Identifying Key Molecular Targets in Metastatic NSCLC

Transcript:

Charu Aggarwal, MD, MPH: Melina, which genetic mutations are you looking for in the molecular profiling? You talked a little bit about plasma and tissue already, but tell me what you’re seeing in clinic and what’s most important to you.

Melina E. Marmarelis, MD: Charu, this is where it gets complicated. So, you have both point mutations where you’re looking at EGFR, KRAS, and BRAF, and that can be detected by next-generation sequencing [NGS]. Ideally, that looks at a variety of different areas and could be detected by PCR [polymerase chain reaction] but those are actually going to miss a lot of the uncommon [mutations.] In particular let’s talk about EGFR, the most common being exon 19 deletions and L858R, but you’re not going to see things in exon 20 really if you’re doing just PCR for those hot spots. So I think [it is] important to look at those broader panels because now we do have a number of targeted therapies in that space, and then you know that’s not it.

Unfortunately, you also need to look for a bunch of fusions. ALK, ROS1, RET, and NTRK fusions are best detected not on DNA-based panels and not by NGS but by RNA fusion panels or RNA-based panels that can actually see those abnormal fusions together. I think this is part of the reason that molecular testing is so hard in lung cancer is that it’s not just one thing. There are certainly, of course, companies that do this testing and are putting together packages for lung-specific testing, but not all of them include RNA. So it is important to know exactly what you’re getting when you’re ordering a test. Ideally, it would include DNA NGS and an RNA component to best identify those fusions. That can be done on tissue most easily to get that most complete information, but also, to some degree, on the liquid biopsies on the plasma testing.

Charu Aggarwal, MD, MPH: Absolutely. I think another layer there is that not all mutations are created equally. For example, EGFR mutation, we have both classical sensitizing mutations and EGFR exon 19 and 21 that are treated very differently than your EGFR uncommon mutations that may be in exon 18. We are learning a lot about new drugs and developments in EGFR exon 20 insertions and compound mutations. So I think once you test, you also have to have the ability to interpret as well as direct treatment based on what you find. And the same holds true for BRAF. Not all BRAF mutations respond to treatment. We really have to focus on the ones that do. For lung cancer, for example, BRAF V600E mutations are the ones that are immediately actionable, and the others probably don’t respond as well to the currently available BRAF inhibitors, although there may be others that are in development and clinical trials right now.

Transcript edited for clarity.