Evolving NSCLC Treatment Paradigm - Episode 13

Trials of I-O Therapy in Driver Mutation NSCLC

Alexander Drilon, MD:This was an interesting prospective phase II trial that looked at the utility of single-agent immune checkpoint inhibition forEGFR-mutant lung cancers. And the results were consistent with retrospective analyses of the utility of immunotherapy for these patients and subset analyses of prospective trials. The response rate was low. It was 9% in this phase II study. However, that was just one patient given the smaller overall N. It turns out that that patient, on subsequent analysis of the tumor, the tumor ended up not harboring anEGFRmutation on subsequent testing. So, this really highlights that there are certain therapies that are much more of a fit for particular patients up front in the first-line setting. And this supports the fact that we should look at giving targeted therapy as a standard of care in the treatment-naïve setting for patients with advancedEGFR-mutant lung cancers and not give a single-agent immune checkpoint inhibitor.

We know thatEGFR-mutant lung cancers, like other driver-positive lung cancers, can express PD-L1, and a certain proportion do have PD-L1 expression of 50% or greater. But even in that situation, I would personally prefer to give targeted therapy rather than considering something like pembrolizumab, well recognizing that the trials that showed the activity of pembrolizumab or 50% or higher excluded patients withEGFR-mutant lung cancers.

Justin Gainor, MD:From a retrospective single-institution series performed at my own institution, we’ve seen thatEGFR- andALK-positive patients have about a 3% response rate to single-agent checkpoint inhibitors. More recent meta-analyses have looked at the randomized studies, generally in the second-line setting comparing single-agent checkpoint inhibitors versus docetaxel, and specifically amongEGFR-mutant patients, really seeing that single-agent checkpoint inhibitors did not result in an improvement in survival compared with docetaxel.

In addition to that, we’ve now gotten some prospective data, and I think the best prospective data with single-agent checkpoint inhibitors came from the ATLANTIC study. And this was evaluating durvalumab in specific subgroups, and that included patients withEGFRmutations andALKrearrangements. Notably, even when that study tried to enrich for responders by focusing on PD-L1 expression—in here, it was 25% or greater—the response rate amongEGFRpatients with that degree of PD-L1 expression was only 12%. And there were no responses observed in theALKsubgroup, despite having high PD-L1 expression. And I think this speaks to a point that PD-L1 expression is a less reliable predictive biomarker in patients withEGFR- andALK-positive disease.

Transcript edited for clarity.