Mark A. Socinski, MD: Okay. Heather, there was a small percentage of EGFR mutation-positive patients in this trial. And then they also did look at PD-L1 [programmed death-ligand 1] In the United States this is not an issue, but it became an issue in the European approval. I wonder if you could comment on those 2 things. Do you look for EGFR mutations in stage III disease routinely?

Heather A. Wakelee, MD: So it differs; we’re in Northern California. A very high percentage of our patients do have EGFR mutations across stages. And so we do look, it’s something that’s sort of done reflexively. And we do also look for PD-L1. Now at this point the data from PACIFIC did show that in the EGFR subset there was a very similar disease-free survival benefit. We haven’t yet seen the overall survival benefit in that subtype because it was relatively small.

Mark A. Socinski, MD: Small numbers.

Heather A. Wakelee, MD: Right. And so in practice I actually have 5 patients I think so far, who have no EGFR mutation, who have had their concurrent chemoradiation, who are on durvalumab. It might even be more if you add in all of our groups. So this has been our practice, so we do look, we do know, we continue as if they were anybody else. For the PD-L1 it’s the same idea. And you already commented on the fact that it was not a planned analysis, it was a smaller subset. And so to me it’s very surprising that the European entities voted that this was only an option for patients that did have PD-L1 expression.

In the United States we don’t have to worry about that, and I think this is something that’s worth further exploration. I mean, PD-L1 is a biomarker. It’s something we all talk about a lot at conferences and debate because it’s not a perfect biomarker. There are absolutely patients without PD-L1 expression who are benefitting in metastatic disease with the checkpoint inhibitors. And so it would make sense that we would be seeing the same thing in earlier stages of disease. Perhaps less, but it’s not none, and I think we need to continue work trying to figure who’s really benefitting, and that’s across stages.

So we’re going to have this question if the adjuvant trials come out positive, if the neoadjuvant trials come out positive in this setting, stage III, and continuing, of course, in metastatic as well. So, yes, we check for PD-L1. I treat regardless, but I do talk to the patients about the fact that maybe they’re not going to benefit as much. We do check in EGFR. We talk about that disease-free survival benefit, the fact that we don’t know overall survival yet, but we still do that as our practice.

Mark A. Socinski, MD: So, Jarushka will give us the Johns Hopkins University perspective.

Jarushka Naidoo, MBBCh: I completely agree with Heather. We adopt a similar approach in that we reflectively do NGS [next-generation sequencing] testing for all of our lung cancers, regardless of stage, so we know what their mutation status is going in, but we don’t have data to say that that is relevant in the early stage setting yet, including stage III. So we would certainly offer DURVA [durvalumab] to all of our patients, including the stage III patients. In PACIFIC only I think 6% of the population had EGFR mutations. So probably not a representative of the population. Their confidence intervals were wide on the forest plot. I think where it will become relevant is when those patients progress, giving them TKIs [tyrosine kinase inhibitors] that have a known pneumonitis risk. And I think that’s obviously going to be the subject of further study in the future.

Mark A. Socinski, MD: Is there anyone on the panel that is swayed by PD-L1 status in this setting?

Mohammad Jahanzeb, MD: I’m not. I recently put one of our chemotherapy nurses on durvalumab who’s PD-L10. I explained all the caveats to her and she wholeheartedly agreed that she should be on it. One thing I want to point out, we didn’t touch on toxicity at all. But when you look at toxicity numbers, grade 3/4, 26%, initially appears high compared to other monotherapy, immunotherapy numbers in stage IV disease. But it’s interesting that in the placebo arm that number was 23%. So that needs to be pointed out that it’s probably chemoradio-related, delayed toxicities that are being documented.

Mark A. Socinski, MD: Yes, and I think that one of the concerns in waiting for the results of this was were there going to be issues with radiation, pneumonitis, or immune mediated pneumonitis. And PACIFIC was relatively reassuring. There was a bit more grade 1 or 2 of pneumonitis. But grade 3 or 4 pneumonitis was essentially 3% on both arms. So it was really no different between arms. John?

John V. Heymach, MD, PhD: I think the issue with PD-L1 and with EGFR raises an important point, that we can’t extrapolate from the metastatic disease, we’re using monotherapy, into the setting. And the reason is, chemotherapy and radiation together actually impact PD-L1 levels. They impact the microenvironment. So there’s a lot of data supporting they turn up PD-L1. So if you take an EGFR mutant tumor and just gave them PD-1 [programmed cell death protein 1] inhibitors, the response rates would be really low, about 5%. But in the setting of radiation where you may be turning up the PD-L1, I think it wouldn’t be appropriate to exclude EGFR mutants or PD-L1 negative patients given that it’s a different disease setting. And you know the PACIFIC study was a large, well done, randomized study, and those groups did have the same sort of trend as the rest of the groups as well.

Mark A. Socinski, MD: Exactly. Jarushka, did you have something?

Jarushka Naidoo, MBBCh: I wanted to comment a little bit about the pneumonitis. We were involved in the subset analysis of those patients; this was presented by Johan Vansteenkiste, MD, PhD, at World Conference on Lung Cancer. So interestingly in PACIFIC, the rates of pneumonitis are grouped together as radiation pneumonitis and immune related. There wasn’t really an effort to separate them, and I think that speaks to the fact that we don’t know how to separate them.

Mark A. Socinski, MD: You can’t separate them.

Jarushka Naidoo, MBBCh: And we don’t know what are truly the features that will distinguish RT [radiotherapy] from immune related pneumonitis in the context of getting recent chemoradiation. So we certainly have advocated for our doing studies to BAL [bronchoalveolar lavage], other features to help us discern this because the management may be different.

Transcript Edited for Clarity