Frontline Immunotherapy in PD-L1+ NSCLC

Paul K. Paik, MD:Pembrolizumab is now the standard-of-care treatment for all of our non—small cell lung cancer patients whose tumors have a high expression level of PD-L1, and the cutoff in the trial was ≥50%. All of the efficacy endpoints were improved. Right from the beginning of the presentation, and as in an update last year, this was the response rate, the PFS, and the overall survival. And the differences were not subtle. PFS was the strongest so far. The hazard ratio for that was just north of 0.5, a median PFS of 10 months versus 6 months. And it looked like all histologies benefitted, squamous cell and lung adenocarcinoma.

One of the more recent studies in the field of immunotherapy that was presented and published is the BIRCH trial. This was a randomized trial not against standard-of-care chemotherapy but an interesting trial of randomization within itself. This was taking a look at atezolizumab, which is a PD-L1 inhibitor, in the 3 different lines of therapy that we most frequently treat: first line, second line, and third line. And so, in this way, the trial was unique. Within a single trial, it was trying to take a look at whether or not there were actually meaningful differences in effectiveness for atezolizumab if you gave it at the beginning of diagnosis or after patients got subsequent therapy, particularly chemotherapy. In terms of the data, there are lots of different ways to take a look at the endpoints for the trial. I think the most meaningful look at the data has to do with, did atezolizumab actually work better in the first-line setting versus the second- and third-line settings and beyond? That really is the heart of the question because that’s what we need to know in comparison with, for example, pembrolizumab in the first-line setting.

And the short answer is that it did appear to work better. This was in the intention-to-treat population as well as in the subgroups that it took a look at, which were basically the high PD-L1 expressers. In this study, the PD-L1 expression was not quantified by the amount, in the traditional sense, by percent staining; it was this composite tumor cell and immune cell PD-L1 score that’s unique to atezolizumab and the antibody that they used. And the short answer, again, is that there were increased improvements in PFS in particular, overall survival in the intention-to-treat population, as well as in the high PD-L1 expressers, the TC3/IC3 subgroup.

The issue is that the difference was actually not that big. The median PFS, in particular, for the high PD-L1 expressers in the first-line setting was somewhere around 5.6 months, 5.8 months. The median PFS in the second- and third-line settings was around 2.5 months—so again, a meaningful difference. But that magnitude of the difference is actually quite small when you think about the median PFS that we saw for pembrolizumab in the first-line setting, which was 10 months.

In fact, these data are very similar to the CheckMate-026 data of nivolumab in the frontline setting where the median PFS was actually not that much better. It was actually somewhat inferior to chemotherapy at around 5.5 months. So, for me, the value of this trial is that it was an important trial to do and it was a good trial to do. The results are perhaps not as great as we were expecting, but valuable insofar as it did confirm the results from the CheckMate-026 trial were perhaps not a fluke. Perhaps what was most interesting is that in the pembrolizumab study, pembrolizumab performed better than we had anticipated. And this provides a larger data set for us to go back and take a look at exactly what’s going on. What is the right biomarker? So, there is value in this study, perhaps not practically speaking for clinicians, but for us in the academic world, to be able to take a look at how to answer some other important questions that are in the field.

Transcript edited for clarity.