Treatment of EGFR Mutant Non-Small Cell Lung Cancer - Episode 4
Roy S. Herbst, MD, PhD:This is a very interesting question. When do you switch therapies with an EGFR inhibitor? My feeling is that you want to maximize your frontline EGFR inhibitor as long as possible. Of course, when to switch would depend on the patient’s symptoms and the options you have next. So, if this is a patient who’s beginning to progress but it’s a slow progressionthere are few symptoms—I would do a few things. I would probably try to keep the EGFR inhibitor going for as long as possible.
Tumors are polyclonal, and, of course, there could be a resistant population and a sensitive population. With time, of course, under the selection pressure of a first-line EGFR agent, we will move more towards the resistant population. But I would try to keep the frontline drug going for as long as possible. I would, at some pointwhen it became convenient, when there’s something easy enough to biopsy—get a new biopsy, and then test it forT790Mmutation, which is a secondary mutation and the most common form of resistance. So, that would be the first thingkeep the agent going as long as possible, and gain the knowledge of what the resistance mechanism is. Perhaps the patient has c-MET amplification. That’s another treatable, albeit in clinical trial, type of abnormality.
Then, of course, if the patient had noT790Mmutation, I’d really try to keep the first-line EGFR agent going as long as possible. Because I know, if we stop that, there will be a flare, and when we go to chemotherapy, the chance of response will be 20%maybe 25% to 30%—and it won’t go that well, even though we can do it. Of course, we could consider immunotherapy at that point. The problem is that, at least from some of the big randomized studies, patients withEGFR-mutated disease did not do that well with single-agent immunotherapy, probably because their mutational burden is low. The tumor was addicted and driven by one mutation, and that makes the patient less likely to respond.
Now, if the patient had aT790Mmutation, the light goes off again, because that tells you that you have a patient for whom you have the next drug. Then, the question is, how long can you eek out the benefit of the frontline agent before starting a new drug? But at some point, you do want to make sure that the patient gets a new drug. Also during this period, if someone is progressing, keep an eye on the brain, because sooner or later the disease will end up there and, of course, the morbidity can be much higher.
My sense for this patient is to look for anEGFRmutation. If you don’t look, you won’t find it. If you have it, treat for it, even in patients with poor performance statuses. If they then recur before going to chemotherapy, do everything you can to see if they have aT790Mmutation, because, if they have that secondary mutation, your chance of response would be 60% to 70%. Then, you have the ability to use a drug called osimertinib, which gets bothEGFR-mutant receptors as well as the receptors for theT790Msecondary mutation and is much more specific for the mutant than the wild-type receptors. So, you have far less rash and diarrhea with this drug. Keep that in mind as a treatment. And then, of course, we need to do more research into how to integrate immunotherapies and some of the other targeted therapies, whether it be for c-MET or other targets, into this setting.
Transcript edited for clarity.