Mark A. Socinski, MD: What do you do in the surgical population? Or, are there patients that maybe before we would have considered surgery, but because of these very positive results we would go the chemoradiotherapy route. What are your thoughts there?

John V. Heymach, MD, PhD: It’s a great question, and this is one that comes up clinically all the time. So here we’ve got a tremendous advance with durvalumab from the PACIFIC study, adds a very clear benefit. But it also raises the question, should we discard the benefits that other treatment paradigms may bring in there?

There was a study done by the CALGB [Cancer and Leukemia Group B] led by Kathy Albain, MD, a little more than a decade ago where they asked the question: Can surgery add benefit for stage III disease? And there were a couple of take-homes from that. So overall in the stage III population, it didn’t add benefit. But if you took the group of patients who got surgery after chemoradiation, and it was only a lobectomy, not a pneumonectomy, that group actually got an appreciable difference. They had longer survival, overall survival, and recurrence-free survival.

And so our practice at The University of Texas MD Anderson Cancer Center is if somebody is potentially a surgical candidate, we try to integrate that with other treatments. For example, if it’s a single station low-volume disease, or perhaps 2 stations but low-volume mediastinal disease. Or if they clear their mediastinum after chemoradiation, or in some cases chemotherapy, then we do consider surgery.

Now in the PACIFIC study, surgery wasn’t one of the options. Everybody got chemoradiation and then were randomized to durvalumab or not. But this raises the question, if somebody got chemoradiation and was a surgical candidate, do you choose between surgery or durvalumab, or do you put them together and say there’s a benefit from surgery, there’s a benefit for durvalumab? So here I have to say this very cautiously: You know our practice is to certainly consider integrating surgery with the recognition that it isn’t exactly what was done in the clinical study, but here we’re inferring, there’s no reason you shouldn’t get benefit from both of those. And I think this is a great subject for future randomized studies.

Mark A. Socinski, MD: Trials.

John V. Heymach, MD, PhD: We’re excited about exploring, for example, induction chemotherapy and immunotherapy, integrating surgery where possible on top of radiation and immunotherapy afterwards.

Mark A. Socinski, MD: Heather, your thoughts about that question, and maybe comment a little bit on the trials ongoing in the truly adjuvant setting.

Heather A. Wakelee, MD: Sure. From this particular study, for the PACIFIC, for a patient who would have been a candidate for surgery, I still think you need to decide that beforehand.

Mark A. Socinski, MD: Yes.

Heather A. Wakelee, MD: You don’t want to start with the chemoradiation and then say, “Oh, maybe we should go to surgery.” These are always patients who need a multidisciplinary discussion in the tumor board upfront ideally. So in our practice we’re still making that decision—surgery or not—before we start any treatments. For those who aren’t getting surgery, we absolutely are following the PACIFIC regimen, which fortunately gives us a lot of leeway with the chemoradiation, but then adding in their durvalumab afterwards.

We haven’t yet done that for a patient who then went to surgery. We’re sort of putting them into the different camps. And it’s tricky because for the ongoing postoperative trials looking at immune therapy, none of them are allowing for patients, unless it’s defined upfront, who are getting the chemoradiation before that surgery. So it’s a little tricky.

We do have for our patients who are earlier stages who have gone to surgery, or the sort of surprise N2s who’ve had their surgery done, then we do have open trials looking at giving them adjuvant. And in this case it’s the ANVIL study. We had other immune therapy studies open in the past. And just for the audience who’s not aware maybe, there are 4 global studies going on looking at adjuvant immune therapy—there’s a nivolumab study, that’s the ANVIL study. There’s the pembrolizumab study, an atezolizumab study, several others, as well as the durvalumab study.

Mohammad Jahanzeb, MD: And ANVIL is part of the ALCHEMIST trial.

Heather A. Wakelee, MD: I was going to say ALCHEMIST, right. And so they’re all a very similar design, but we don’t really know yet about giving these drugs after surgery, we just don’t have that data back.

Mark A. Socinski, MD: Stay tuned.

Heather A. Wakelee, MD: Exactly because they’re all nearing enrollment. But there’s also then I think getting back to this question about what if you’ve already given them the treatment ahead of time? And that’s where there’s so much neoadjuvant data now coming out, and obviously MD Anderson has been leading some of that work with their NEOSTAR study that was presented at ESMO [the European Society of Medical Oncology meeting] this year, 2018, looking at nivolumab, or nivolumab/ipilimumab. But those weren’t with chemo. And I think where all the cutting edge is, do we do chemo with immune therapy? Do we do immune therapy alone? Do we bring the radiation in before the surgery or more often after the surgery if it’s a known N2? And for some of these ongoing neoadjuvant trials that are looking at chemo plus immune therapy, they do allow for the radiation after surgery if it was an N2. So that might give us more information also, right? It sounds like you had something else you need to bring in.

John V. Heymach, MD, PhD: Well, I agree with all the things that Heather said in talking about these results, and obviously we’re going to have a lot of new exciting data coming out soon. One really interesting one presented at ESMO led by a Spanish group was for a single-station N2 disease with chemo and nivolumab. We’re having extremely high response rates, and that’s actually a regimen, and we’re testing neoadjuvant chemo and NIVO [nivolumab] right now as well.

But today I guess in the clinic, if you’ve got somebody that had low-volume mediastinal disease, they responded well to chemoradiation and they were a surgical candidate, you do have to make a choice after that surgery—do you give them durvalumab or not? And it happens in common clinical practice that the way you’re treating somebody isn’t exactly what’s followed on the study. Given that we do have to make a decision, I still lean towards giving them the potential benefits of the adjuvant durvalumab, while explaining to the patients the limitation that it’s not exactly the way the study was followed. But I realize it’s a debatable point.

Mark A. Socinski, MD: My only concern about that is establishing the safety of that. You know we don’t have large studies, phase III trials that would define the safety of that.

Transcript Edited for Clarity