Molecular Testing in Metastatic NSCLC


John V. Heymach, MD, PhD: Hi, I’m John Heymach. I’m the chair of thoracic head and neck medical oncology at The University of Texas MD Anderson Cancer Center in Houston, Texas. During this OncLive®Insights®program, we’ll be having a conversation about EGFR-mutated non–small cell lung cancer. The conversation today will be with Dr Edgardo Santos. Dr Santos, would you like to introduce yourself?

Edgardo S. Santos Castillero, MD, FACP: Thank you, John. It’s always a pleasure to be with you. My name is Edgardo Santos with Florida Precision Oncology, precision thoracic oncology, in Aventura, Florida. I am the medical director of research services.

John V. Heymach, MD, PhD: Wonderful. I’ll let the audience know that Eddie and I share a number of patients, so these are real-life issues that we get to discuss on a day-to-day basis. Let me start, Eddie, and let’s talk about molecular testing in non–small cell lung cancer. This is such an exciting and rapidly changing area because now, just in the last couple of years, the number of new targeted agents we have is exploding. We now have at least 7 targetable oncogenes for which we routinely need to test, so this is something that is changing month by month with these new approvals. Let me start by asking this: What’s your approach for molecular testing in patients, and what platform or approach are you using? Are you still including things like FISH [fluorescence in situ hybridization]–based assays, IHC [immunohistochemistry], or NGS [next-generation sequencing]? What are you doing for EGFR, specifically?

Edgardo S. Santos Castillero, MD, FACP: As you know, this field has changed significantly in the last few years. We are more ahead compared with the initial times when we were using immunohistochemistry and perhaps PCR [polymerase chain reaction] and FISH analysis. The technology has advanced so much nowadays that most oncologists are using next-generation sequencing, which allows us to cover multiple gene abnormalities. A big part of that genome is that you want to say that, by doing next-generation sequencing, we may have a better understanding of the spectrum of what’s going on with a patient. It also uses a small piece of the tumor tissue, which is valuable for the future of management and research. It’s always better not to utilize all the entire block where the tissue from the biopsy is.

EGFR is perhaps 1 of the most common driver mutations that we have, specifically in lung cancer. You start with the panel. If you order next-generation sequencing with any kind of vendor, most likely the EGFR is there plus many others, so that’s what I use. I don’t recall the last time I sent a specific patient for just EGFR testing.

The other thing that’s new, as you just mentioned, is the advances we have done on next-generation sequencing now using the blood: It’s what we call liquid biopsy. They also use next-generation sequencing as the platform, and that has helped us make a faster, more liquid diagnosis because the results are coming faster than the tissue molecular profile would. That has impacted the patient care, not only in lung cancer but also in other tumor types.

John V. Heymach, MD, PhD: Yes. I have a few more questions about EGFR. You and I have both been treating lung cancer for a long time. You remember early on there were a lot of data about EGFR amplification and doing a FISH for that. Are you ever doing IHC or looking for EGFR amplification, or are you focused on the mutations?

Edgardo S. Santos Castillero, MD, FACP: On the EGFR, I focus on the mutation. I’m not using an amplification as you mentioned. There are some cases for which immunohistochemistry was also used. I focus on the mutation. As you know, there are several EGFR mutations, so that’s what I do. What do you do in your practice?

John V. Heymach, MD, PhD: It’s the same. We used to do IHC, and we used to do amplification, but now we’re focused on those mutations. It’s worth discussing. We used to have a PCR [polymerase chain reaction]–based platform that focused on the 2 classical mutations: the L858R and the exon 19 deletion. With the next-generation sequencing, we’re covering a much wider range of potential mutations. We have T790M, and we’re getting the exon 20 insertions and the other atypical mutations. What’s your approach there? Are you covering a wide range of mutations, or is your platform catching the classical mutations only?

Edgardo S. Santos Castillero, MD, FACP: Specifically for EGFR, John, we cover the entire EGFR exon. We cover all of them that you just mentioned: those atypical or uncommon mutations, some of which are sensitive. We cover all of the EGFR domain.

John V. Heymach, MD, PhD: Yeah, it’s great. It is not just important for selecting standard therapies. We know our standard therapies for EGFR-mutant lung cancer after the classical mutations, but we do have afatinib now approved for some atypical mutations: the L861Q mutation, the S768I mutation, and the 719 mutation as well. You want to be profiling them. From a research perspective, this is an area that we’re interested in at MD Anderson. We now have some drugs that are active against exon 20 insertions as well. Even though they’re not FDA approved, it’s important that we identify them so we can get those patients on clinical trials. Has that been your experience as well?

Edgardo S. Santos Castillero, MD, FACP: Yes, John, it’s the same thing. Either we put a patient on a clinical trial, or we at least know the aggressiveness of the disease and look for a therapy if there is no research available. I completely agree with you. For exon 20 insertions, as you know, there are some drugs in latest development stages, and hopefully we’ll have them soon.

John V. Heymach, MD, PhD: Here, I’ll mention that we take the same next-generation sequencing approach that you mentioned as well, because if you think about all the different alterations besides EGFR, we’ve got to cover it. Before, we just had EGFR and ALK. Now we’ve got EGFR, ALK, and ROS1. Now we’ve got RET fusions, for which RET inhibitors are approved. We’ve got MET exon 14, with the approval of capmatinib as well, and of course BRAF and NTRK1 fusions. We used to do a lot of these FISH assays for the fusions, but for the reason you mentioned before, it seems impossible to do all those FISH assays. That’s 5 different FISH assays.

Are you all doing FISH assays or are you trying to cover it all with the NGS?

Edgardo S. Santos Castillero, MD, FACP: As you know, we talked about next-generation sequencing, but that technology has also improved because now several vendors also have RNA generation sequencing. That next-generation sequencing is targeted and developed to the DNA analysis, and now RNA is also on board. It’s difficult to miss a fusion protein or an abnormality when you combine the NGS of both DNA and RNA. We will be able to catch a lot of those things that you just mentioned: all those official proteins for which FISH is good, like RET and NTRK1. Sometimes they’re very picky, but with the RNA on board, we’ll be able to catch them. It’s good because we look forward to seeing an increase in the number of patients being diagnosed with them because we now have targeted therapy for those patients.

John V. Heymach, MD, PhD: Right. The therapies for those rarer alterations, the things like the fusions, are really good. The patients can have a dramatically improved outcome, so there’s probably nothing more important an oncologist can do than to make sure they get the right driver mutation for patients.

Transcript Edited for Clarity

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