Nuances in Treating Advanced Lung Adenocarcinoma - Episode 10
Mark A. Socinski, MD: The other advancement we’ve had is the understanding that the major resistance mutation is T790M. We look for it. We have a drug approved. If you find it, osimertinib…I want to ask David to comment on how this is now the first of the third-generation drugs out there. We have an ongoing trial, the FLAURA trial. This is a first-line trial in EGFR mutation. Is it restricted to exon 19 and exon 21, or all mutations?
David R. Spigel, MD: I think it’s sensitizing mutation. You don’t have to have T790M.
Mark A. Socinski, MD: Yes. It’s comparing osimertinib to choice. So, David, what are your thoughts, first about osimertinib, and then about FLAURA?
David R. Spigel, MD: I think osimertinib has been a fantastic drug. It’s gratifying to see patients who’ve done well on drugs like erlotinib for a long time, when they lose that benefit and then they start this and say it’s even easier than what it was like being on erlotinib. Mark, you don’t know this, but I talk about you every time I talk to a patient about osimertinib. Because when I have the discussion about “What are we going to do next, Dr Spigel?” I say, “Well, we have to test you for T790M, but I need to let you know that one of my colleagues in New York has espoused to just treat you and see how you do.” I don’t know if you still practice that way, Mark. I’ve tried that 1 time, and I got rejected from my registrar on getting it approved. So, I do go the route of testing for T790M. What has been weird for me the last few months has been testing urine. I didn’t think I’d ever do it, but I had a situation where I tested a woman’s blood, I did a biopsy of her tissue, and she still really wanted the drug. I said, “I can check your urine; I’ve never done this test before,” and it came back positive. She’s doing great on osimertinib.
Mark A. Socinski, MD: It was negative in blood and in tissue?
David R. Spigel, MD: In tissue. I’ve told people that story, and they ask, “Why don’t you just send urine and blood in at the same time?” I think that’s overkill, but I’ve done that on another patient, and urine came back positive. I’ve heard the company that makes the urine test may not be around much longer, so I’m not sure that test will be available.
Jared Weiss, MD: Well, send them off in a hurry.
David R. Spigel, MD: Right. So, right now I’d love to find it in the blood and use that as my gateway to getting osimertinib.
Mark A. Socinski, MD: Ross, were you going to say something?
Ross Camidge, MD, PhD: I was going to say that one aspect of looking in these other body fluids is the shed ability of the tumor, which may not be constant throughout the day. And so, I’ve actually had people whose cancer is progressing, and I know at one time their blood is positive for T790M, and nothing has changed other than their cancer getting worse, but then it’s negative. So, regarding the urine, is it more sensitive, or was it just that you picked the right time to do it?
Mark A. Socinski, MD: You collected a lot of it.
Ross Camidge, MD, PhD: Yes, because it averages your entire day.
Mark A. Socinski, MD: So, David, you didn’t comment on FLAURA.
David R. Spigel, MD: FLAURA is exciting to imagine. That’s one that if you asked me to bet on, I’d say it is not going to hit. I think the bar is too high to cross for that trial.
Mark A. Socinski, MD: Well, the question is, how high does the bar have to be?
David R. Spigel, MD: I’m happy to be wrong on that. I do wonder what’s next for a patient who gets osimertinib—hopefully, the best therapy available, and then it’s moving on to chemotherapy afterwards.
Mark G. Kris, MD: Not necessarily. Those people, they don’t have T790M, and C797S is not necessarily resistant to our first generation of drugs.
Ross Camidge, MD, PhD: Yes, and we should recognize that there are other pathways of resistance. So, MET, which was this little small slice of the pie—when you wipe out T790M and stretch your pie chart out again, I think MET application is a mechanism of acquired resistances becoming more commonly seen.
Mark A. Socinski, MD: After osimertinib?
Ross Camidge, MD, PhD: Yes, I think after osimertinib.
David R. Spigel, MD: Have you used an anti-MET strategy in patients like that and had benefit with crizotinib?
Ross Camidge, MD, PhD: Yes. Well, actually, I had a patient who had progressed on osimertinib. We rebiopsied, found high-level MET amplification, and then jury-rigged the combination with crizotinib. He’s had a beautiful response for 9 months.
Mark A. Socinski, MD: I had the same situation.
David R. Spigel, MD: With crizotinib and continued osimertinib?
Ross Camidge, MD, PhD: Yes.
Mark A. Socinski, MD: Well, actually, on rebiopsy, my patient had a very high MET amplification but did not have T790M. So, I went back to erlotinib plus crizotinib—jury-rigged the regimen there. There were some ASCO phase I data.
Ross Camidge, MD, PhD: To be honest, in mine, the T790M was still being suppressed, so another clone had come up. But rather than play Whac-A-Mole, I just kept one going and added in another.
Mark A. Socinski, MD: Well, Mark, you brought up C797S. What do we know about resistance patterns?
Mark G. Kris, MD: Not a lot, because you only see it after progression on osimertinib. And the people who got osimertinib second-line are a different beast. They have a sensitizing mutation, they have T790M, and they have C797S. Only now are we collecting people who have had osimertinib upfront, and they don’t have T790M. So, we’re scurrying to get those cases, to make some primary diagnoses, and to start studying them. But, David, I’m intrigued by your registrar. I think you need a new registrar. Why don’t they even ask the insurance company? I have to tell you, I’ve never had osimertinib turned down, and I’ve got it upfront. I’ve gotten it adjuvantly.
David R. Spigel, MD: No, it doesn’t stop at the registrar. The registrar goes to the insurance company.
Mark G. Kris, MD: But they’ve been approving it. Have any of you been able to get osimertinib without T790M?
Ross Camidge, MD, PhD: Absolutely.
Jared Weiss, MD: I’ve tried and failed. I don’t think differently from you; I’ve just not been able to get it.
David R. Spigel, MD: I’d love it if I could.
Mark G. Kris, MD: I haven’t had it turned down yet.
Mark A. Socinski, MD: OK, let me ask Ross this. Tell us what the average community oncologist should know about liquid biopsies.
Ross Camidge, MD, PhD: Well, the great thing is that they’re good at ruling things in and they’re not very good at ruling things out, to put it simply.
Mark A. Socinski, MD: So, if you find something, you can believe it? Act on it?
Ross Camidge, MD, PhD: Yes.
Mark A. Socinski, MD: But if you don’t find something, you can’t believe it.
Ross Camidge, MD, PhD: Here’s the analogy. You’re in a darkened room, and you can see something vaguely on the other wall. If it looks like Abraham Lincoln, it’s probably Abraham Lincoln. If you can’t see it, you can’t say it’s not there.
David R. Spigel, MD: I use a fishing analogy. If you catch a fish, that’s a fish. If you don’t catch it, it doesn’t mean there are no fish in the water.
Mark A. Socinski, MD: Is it a part of your standard evaluation in patients?
Ross Camidge, MD, PhD: So, I think it really came home to roost in the EGFR-mutant T790M. And the reason that’s a perfect example is that you have a positive control. If you can’t find the original activating mutation, you can’t really interpret that assay. If you find it, at least if you don’t see the T790M, you feel a little bit more comfortable because you can see the original EGFR mutation—but you still can’t take it to the bank. You’re still going to have to do what Dave did: Biopsy, test the urine, etc.
Mark A. Socinski, MD: Or wait another 3 months?
Ross Camidge, MD, PhD: Yes, I think you can recheck it. It depends on what’s happening with the patient. If they’re crashing and burning, you do all you can, and sometimes you have to shoot from the hip. Mark’s “shoot from the hip” is to start osimertinib. Mine would be to start something different.
Mark G. Kris, MD: With T790M-negative disease?
Ross Camidge, MD, PhD: Yes.
Mark G. Kris, MD: No, if somebody was really sick, I would give chemotherapy.
Mark A. Socinski, MD: Well, that’s what I was going to say. What’s your strategy in the T790M-negative patients, if they need a treatment change? If they’re getting sick, you’ve got to do something.
Mark G. Kris, MD: If you don’t have time to interrogate the tumor, then I would give chemotherapy and bevacizumab.
Mark A. Socinski, MD: We all agree?
Mark A. Socinski, MD: OK, with bevacizumab, you said. Jared?
Jared Weiss, MD: Yes, I agree with that. There are actually data for secure efficacy in the never-smoking—particularly with EGFR—population with pemetrexed/carboplatin/bevacizumab to further back that up.
Mark G. Kris, MD: Well, the data in the IPASS trial show the carboplatin/Taxol [paclitaxel] response rate was doubled.
Jared Weiss, MD: No, I mean for the bevacizumab questions, that the never-smokers may particularly benefit.
Mark G. Kris, MD: Oh, I didn’t know that.
Transcript Edited for Clarity