Suresh S. Ramalingam, MD: So, let’s then take the discussion to the next line of therapy, which is second-line treatment. Let’s assume that the patient we are talking about or we have in mind has not seen a checkpoint inhibitor in the first-line setting and has seen platinum-based chemotherapy. Then for salvage therapy, we have 3 immune checkpoint inhibitors that are approved: pembrolizumab, nivolumab, and atezolizumab—2 PD-1 inhibitors and 1 PD-L1 antibody. Benjamin, walk us through some of the key data in the second-line space, the salvage therapy, and how should physicians go about making decisions for their patients.

Benjamin Besse, MD, PhD: Nivolumab and atezolizumab were tested against chemotherapy in all-comers. Whereas for pembrolizumab, it’s restricted to PD-L1-positive tumors with a threshold of 1%. So, roughly one-third of the patients would be PD-L1-negative and will not be treated with pembrolizumab. All these studies are positive and show that in all-comers, or those PD-L1-positive for pembrolizumab, the immunotherapy performed better than chemotherapy.

This was the first study done with immunotherapy, but the field is moving fast. And now we have immunotherapy in the frontline setting, meaning that we will treat a second-line population that is different because one-third of the patients will receive immunotherapy frontline. And now in second-line therapy, we will enrich in PD-L1-weak, or PD-L1-negative, NSCLC patients, and we don’t have that data on this specific population. We have subgroup analyses from the phase III study that showed that there is clearly a link between the activity of the immunotherapy and the positivity of PD-L1. Now, in the PD-L1-negative, which is one-third of the patients, roughly the study says it’s equal—it’s maybe a bit better, maybe a bit worse, but it’s equal. So, a lot of people say, “Well, let’s give immunotherapy to anybody in the second-line setting because it’s less toxic than chemotherapy,” and it’s true. It’s less toxic and it’s the same efficacy. But I completely disagree with that.

We have PD-L1 testing. But if it’s not available or not done or there’s not enough tissue, there are other factors that you can rely on. Smoking status is really something that is predictive of the efficacy, and in a never-smoker, we should probably avoid giving second-line immunotherapy. In EGFR-mutated patients, it’s also proven in 10% of our patients that immunotherapy is probably not the best option.

We know that in a subset of patients—maybe 15% of the patients—immunotherapy may hurt because there are new data that show that the progression of the disease may be increased by immunotherapy in some cases. We don’t know why, but it might explain why the survivor curves cross when you combine the therapy to chemotherapy. So, I think second-line immunotherapy must not reflect second-line. We still have to select the patient for second-line.

Suresh S. Ramalingam, MD: Thank you. That was very helpful to make choices in the second-line setting. Can I also ask the panel about the role of chemotherapy/docetaxel/ramucirumab as an approved salvage regimen? Where do you see that antiangiogenic chemotherapy combination in non—small cell lung cancer? Giorgio?

Giorgio Scagliotti, MD, PhD: As Benjamin just said, there is a subgroup of patients in which immunotherapy is not probably the right choice, OK? We have different therapeutic options, and in the United States and in Europe, we have the ramucirumab/docetaxel combination. In Europe, we have an additional indication in second-line therapy related to another VEGF TKI, which is nintedanib, in combination with docetaxel. There are therapeutic options that are coming with some toxicities, and this is something that we need to factor in our treatment strategy.

It is true that we are dealing with some toxicities with immunotherapy that are definitively less than with standard chemotherapy. But also in the combination of the antiangiogenic agent and docetaxel, we are dealing with a significant amount of, mainly hematological but also nonhematological, toxicities. And, again, I believe that one of the major challenges that we have in our clinical practice is to profile, in the best way, our patient, to match each individual patient with multiple therapeutic strategies that we have.

Benjamin Besse, MD, PhD: Well, Giorgio, in these second-line antiangiogenic studies, one thing was quite impressive. It’s the activity of the combination in the refractory patients, the one that progressed at 3 months after the end of the platinum-based chemotherapy. And I might prefer this treatment in these refractory patients, this kind of chemotherapy/antiangiogenic combination, at least when there is no high PD-L1 expression.

Giorgio Scagliotti, MD, PhD: Yes. When I was alluding to the patient’s profile, I was exactly alluding to what you are referring.

Marina Garassino, MD: And I think that also performance status must be considered for the choice of the second-line, which is maybe the most important factor.

Suresh S. Ramalingam, MD: So, we have immunotherapy as one line, we have platinum doublet as another line, and potentially for patients who still have a good performance status, then the docetaxel/ramucirumab combination could be another line of therapy. Clearly, we now have effective options. It boils down to selecting patients based on molecular status for targeted therapy, for EGFR, ALK, ROS1, BRAF, which we’ll talk about in a few minutes, and PD-L1 expression, which helps us decide which patient gets first-line immunotherapy versus first-line platinum doublet. So, very exciting observations and developments in that space.

Transcript Edited for Clarity