Mutation Testing in Nonsquamous NSCLC

Benjamin P. Levy: I think every patient now with an advanced adenocarcinoma of the lung needs to have genetic interrogation or comprehensive genomic profiling. There are too many mutations now that we can act upon with targeted therapies, and, as such, we do a 50-gene panel by the Ion Torrent AmpliSeq platform. We test for EGFR, we test for KRAS, we test for BRAF, and we test for other genes in that Ion Torrent panel. We also test ROS and ALK by the FISH assay, to look for those rearrangements. But, at the bare minimum, every patient with an advanced lung adenocarcinoma needs to be tested for EGFR, ALK, ROS, and BRAF. I would say that the list is going to grow even longer in the next 1 to 2 years, where we’re going to need to be doing more and more testing. There are rarer mutations that are potentially predictive of efficacy of other targeted therapies, so we need to keep that in mind. But, clearly, EGFR, ALK, ROS, and BRAF are the mutations that need to be tested up front in all patients.

A large majority of patients who have lung adenocarcinoma have a driver mutation, if you include KRAS. That’s probably 60% to 70% of patients who have some sort of driver mutation. It’s a little bit of a different question if you ask what proportion of patients have a driver mutation that you can wed to a targeted therapy, and I think that’s what’s important. So, if you look across the board, about 20% to 30% of patients now have a driver mutation that we can act upon with a targeted therapy. That still leaves about 60% to 70% of patients who don’t have an actionable mutation in which we can deliver precision medicine. But I would say, again, that the list is growing longer of rarer yet actionable mutations in lung adenocarcinoma. That’s outside of EGFR, ALK, ROS, and BRAF. We have MET exon 14 skipping mutations. There are NTRK fusions that may be predictive of a drug called entrectinib. So, the list is growing longer. We need to be mindful that things are changing rapidly, and we need to stay ahead of the curve and stay on top of the data.

PD-L1 testing is now the standard of care, not only for advanced adenocarcinomas but also squamous patients with stage 4 disease. This was based on a trial comparing single-agent pembrolizumab, KEYTRUDA, to chemotherapy in patients who had a PD-L1 tumor proportion score of greater than 50%. And, in that trial, there was a benefit in response rate, progression-free survival, and overall survival for single-agent pembrolizumab. As such, based on that trial, every patient who walks through the door needs PD-L1 testing. For every patient who has advanced non—small cell lung cancer, whether they be squamous cell or adenocarcinoma, if they have a PD-L1 score greater than 50%, then they warrant single-agent pembrolizumab based on that trial. This gets into a larger question of you having to do genetic testing and you having to do PD-L1 testing. It gets into a whole issue of what’s called “tissue stewardship,” where you need enough tissue not only to do the genetic testing for adenocarcinomas, but enough tissue to also do the PD-L1 testing.