Dual Checkpoint Inhibition in NSCLC: CheckMate-227

Justin Gainor, MD:CheckMate-227 provided us with important insights into the roles of PD-L1 expression as well as tumor mutation burden, or TMB, as biomarkers. I think this is an important study in that it is a prospective study that really validated the role of TMB as a biomarker. It also showed that PD-L1 expression and TMB are really independent biomarkers of response to checkpoint inhibition. CheckMate-227 was a very large study. We still haven’t seen all the data that are going to come out of CheckMate-227. There are multiple arms, multiple subgroups, and so I think we’re going to be seeing more and more data in the coming years to really wrap our heads around this. But the data that we’ve seen so far were really focused on the biomarker of TMB high, which was defined as 10 mutations per megabase or greater. That cut point was defined based upon a second study, CheckMate-568. In that study, 10 mutations per megabase really have the best AUC when they were evaluating it as a biomarker.

And so, CheckMate-227 prospectively evaluated this biomarker of TMB-high. I think TMB as a biomarker right now, there are still a number of questions about the standardization of it. In CheckMate-227, this was determined based upon the FoundationOne platform. But how does that compare with whole-exome sequencing or other standard assays or other assays used at various institutions? There has been some analysis showing that compared with whole exome data, FoundationOne, there’s high concordance in TMB estimates. The initial studies were done using whole exome sequencing, but it does look like there’s concordance there.

Nonetheless, how we actually take that into clinical practice I think remains to be seen. We discussed earlier that rates of EGFR and ALK testing in the United States aren’t where we want them to be, and TMB is a whole order of magnitude greater of a complex biomarker. And so, being able to actually do that routinely for all patients with advanced lung cancer, I think today in 2018 is a bit challenging.

I think the greatest example of where we might think about using the CheckMate-227 data are around the use of nivolumab and the CTLA4 inhibitor, ipilimumab, particularly in patients who are PD-L1 low yet TMB high. And in that subgroup, it did look like the combination of nivolumab/ipilimumab did provide an advantage compared with chemotherapy alone. I think the elephant in the room, though, is, how does that match up against chemotherapy plus PD-1 combinations and will clinicians actually use I-O/I-O combinations in lieu of chemotherapy plus I-O combinations? I think right now in the absence of cross-trial comparisons, from a feasibility standpoint in the United States, we’re more commonly seeing chemotherapy plus I-O combinations based upon the KEYNOTE-189 data. And I think that nivolumab plus ipilimumab right now, given the more complex biomarker as well as just the collection of the efficacy and the safety data, is still searching for a place to be used.

Alexander Drilon, MD:Given the fact that this therapy is a combination and that there is the possibility for increased adverse events, if this treatment does eventually get approved, l think I would personally consider it for patients who are more fit and have less comorbidities, certainly patients who do not have a substantial history of a prior autoimmune disease. And as we mentioned based on the trial design, this would be for the first-line setting for patients with non—small cell lung cancer.

Transcript edited for clarity.