Transcript:
Helen Ross, MD: I'm Dr. Helen Ross. I direct the Thoracic Malignancies Program at Mayo Clinic in Arizona. Let me talk now about how to manage oncogenic drivers, and how to sort through the chaos of the different oncogenic driver mutations which we are seeing now.
Again, this is something that came up primarily in the early 2000s, which was the first time that we started realizing that there was a different population of non-small cell lung cancer patients who responded to targeted agents because of the presence of driver mutations.
The paradigm for this driver mutation was EGFR mutations. These are of two common types, an exon 19 deletion and an L858R mutation. We began to learn in the late 2000s that these patient populations were responsive to first-generation tyrosine kinase inhibitors which targeted these agents.
We've begun to test more and more commonly to see for the presence of driver mutations in patients with non-small cell lung cancer of all histologies, but particularly in adenocarcinomas. We find that driver mutations are present in about half of patients, although, not all of these are targetable.
We know that with addition of techniques like next-gen sequencing both from tissue and blood, we're able to identify these driver mutations very efficiently. Patients who have driver mutations do better with targeted therapy aimed against the driver than they do with non-specific therapy like chemotherapy.
Certainly for the case of EGFR, ALK, and ROS1, which are among the most common driver mutations, these patients are not patients that do particularly well with immunotherapy.
It's always worth waiting to get the results of your next-gen testing before you start treating patients, especially if you think that they are in a risk group which may have a high chance of having a driver mutation such as younger patients, patients who have been never smokers, females, and Asian patients.
When we treat patients with the appropriate targeted therapy against the appropriate target, they have better overall and progression-free survivals and better qualities of life. With targeted agents now, we have first-, second-, third-line therapies and beyond in many circumstances.
We've now gone beyond the so-called big three of EGFR, ALK, and ROS1, and have targetable opportunities with RETs, BRAF. a number of other mutations, MET mutations and MET exon skipping mutations are seen as a resistance mutation for EGFR patients and also de novo.
We very recently have data now in KRAS which is the most common mutation that has not been targetable in the past. We've just seen phase I data for a couple of compounds which have shown very encouraging response rates in these KRAS-G12C mutants which is leading to phase III trials, which we hope we'll actually make it a reality that we can give targeted therapy for up to half of all patients with non-small cell lung cancer.
The take-home message for those patients is that they should be screened for actively. next-gen sequencing is the best way to do that, because that will detect multiple drivers across a broad spectrum, and also gives us an opportunity to enroll patients in clinical trials when appropriate.
In addition to screening for mutations at diagnosis, it's important to do next-gen sequencing either with tissue or in the blood at the time of progression, because molecular mechanisms of progression vary among patients with first-line targeted therapy.
We now have second, third line and beyond targeted opportunities depending upon the mutations which are present at the time of progression.
