Mark A. Socinski, MD: Let’s transition to stage IV disease. What we’ve accomplished over the past year or so is to take all the standard first-line regimens that we have in this disease that don’t have driver mutations in the standard second-line treatment, which was immunotherapy [I-O], and just kind of put them together. And I’m going to ask Jarushka to review the nonsquamous set of trials and tell us how that’s changed the standard of care. Then I’ll ask Heather to talk about the squamous subset.

Jarushka Naidoo, MBBCh: So this really has been what I was saying earlier was an avalanche of data for all of us to try to assimilate, and I think there’s been pearls of wisdom that we can take from each of the major studies. I think the main thing that’s different in 2019 or has come out of the last year is, chemotherapy alone is not enough as a first-line treatment for lung cancer, and immunotherapy is going to be part of our treatment paradigm. And PD-L1 [programmed death-ligand 1] has helped us in some ways to sift through how we should be thinking about these patients. So right now it would be our practice to do a PD-L1 22C3 assay in patients who are high expressors of greater than 50%. We would advocate for a single-agent pembrolizumab based on KEYNOTE-024, and in some way supported by KEYNOTE-042, even though that wasn’t the remit of that particular study. So KEYNOTE-024 has this now unprecedented survival of 30 months. There was an updated overall survival output from World Conference on Lung Cancer. So I would consider that certainly a new standard of care.

The other compelling data are KEYNOTE-189, which is the combination of platinum, pemetrexed with pembrolizumab. And that showed a benefit in both progression-free survival [PFS] and overall survival [OS] across all PD-L1 strata, and with a hazard ratio of 0.49 for all comers in patients who got the triplet combination compared to chemotherapy, which is really something we haven’t seen in a nononcogene-addicted group such an impressive hazard ratio.

And then, sitting next to you [points to Dr Socinski], I couldn’t possibly not mention IMpower150. So that’s another option I think for us.

Mark A. Socinski, MD: I was wondering what was taking you so long.

Jarushka Naidoo, MBBCh: That is a very complicated study, a 3-arm study looking at, the primary endpoint was arm B versus arm C, which is the 4-drug combination of a platinum, taxane, atezolizumab, and bevacizumab, with the control arm, ECOG 4599, platinum, taxane, and bevacizumab. And that did show both the progression-free and an overall survival benefit. I think what was really interesting about that data was that there was some enrollment of the EGFR and ALK population and showed a benefit in that population and in a patient with liver metastases, which I think was based on the data in ECOG 4599, which also showed a benefit in that group. So I think this is compelling, and probably the EGFR-ALK may be a niche where that is used.

The other 2 studies that I think are important are probably IMpower132, which uses platinum, pemetrexed with atezolizumab. That showed a PFS benefit. No overall survival benefit. And then lastly IMpower130, which is a somewhat unusual chemotherapy backbone. Platinum and nab-paclitaxel with a maintenance of either supportive care or pemetrexed, and then the investigational arm adding ATEZO [atezolizumab] to that. And that showed both a PFS and OS benefit, and I think it’s being submitted now for regulatory consideration.

Heather A. Wakelee, MD: So in the squamous patients who are not having a driver mutation, which is going to be the majority of them, but it’s important to know who they are. We had a couple of trials that were presented at ASCO [the American Society of Clinical Oncology] in 2018, both with the same idea of carboplatin, taxane, and 1 of them it was taxane either being paclitaxel or nab-paclitaxel, 1 just being the nab-paclitaxel, and then either with or without pembrolizumab, or with or without atezolizumab. And they both showed a good PFS benefit, but more so with the pembrolizumab trial than with the atezolizumab study. The pembrolizumab study also had an overall survival benefit.

And so that actually has become a regimen. I don’t see a whole lot of squamous patients but I do have a couple. And we have started now with carboplatin. And I usually just use paclitaxel to start with, unless there’s been some sort of a sensitivity reaction, and then I’ll switch to the nab-paclitaxel. And then adding in the pembrolizumab. But the atezolizumab data are still maturing. There was a lot of discussion around how do we break these subsets down and look at their PD-L1 levels and various subsets, and does that change outcomes. And I wasn’t overly convinced by that, but I still think that just as we do in nonsquamous and squamous as well, there still are patients who are benefiting more than others.

When you’re doing the chemotherapy combinations, more are benefiting more, and therefore, I’m not using PD-L1 as a necessary exclusion, but there are patients who maybe aren’t benefiting as much, and I think we need to be still exploring that and not just have it everybody gets the same thing.

One of the things we haven’t really talked about yet, but I’m sure we’re getting to, is this idea of who should not get immune therapy. And there definitely are patients from a toxicity standpoint who should not be getting these drugs, and those are patients who are already having very active autoimmune diseases. Even though it’s very rare outside of academic settings; the patients who have had organ transplants and some debate over, well if it’s kidney transplant, is that different than others? But I think we need to make sure that that’s part of the education that everyone’s hearing. It can’t just be reflex; you have to stop and really make sure that you understand the patient’s history and there isn’t some lurking serious autoimmune thing that they forgot to talk to you about.

Transcript Edited for Clarity