Understanding EGFR-Mutant NSCLC Subsets

Transcript:Ben Levy, MD: Lung adenocarcinoma is not one disease. It can now be parsed out into distinct genetic alterations or genetic subsets that are generally mutually exclusive. If we can identify these genetic subsets, we can allow the patient to receive targeted therapies versus chemotherapy, and there’s a lot of heterogeneity. Of course, there’s EGFR-mutant lung cancer, there’s KRAS, there’s HER2, there’s BRAF, there’s MET that acts on 14 skipping mutations, there’s ROS, and there’s RET. It’s very confusing, but the bottom line is that each of these cancers behaves differently and responds differently based on what targeted therapy you’re going to give them, and really just speaks and underscores the importance of comprehensive genomic profiling. One patient with lung adenocarcinoma who walks through the door may be very different, behave differently, and respond differently than another patient with lung adenocarcinoma who walks through the door. So, there’s a lot of heterogeneity, and that heterogeneity speaks volumes to the fact that we need to make sure these patients have comprehensive genomic profiling as they walk through.

Luis Raez, MD: EGFR mutations are very interesting because we have discovered that the prevalence of the mutation depends of the ethnicity of the person. For example, in Caucasian populations, maybe 10% to 15% of the patients can carry these genetic aberrations. However, in Japanese, Chinese, and other Asian populations, these genetic aberrations can be like 40% or 45% of the patients with lung cancer. I have personally published in Latin America, for Hispanic patients, for example, that the genetic aberrations are in the middle, between 25% and 30%, where in some countries, it’s 35% of the patients. So, that will depend of the ethnicity of the patient to see what the frequency of these EGFR mutations is.

We have been discovering that there are a lot of mutations in this EGFR gene, especially because in the old times, we used to do like a hotspot, only analyzing one area of the gene. But now, we know that there are several areas of the gene that can have mutations. For example, in the tumor, the more common mutations are the ones that are exon19 and exon21. In these 2 areas of the gene, we have close to 90% of all the mutations. However, there is probably 10% of mutations that are in other areas of the gene, including exon20. Commercially speaking, a lot of industry vendors only test for the most common ones because it’s more work to test for the uncommon ones. However, we need to probably do a comprehensive analysis of the gene because you can say, “Oh, we’re only missing 10% of the patients.” But lung cancer is a very prevalent disease. You are talking about 225,000 Americans every year with lung cancer as new patients, so if you miss 10% of the patients, you are missing a lot of people. That’s why we advocate the use of next-generation sequencing. We do a whole testing of the gene so we’re not missing even these small populations of mutations that can be relevant or could be resistant for the treatment with tyrosine kinase inhibitors.

Ben Levy, MD: It’s important to note that not all EGFR mutations are the same. The most common EGFR mutations—exon19 deletions, L858R, exon21—those are the mutations that are more likely to confer sensitivity. If you have a mutation in del19 or 21, these patients should be offered, in their advanced stage, a frontline TKI, either gefitinib, erlotinib, or afatinib.

The story gets a little more confusing with other more rare EGFR mutations. For instance, with EGFR and exon18 mutations, it depends on what type of mutation it is. Some are resistant, some are sensitive. The one that I think we know for the most part is resistant to TKIs is exon20, and T790M is an exon20 mutation. But exon20 mutations, if identified up front, should not be offered a TKI. These patients should generally be given chemotherapy, and that’s an important message to the community. Not only are all lung cancers not the same, but not all EGFR mutations are the same, and exon19s and exon21s predict sensitivity. The exon20s generally confer resistance, the exon18s are really individualized. You’ve got to really think hard and look up the data on which exon18s may be sensitive versus resistant to TKIs.

Transcript Edited for Clarity