Molecular Testing in Lung Cancer

Transcript:Philip C. Mack, PhD: I always advocate for multiplex testing. If possible, I would recommend next-generation sequencing approaches. The main reason is not only do we have a broad number of markers in that panel, but we can also identify rare mutations that don’t necessarily show up on all the hot-spot analyses. So, in my mind, you should always be looking to do a next-generation sequencing approach first.

So, the question becomes, when is it feasible not to do that? When is it necessary not to have an expansive analysis? Several situations occur to me. First of all, when there’s insufficient time for the patient, and it’s urgent that they start treatment. You may want to do some rapid analysis, something with a 1 or 2-day turnaround time—EGFR plus ALK for instance—so that you can get the patient on the appropriate therapy fast. If you have a positive identification, that’s great. But if you don’t, I think it’s incumbent upon the team to go back and perform that multiplex analysis to look for the rare markers and see if there’s some additional options for the patient.

The most common mutations in EGFR are the exon 19 deletion, which is actually a whole family of different deletions, but they serve the same purpose in activating EGFR—and the L858R point mutation in exon 21. After that, the third most common type of mutation is actually an exon 20 insertion. These typically do not respond to current EGFR inhibitors. Beyond that is a whole suite of very rare EGFR mutations, many of which are perfectly responsive to erlotinib, gefitinib, or afatinib. That’s one of the reasons why I advocate for a sequencing approach: to identify these rare mutations that could benefit from treatment. Collectively, they represent at least 10% of the population.

I would recommend in a squamous cell carcinoma that PD-L1 is always conducted. In adenocarcinoma, you should do PD-L1, but it’s secondary to molecular marker analysis. It’s more important for the patient to determine whether or not they have an EGFR, an ALK, a RET, a ROS, or a BRAF mutation, or one of the MET abnormalities, than it is to have PD-L1. You should do both. In an ideal world, you will do both molecular analyses for mutations and PD-L1 expression in adenocarcinoma.

However, patients do not seem to benefit from immuno-oncology as well if they are positive for an EGFR mutation or an ALK mutation. The level of benefit for these patients is considerably lower, so it serves the patient’s best interest to put them on an EGFR inhibitor if they have an EGFR mutation long before you’d even consider immune oncology. So, the sequence of testing in adenocarcinoma, once you’ve determined histology, should be molecular marker analysis and then PD-L1. If you can do it all in one fell swoop, that’s perfect.

Transcript Edited for Clarity