplatin]. This led to a major pathologic rate in the 70% to 80% range in pathologic CRs [complete responses]; eradication of N2 disease, and eradication of the primary in over 50%. That approach is now being explored prospectively in a number of different randomized trials basically looking at chemotherapy plus or minus immunotherapy in the neoadjuvant setting. Some of these trials have finished accrual. Stay tuned. There will be major data. Whether it’s a data dump or practice-changing approach remains to be seen, but there is certainly a lot of excitement. Frankly, I have more excitement for the combinations than for single agents in this setting.

Mark A. Socinski, MD: I think every one of the known immunologic agents we have approved in lung cancer are also in an adjuvant trial, right? And some of those have completed their accrual. So whether neoadjuvant or adjuvant is the optimal way to go is a matter of debate.

Heather A. Wakelee, MD: Right. Until we have the data, we can keep debating.

Mark A. Socinski, MD: Until we have the data, yes.


Transcript Edited for Clarity

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Transcript: 

Mark A. Socinski, MD:  At our site, we have it seems like an increasing number of patients who get SBRT [stereotactic body radiation therapy], for one reason or another. Some are medically inoperable. Some prefer not to be operated on. I think this PACIFIC data do open the door to exploring this approach in earlier-stage disease, and I just wanted to get your comments on PACIFIC-4, specifically.

Kristin Higgins, MD: Yes. So we have an RTOG Foundation trial that is now active, PACIFIC-4, and it’s testing durvalumab following SBRT for patients with stage I, medically inoperable or high-risk early stage lung cancer. The patients will get SBRT, standard of care, fractionated based on the treating radiation oncologist. They then get registered to the trial, and they will get durvalumab every 4 weeks for 24 months.

Mark A. Socinski, MD: A little more convenient.

Kristin Higgins, MD: It is, but it does extend for 24 months. And the primary endpoint is PFS [progression-free survival] with OS [overall survival] as a secondary endpoint. So we’re very excited, and I think it’s a great opportunity for these early stage patients to be able to receive immunotherapy. Certainly after SBRT, distant failure is the dominant pattern of failure. So we need to do something else for these patients.

Mark A. Socinski, MD: Paul, I want to get your thoughts. We’ve seen some early data in the surgical setting, the neoadjuvant setting, with a number of different approaches.

Paul K. Paik, MD: Right. And Jamie Chaft, MD, and Patrick Forde, MBBCh, have been instrumental in releasing that initial data presented at ASCO [the American Society of Clinical Oncology] and published in the New England Journal of Medicine, which was quite compelling because we were seeing really major pathologic responses. So these are responses in the site of tumor upon resection. It may not have been evident radiographically, telling us that this does have activity. In my mind, this was great information. It certainly is sort of hypothesis generating, insofar as the great bulk of the work now is in trying to figure out what the ideal way to use this, probably in combination, is in the early stage setting.

Some of the newer data that will be presented and that are present in abstract form, in terms of induction or neoadjuvant, atezolizumab as a single-agent immune checkpoint inhibitor, and some data on ipilimumab and nivolumab as an induction regimen prior to surgery, again show activity that sort of ranges in spectrum, in terms of how promising induction atezolizumab is. The major pathologic response is varied from about 8% in PD-L1 [programmed death-ligand 1]–negative patients to maybe 25% in PD-L1–positive patients.

Again, radiographic response rate was not that great. It was about 7%. Ipilimumab/nivolumab was a little bit higher in that arm. It was about 25%, 29% for major pathologic response. But I think the issue is that for chemotherapy alone, we know from a couple of studies that the major pathologic response rate is about 22%. Again, that’s the context in which we’re operating. So I do think that this is very promising. But kind of like what we’ve seen in stage IV disease, I think the combination is where it’s going to be.

Mark A. Socinski, MD:  When you say combination, you mean chemoimmunotherapy?

Paul K. Paik, MD: Yes, that’s right.

Mark A. Socinski, MD:  Corey?

Corey J. Langer, MD: That’s been borne out. At World Conference on Lung Cancer last year, there was a small study. This was phase II, stage IIIa patients, with a neoadjuvant combination of nivolumab with [paclitaxel/carboplatin]. This led to a major pathologic rate in the 70% to 80% range in pathologic CRs [complete responses]; eradication of N2 disease, and eradication of the primary in over 50%. That approach is now being explored prospectively in a number of different randomized trials basically looking at chemotherapy plus or minus immunotherapy in the neoadjuvant setting. Some of these trials have finished accrual. Stay tuned. There will be major data. Whether it’s a data dump or practice-changing approach remains to be seen, but there is certainly a lot of excitement. Frankly, I have more excitement for the combinations than for single agents in this setting.

Mark A. Socinski, MD: I think every one of the known immunologic agents we have approved in lung cancer are also in an adjuvant trial, right? And some of those have completed their accrual. So whether neoadjuvant or adjuvant is the optimal way to go is a matter of debate.

Heather A. Wakelee, MD: Right. Until we have the data, we can keep debating.

Mark A. Socinski, MD: Until we have the data, yes.


Transcript Edited for Clarity
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