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PACIFIC Trial: Durvalumab for Stage 3 NSCLC

Panelists: Everett Vokes, MD, University of Chicago Medicine and Biological Sciences; Roy Herbst, MD, PhD, Yale Cancer Center; Fred Hirsch, MD, PhD, University of Colorado School of Medicine; Suresh Ramalingam, MD, Winship Cancer Institute Emory University; Naiyer Rizvi, MD, Columbia University Medical Center
Published Online: Tuesday, Oct 10, 2017



Transcript:

Everett Vokes, MD: Roy, do you think this is a dataset that could be extrapolated to even earlier stage disease? Also, what do we know about adjuvant therapies for earlier stage disease at this point?

Roy Herbst, MD, PhD: I wish that they had added in a new biopsy, there, and had taken a biopsy after chemoradiation to compare it to a prebiopsy to tell us if we really are affecting the immune microenvironment. One of us should do that quickly. Finding those datasets is not easy. But as far as adjuvant therapy, yes. Why wouldn’t these agents work, earlier? These trials are going to need a large number of patients—more patients, depending on the stage you take. If you take stage 2 patients, for example, it will take a lot longer. But, yes, you probably wouldn’t want to use radiation in all of those scenarios. Maybe in some, but most of those patients would get chemotherapy. And, again, we don’t know whether the chemotherapy and/or radiation we’re enhancing here…

But, yes, I think the trial that’s going on, and Ram [Suresh] can probably talk to this better than me: his group, with the trial with nivolumab as adjuvant therapy, is great. There are other trials with other drugs. So, I certainly think moving these agents closer—and then, of course, the neoadjuvant trials that are going on—and just combinations with chemotherapy are all steps forward. You can even make the case in the PACIFIC trial. Maybe we should do that? What’s a bigger ocean than the Pacific? Is there a bigger one?

Everett Vokes, MD: Not that I know of.

Roy Herbst, MD, PhD: But, maybe call it “Mars” or something? A trial to have chemoradiation and bring in the immune-oncology (IO) right away and then move on to what we’ve seen here? That would be applicable. I think all is on the table right now, and we think about stage 3 disease. When I was a Fellow, that was really the only bright spot you could point to in lung cancer. I know you’ve done so many trials, Everett, where you can say, “Yes, we can cure lung cancer.” And you know, at 5 years, we’d have survivor parties for our patients. We didn’t fill the room too much, but we had patients. I’m sure every one of us has that. And now, this is a group where I think adding in the IO can really make a difference.

Fred Hirsch, MD, PhD: I was approached, recently, as the CEO for IASLC. And someone said, “Fred, you need to put survivorship into your programs.” That is something we haven’t focused on in lung cancer at all. And with how timely and how justified that is today, absolutely. We need to think differently today than before. We are fortunate to have survivors these days.

Everett Vokes, MD: Yes, and this will hopefully further that step in that direction. I just want to ask Naiyer and Ram [Suresh] a little bit more about neoadjuvant chemotherapy. Is that something that excites you, and where is the field at that at this point?

Naiyer Rizvi, MD: I think it’s in exploration mode. Certainly, the positive PACIFIC trial supports the premise to move immunotherapy into earlier stages of disease. There really are only small data sets right now. There are some modest data around giving nivolumab, preoperatively, for 2 doses (and that was presented at the 2017 ASCO Annual Meeting). And what was really pretty remarkable in this very small study was that with just 2 doses of nivolumab, preoperatively, really independent of PD-L1 status, there was clearly tumor necrosis, T-cell infiltration, and major responses, pathologically. Honestly, I wouldn’t have predicted that extent of effect. Neoadjuvant is a space that is done at various places. For some places, it’s considered a standard of care. For some places, it isn’t. We tend to give neoadjuvant chemotherapy for stage 3A disease that’s resectable. We have a trial that’s ongoing giving atezolizumab with chemotherapy, preoperatively.

So, I think that the potential advantage of giving it neoadjuvantly versus adjuvantly is you have a tumor board. As you destroy the tumor, you release antigens and you can magnify your T-cell response to tumor neoadjuvants. I think moving immunotherapy, preoperatively, makes sense. We’re definitely going to see more of that on the coming report.

Everett Vokes, MD: And you see when it’s not working.

Fred Hirsch, MD, PhD: Can I make a comment, Everett?

Everett Vokes, MD: Yes.

Fred Hirsch, MD, PhD: The neoadjuvant approach has been laid down for many, many years in lung cancer. Some of us have advocated strongly for it, and a good reason, these days, is certainly also to learn more about the biology around those treatments—whether it is targeted treatment or it is immunotherapy. And to that end, I would like to say that our organization was recently approached by the FDA and was asked if we are willing to make a workshop to try to define response criteria for neoadjuvant therapy and standardize trial designs. And that is, of course, a result of the increased interest for neoadjuvant treatment approaches. I think it is very timely to do that. So, at the beginning of 2018, we will be working with the FDA and will have a workshop for trying to define those things. Hopefully, by bringing experts to the table, we will be able to come up with some recommendations for trial designs and, particularly, a definition of endpoints.

Everett Vokes, MD: Excellent. Ram [Suresh], can I ask you, just briefly, to describe and comment on ALCHEMIST?

Suresh Ramalingam, MD: ALCHEMIST is a trial that’s being done across the US Cooperative Groups with the National Cancer Institute to look at individualized therapy in the adjuvant therapy setting. In the trial, for those patients with resected non–small cell lung cancer stage 1B, 2, and 3A, we do molecular testing for EGFR and ALK. If there is a molecular abnormality, they then get randomized to targeted therapy or observation. And in the third arm, we randomize patients who don’t have EGFR or ALK to nivolumab versus observation, and the treatment is given for 1 year. The adjuvant immunotherapy arm is accruing very well. Accrual to the targeted therapies arm is a little slower than what we would like it to be. But I think as the study progresses, we will have the ability to see if adjuvant immunotherapy given after you receive the standard adjuvant chemotherapy will result in better cure rates for patients.

Everett Vokes, MD: It’s really remarkable. A large effort, right? We should encourage people to support and to participate. In addition to Lung-MAP, it’s really the second example of excellent collaboration between the cooperative groups.

Transcript Edited for Clarity 

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Transcript:

Everett Vokes, MD: Roy, do you think this is a dataset that could be extrapolated to even earlier stage disease? Also, what do we know about adjuvant therapies for earlier stage disease at this point?

Roy Herbst, MD, PhD: I wish that they had added in a new biopsy, there, and had taken a biopsy after chemoradiation to compare it to a prebiopsy to tell us if we really are affecting the immune microenvironment. One of us should do that quickly. Finding those datasets is not easy. But as far as adjuvant therapy, yes. Why wouldn’t these agents work, earlier? These trials are going to need a large number of patients—more patients, depending on the stage you take. If you take stage 2 patients, for example, it will take a lot longer. But, yes, you probably wouldn’t want to use radiation in all of those scenarios. Maybe in some, but most of those patients would get chemotherapy. And, again, we don’t know whether the chemotherapy and/or radiation we’re enhancing here…

But, yes, I think the trial that’s going on, and Ram [Suresh] can probably talk to this better than me: his group, with the trial with nivolumab as adjuvant therapy, is great. There are other trials with other drugs. So, I certainly think moving these agents closer—and then, of course, the neoadjuvant trials that are going on—and just combinations with chemotherapy are all steps forward. You can even make the case in the PACIFIC trial. Maybe we should do that? What’s a bigger ocean than the Pacific? Is there a bigger one?

Everett Vokes, MD: Not that I know of.

Roy Herbst, MD, PhD: But, maybe call it “Mars” or something? A trial to have chemoradiation and bring in the immune-oncology (IO) right away and then move on to what we’ve seen here? That would be applicable. I think all is on the table right now, and we think about stage 3 disease. When I was a Fellow, that was really the only bright spot you could point to in lung cancer. I know you’ve done so many trials, Everett, where you can say, “Yes, we can cure lung cancer.” And you know, at 5 years, we’d have survivor parties for our patients. We didn’t fill the room too much, but we had patients. I’m sure every one of us has that. And now, this is a group where I think adding in the IO can really make a difference.

Fred Hirsch, MD, PhD: I was approached, recently, as the CEO for IASLC. And someone said, “Fred, you need to put survivorship into your programs.” That is something we haven’t focused on in lung cancer at all. And with how timely and how justified that is today, absolutely. We need to think differently today than before. We are fortunate to have survivors these days.

Everett Vokes, MD: Yes, and this will hopefully further that step in that direction. I just want to ask Naiyer and Ram [Suresh] a little bit more about neoadjuvant chemotherapy. Is that something that excites you, and where is the field at that at this point?

Naiyer Rizvi, MD: I think it’s in exploration mode. Certainly, the positive PACIFIC trial supports the premise to move immunotherapy into earlier stages of disease. There really are only small data sets right now. There are some modest data around giving nivolumab, preoperatively, for 2 doses (and that was presented at the 2017 ASCO Annual Meeting). And what was really pretty remarkable in this very small study was that with just 2 doses of nivolumab, preoperatively, really independent of PD-L1 status, there was clearly tumor necrosis, T-cell infiltration, and major responses, pathologically. Honestly, I wouldn’t have predicted that extent of effect. Neoadjuvant is a space that is done at various places. For some places, it’s considered a standard of care. For some places, it isn’t. We tend to give neoadjuvant chemotherapy for stage 3A disease that’s resectable. We have a trial that’s ongoing giving atezolizumab with chemotherapy, preoperatively.

So, I think that the potential advantage of giving it neoadjuvantly versus adjuvantly is you have a tumor board. As you destroy the tumor, you release antigens and you can magnify your T-cell response to tumor neoadjuvants. I think moving immunotherapy, preoperatively, makes sense. We’re definitely going to see more of that on the coming report.

Everett Vokes, MD: And you see when it’s not working.

Fred Hirsch, MD, PhD: Can I make a comment, Everett?

Everett Vokes, MD: Yes.

Fred Hirsch, MD, PhD: The neoadjuvant approach has been laid down for many, many years in lung cancer. Some of us have advocated strongly for it, and a good reason, these days, is certainly also to learn more about the biology around those treatments—whether it is targeted treatment or it is immunotherapy. And to that end, I would like to say that our organization was recently approached by the FDA and was asked if we are willing to make a workshop to try to define response criteria for neoadjuvant therapy and standardize trial designs. And that is, of course, a result of the increased interest for neoadjuvant treatment approaches. I think it is very timely to do that. So, at the beginning of 2018, we will be working with the FDA and will have a workshop for trying to define those things. Hopefully, by bringing experts to the table, we will be able to come up with some recommendations for trial designs and, particularly, a definition of endpoints.

Everett Vokes, MD: Excellent. Ram [Suresh], can I ask you, just briefly, to describe and comment on ALCHEMIST?

Suresh Ramalingam, MD: ALCHEMIST is a trial that’s being done across the US Cooperative Groups with the National Cancer Institute to look at individualized therapy in the adjuvant therapy setting. In the trial, for those patients with resected non–small cell lung cancer stage 1B, 2, and 3A, we do molecular testing for EGFR and ALK. If there is a molecular abnormality, they then get randomized to targeted therapy or observation. And in the third arm, we randomize patients who don’t have EGFR or ALK to nivolumab versus observation, and the treatment is given for 1 year. The adjuvant immunotherapy arm is accruing very well. Accrual to the targeted therapies arm is a little slower than what we would like it to be. But I think as the study progresses, we will have the ability to see if adjuvant immunotherapy given after you receive the standard adjuvant chemotherapy will result in better cure rates for patients.

Everett Vokes, MD: It’s really remarkable. A large effort, right? We should encourage people to support and to participate. In addition to Lung-MAP, it’s really the second example of excellent collaboration between the cooperative groups.

Transcript Edited for Clarity 
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