Transcript:Mark Socinski, MD: The discovery of EGFR mutations was in 2004, so now we’re 13 years into it. I think this subset of patients has taught us so many things about the management of cancer. One of the things—back in the time when we only had first-generation, maybe the second-generation agents—where patients initially had a very robust response, 99% reduction in disease, and maybe they’ve got 1 to 2 years or maybe even longer hopefully, they’re doing well with side effects. Then, they have progression, and they have progression in a different flavor—a solitary nodule, maybe 1 or 2 nodules, or maybe just a little bit of progression. So, we got used to treating beyond progression. We’ll come back to the CNS stuff in a moment, but Tracey, I wanted to get your perspective on that. When we were fellows, we were taught that once it progresses, you move on to something else. And many of these patients didn’t want to move on to something else because they were completely asymptomatic and they had, in most cases, minimal volume disease. They didn’t have threatening disease that was going to get them in trouble in the next 3 to 4 months, and we know that progression can be very indolent. So, your perspective?

Tracey Evans, MD: Right. And one thing we know is if they stop the agent that they’re on, then all hell breaks loose. They can get a flare of their disease and get very sick very quickly. And that was a favor in trying to design the second-line trials in this patient population because routinely we would have a washout period of 3 to 4 weeks, and that doesn’t work for these patients. They need to stay on the drug right up until they start the next agent. You’re correct that patients can have indolent progression, and sometimes the best thing to do there is just sit on it, get scans in a couple of months, and see how things progress. Another way that they can progress is they can have one area that tends to grow more rapidly while the remainder of the disease is still being held in check, so-called “oligoprogression.” And one thing we can do with these patients is treat, with local treatment, the site of oligoprogression; use radiation on that, and get more mileage out of their first-generation TKI, if that’s what they’re on, before going on to the next agent.

Mark Socinski, MD: And that would include the brain?

Tracey Evans, MD: Well, absolutely. I do that no matter what. I do that even not in EGFR TKIs. We’ll treat the brain, but yes, absolutely you can treat the brain and keep them on the agent. There are also some small retrospective data that show the addition of bevacizumab at progression can lead to re-responses and also give you a period of disease control. So, that would be a potential option. Of course, the approved option is osimertinib in T790M-positive patients. That requires a biopsy establishing that they have the T790M mutation in addition to their initial mutation or doing a plasma test to find the T790M mutation. One place I struggle, and I’d be curious what everybody else does, is what if people have oligoprogression? Do you biopsy that to figure out if they have T790M or do you just go ahead and treat it with radiation? I’ll do a little of each. If it’s easy to grab, I’ll grab it when I can, but then treat it with radiation and not put them on osimertinib yet until they get the next site of progression. But I’m curious as to what others would do; of course, we use chemotherapy in these patients, too.

Jared Weiss, MD: My radiation oncologist actually makes that easy for me. If I want stereotactic radiosurgery, he really wants fiducials in there. So, while I’m sticking a needle in, I can get a biopsy, leave a little fleck of gold, or whatever they’re using these days, and then treat it. There is a prospective trial going on looking at that oligoprogresser approach, and it would be good to enroll patients on that to prospectively validate that protocol.

Mark Socinski, MD: I think you raise a good point because it raises the point of knowing that there’s a dominant acquired resistance mutation, the T790M, knowing that we have a great drug, but also knowing that you don’t necessarily want to give up on the first sequence of drugs too early. When do you go looking for T790M, which is to your point, right?

Tracey Evans, MD: Right. And the other important point, though: plasma testing can be very useful for finding T790 because that can often get you your osimertinib. But what it doesn’t get you, and what’s important to understand, is that some progression events can be very aggressive. And, in fact, in about 5% of cases, you could have small cell transformation. I was not a believer that that could even happen, but I have seen 3 cases in the past year, the patient with EGFR-mutated disease.

Mark Socinski, MD: When you see it, you believe it.

Tracey Evans, MD: Oh yes, absolutely. And it’s impressive. Then you need to give those patients chemotherapy and they’re not appropriate for osimertinib. So, even though we have the plasma option, there are times where if it looks like a suspicious type of progression, you really do need to get that biopsy.

Transcript Edited for Clarity