Frontline Treatment of Stage IV NSCLC: Biomarkers

Mark A. Socinski, MD: Martin, let’s get your thoughts on PD-L1. We did see, from the EMPOWER-Lung 1 trial, getting a bit more granular with regard to the PD-L1 group greater than 50%, dividing it up into, I think, 50% to 60%, 60% to 80%, and 80% and above, and your perspective on that. But then we’ve heard a lot of buzz about TMB [tumor mutational burden]. There were a couple of presentations at ASCO [American Society of Clinical Oncology annual meeting], some co-mutations like STK11, and KEAP1, and these sorts of things. Let’s start with PD-L1, what are your thoughts there? Then delve into the TMB and the other co-mutation aspects of this.

Martin Dietrich, MD, PhD: I agree. I think the granularity of PD-L1 is going to really shape the selection of therapy in the first-line setting. Greater than 50% is no longer a binary call. I think we’ve seen an incremental benefit in 10% increases going from 50% closer to 100%. I think this also helps in the selection of patients…deescalate to a single-agent PD-1. We have seen, obviously, the combinatorial strategies providing benefit across the PD-L1 spectrum. We’ve had an 11% increase in overall survival at 4 years in combination with ipilimumab. I’ve seen a similar signal with the addition of TIGIT. We are certainly moving forward in getting PD-L1 refined in terms of its application. I would say that low PD-L1, greater than 1% but below 50%, is one where I find the KEYNOTE-042 regimen unsuitable, simply because it wasn’t positive as an overall trial. Addition of chemotherapy or a second immunotherapy agent here is helpful. My take on it is PD-L1 really decides about the intensity of immunotherapy. The closer to 100%, the more likely I would be willing to give a single-agent PD-1. But when in doubt, at 50%, even 60%, I would still consider a combinatorial strategy the right way moving forward.

Mark A. Socinski, MD: And your thoughts on TMB? The first question is, do we know how to measure it?

Martin Dietrich, MD, PhD: It is very difficult, and especially now that liquid biopsy has started to offer TMB assessments as well. It tells you how all over the place it is. If you have synchronous measurements, you can see that there is a high degree of discrepancy with liquid biopsy, typically overestimating tumor mutational burden. I was originally very excited about tumor mutational burden when the first analysis of CheckMate 227 was released in 2018. It has since probably lost a little of its impact. We’ve seen data at AACR [the American Association for Cancer Research annual meeting] this year, showing positive predictive impact in CheckMate 9LA for TMB. I like to think of this as an add-on, so if I have a TMB-high, PD-L1–high level, I have higher expectations, but I don’t use [it] beyond PD-L1 as a true frequent selection marker. The secondary mutations, those are exploratory analyses, and I don’t find them quite ready for prime time for selection against immunotherapy, even though they’ve been looked at. I think it was very interesting to see that in combination with some of the KRAS inhibitors that they would…respond well, but I can’t factor in KEAP1 and STK11 and TP53 mutations just yet as a marker that selects against immunotherapy in any way. I think it’s interesting to see, my expectations are certainly lower but I wouldn’t change my overall take based on the secondary mutations unless we have more prospective data on it.

Mark A. Socinski, MD: I would agree. They are interesting data, helping to identify patients who may not be benefiting as much from immunotherapy approaches and maybe would benefit more from different approaches. What those approaches are, I don’t think we know.

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