Mark A. Socinski, MD: Let’s switch gears. Corey said before that it’s been 25 years. I don’t know if it’s that much that we haven’t made progress in stage III. Chemoradiotherapy. Let’s talk about small cell lung cancer. I think that might be the record where we haven’t seen an advance....

Corey J. Langer, MD: I think we made more advances in locally advanced….

Mark A. Socinski, MD: Yes, than small cell.

Heather A. Wakelee, MD: But we’ve made some.

Mark A. Socinski, MD: Yes. So thinking about small cell lung cancer and extensive-stage disease, Ticiana, we have recently had a new approval and, I would say, another practice-changing phase III trial—IMpower133.

Ticiana A. Leal, MD: Yes. So IMpower133 is a phase III trial investigating the addition of atezolizumab, a PD-L1 [programmed death-ligand 1] inhibitor, in combination with our standard chemotherapy, carboplatin/etoposide. This study enrolled patients with a performance status [PS] of 0 to 1 and patients who had treated stable brain metastases. And I bring that up because we know that our small cell population is different from that population. We have a lot of patients with a performance status that is 2 or greater or who come in first with brain metastases. But in any case, this study allowed these patients who had PS 0 to 1 and stable treated brain metastases to be enrolled. And they were randomized to either carboplatin/etoposide/atezolizumab versus carboplatin/etoposide/placebo. And this was actually a double-blind study.

In this study, we saw that the primary endpoint of overall survival [OS] was positive. There was a 2-month improvement in overall survival. We also saw a PFS [progression-free survival] benefit. It’s about a 1.5-month overall benefit in progression-free survival. It statistically met primary endpoints of OS and PFS. The toxicity of adding atezolizumab seemed to be not too much different than what we would see with carboplatin/etoposide, which I think was reassuring. I think we all had concerns about patients who had paraneoplastic syndromes. Would immunotherapy be an issue? Again, patients with paraneoplastic syndromes were excluded, but we know that sometimes these go undiagnosed. We didn’t really see a major problem in terms of immune-related toxicities beyond what we would see with a combination of chemotherapy and immunotherapy.

This study didn’t really have enough tissue to make any real conclusions about whether there is a biomarker there. They explored blood-based biomarkers, again looking at TMB [tumor mutation burden] in the blood, and they really didn’t see any signal of improvement in one population or another based on the blood TMB. So it’s an interesting trial in the sense that, yes, we see an improvement. I think it’s something to build on. I think it made a lot of sense to use immunotherapy. It’s still puzzling why the benefit wasn’t greater, but I think future studies can address that. And certainly, building upon that platform is how I see this moving forward.

Mark A. Socinski, MD: I guess because we’ve had such a drought in small cell lung cancer, anything that was better is perceived as practice-changing.

Heather A. Wakelee, MD: And it’s immune therapy.

Mark A. Socinski, MD: Right, and that’s my point. I would have thought that immunotherapy would have been much more impactful in small cell disease. I’m not quite sure why I might have thought that, but certainly the clinical data have not. Nivolumab has a third-line indication, but that third-line indication is no better than topotecan. In fact, in the second-line setting, when it was randomized against topotecan, it was no better than topotecan.

Corey J. Langer, MD: It failed.

Mark A. Socinski, MD: Paul, your thoughts on that?

Paul K. Paik, MD: It’s a strange space. Many different trials have been conducted in the maintenance, like switch maintenance, state. As you had mentioned through CheckMate 331, which is a bona fide randomized trial of nivolumab versus dealer’s choice chemotherapy, technically it was negative. But to me, in IMpower133, the benefit seems consistent with what you might get if you just gave someone second-line immunotherapy—either nivolumab or pembrolizumab—right after they got carboplatin/etoposide. Because each of these studies in the second-line or maintenance space, even the ones that were negative, have median PFS values of about 2 [months], which is the improvement that we saw.

Overall survival, of course, is impossible for us to adjudicate across trial comparisons. And there was response rate activity for pembrolizumab in the second-line setting. This was 19%. For me, one of the concerns about everyone getting atezolizumab up front is that this impairs our ability to do trials to find better immunotherapy combinations for these folks. Because now everyone is going to be in this sort of immunotherapy-refractory space. The biology is making the science a little more difficult to figure out.

Transcript Edited for Clarity