Welcome to The Lung Cancer Sessions brought to you by the Video Journal of Oncology (VJOncology).
This exclusive roundtable discussion features leading lung cancer experts Ross Camidge (University of Colorado Aurora, Denver, CO), Rosario Garcia Campelo (A Coruña University Hospital, A Coruña, Spain), Natasha Leighl (Princess Margaret Cancer Centre, Ontario, Canada) and Alexander Spira (Virginia Cancer Specialists, Fairfax, VA).
Watch this on-demand feature to learn about the exciting advances in EGFR-mutant non-small cell lung cancer (NSCLC). The panel dissect the latest considerations around EGFR testing, first-line treatment approaches, the role of immunotherapy, management of brain and bone metastases, reprofiling and what is on the horizon in this field.
“Most patients with an EGFR mutation have what we would call the classic one, exon 19, exon 21. Right? And those are the ones we typically think about osimertinib. Then I kind of look at it into two others right now. I think it’d be exon 20 insertions. So those are where we now have new drugs, at least in the United States, approved. Both mobocertinib and amivantamab. And then I think of these atypical ones, things like exon 19 or G719X, where we have some data for afatinib, some data for osimertinib. And we’re not quite sure what to do with as well. So I kind of lump it into those three things. And then I have a separate category for secondary resistance mutations. For those of us old enough, back in the day we used to think of EGFR mutations and then T790M, and we went from erlotinib to osimertinib. Now, at least in most parts of the world, we start everybody on osimertinib, so we’re seeing less T790M, but we’re seeing the development of new drugs that may lead us to new clinical trials, such as C797S and others. Those are rare, so I kind of put that in my fourth category”
– Alexander Spira
1L treatment approaches: TKIs, toxicities, chemo, and the role of IO?
“I think it’s so important that, you know, you focus on chemotherapy. I think checkpoint inhibitors really don’t work as well in this population… I know some people use chemotherapy plus bevacizumab, but you know, certainly in Canada it would be chemotherapy first and then these new treatments. And when you look at the trials moving to first-line, you know, the amivantamab strategy is to add to chemo, and the mobocertinib strategy is either or. And, you know, when you sort of think about it, like, if you’re just as good, you would probably use mobo first-line if that study were sort of similar or equivalent. But I love the idea of a targeted first paradigm. I just don’t know if we’re going to get there in the exon 20 insertions.”
– Natasha Leighl
Brain efficacy of TKIs and treating bone metastases
[On intercranial activity] “Yeah, I mean, the high-dose osimertinib, again, sometimes, you know, in the real world we do things because we only have certain tools in the toolbox. You know, if you think about osimertinib as a primarily EGFR wild-type sparing agent, it’s the one that’s least likely to work on exon 20, ’cause the structure of the kinase is so similar. So I think, you know, if you’re trapped on a desert island and you only have osimertinib, you try it. I don’t know I’d put a lot of faith in it, but yeah. You know, I think what we’ve touched on is that the brain is gonna be this incredibly important battleground for these new drugs to really, you know, differentiate themselves”
– Ross Camidge
Re-biopsy on progression and future directions
“Usually, we try to rebiopsy. It’s not always easy. Different reasons as you already know. But this is what we try to do. And we try to look for different resistance mechanisms. We have different trials, we try to put these patients on the trials according to resistance mechanisms. And in case we don’t have any trial, or the patient doesn’t want any trial, we offer those patients conventional chemo. But we try to do rebiopsy.”
– Rosario Garcia Campelo
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SECTION 1: What does EGFR mutation positive actually mean?
ROSS CAMIDGE: Hello, everyone! And welcome to the Lung Cancer Sessions of VJOncology. And I am delighted to have three friends with me here today. Alex Spira from Virginia Cancer Specialists. Say hi, Alex.
ALEXANDER SPIRA: Hi, everyone.
ROSS CAMIDGE: Okay, Rosario Garcia Campelo, from the University Hospital in A Coruña, Spain. Say hi, Rosario.
ROSARIO GARCIA CAMPELO: Hi everyone. Hi.
ROSS CAMIDGE: And Natasha Leighl from Princess Margaret in Toronto! Hey, Natasha.
NATASHA LEIGHL: Hi there.
ROSS CAMIDGE: So we are talking today about the field of EGFR-mutation positive, and the reason we’re talking about it is even though we’ve known about these things for nearly 20 years, the field has been changing. So if I say EGFR mutation positive, Alex, you know, what does that mean to you in your clinic these days?
ALEXANDER SPIRA: So, you know, a couple of years ago, it used to be exon 19 and exon 21. It was easy. Now, as I like to say, it’s complicated. There’s a lot more to think about, you got exon 20 insertions, you have exon 18s, and then you have resistance ones coming up for clinical studies. So it’s something you really have to think about and know the answer to. And sometimes we don’t get a lot of guidance by those next-gen sequencing assays that they just say, exon 20 mutation, and say, “Ross, figure it out!” You go from there.
ROSS CAMIDGE: Yeah, maybe, yeah.
ALEXANDER SPIRA: So it’s a bit complicated.
ROSS CAMIDGE: I mean, do you have a structure in your head as to how you group them?
ALEXANDER SPIRA: I do. So the way I think about it is what are the classic ones, right? Most patients with an EGFR mutation have what we would call the classic one, exon 19, exon 21. Right? And those are the ones we typically think about osimertinib. Then I kind of look at it into two others right now. I think it’d be exon 20 insertions. So those are where we now have new drugs, at least in the United States, approved. Both mobocertinib and amivantamab. And then I think of these atypical ones, things like exon 19 or G719X, where we have some data for afatinib, some data for osimertinib. And we’re not quite sure what to do with as well. So I kind of lump it into those three things. And then I have a separate category for secondary resistance mutations. For those of us old enough, back in the day we used to think of EGFR mutations and then T790M, and we went from erlotinib to osimertinib. Now, at least in most parts of the world, we start everybody on osimertinib, so we’re seeing less T790M, but we’re seeing the development of new drugs that may lead us to new clinical trials, such as C797S and others. Those are rare, so I kind of put that in my fourth category.
ROSS CAMIDGE: Okay so, the others, I mean, do you have a different grouping, or the same grouping? Do you use the same nomenclature? You know, he said atypical. I’ve heard other people call these things uncommon. Let’s start with Rosario.
ROSARIO GARCIA CAMPELO: Hi. We usually talk about uncommon mutations, and we have basically the same picture. We talk about the sensitive mutations, exon 19, exon 21. And then we figured out the other group of alterations. It’s true that the next-generation sequencing approach to the new techniques had allow us to increase the detection rate of these uncommon mutations. And we are still facing how to deal, in our daily clinical practice, with sinus-specific rare mutations. So I think we need, in some cases, we need more data, and also we need more specific drugs. I guess we are talking about the new approaches for all these new alterations.
ROSS CAMIDGE: Yeah, I mean, in my mind, I kind of, so I tend to use the common mutations, that’s the classical ones. Uncommon is the term I tend to use rather than atypical. And that was informed by a discussion with Dan Costa, who kind of beat me over the head and said, these things signal in the same way, they’re just uncommon. They’re not atypical. And then the exon 20s I think fall into a different category. So Natasha in Canada, this is a question about testing. Do you think the testing always picks all of these things up?
NATASHA LEIGHL: So, you know, testing is a moving field, especially in, you know, managed care systems like, you know, Canada, Australia and the U.K. And also Spain. So when you’re using NGS, you know, we know for all of these, the sensitivity is better and you’re able to find more common sensitizing mutations, more uncommon sensitizing mutations. And of course, probably double the number of exon 20 insertion mutations. So NGS is, you know, our preferred way, you know, especially when you’re limited by tissue or time, sometimes you’ll have to use a PCR assay or a, you know, a liquid biopsy or ddPCR assay. But whenever possible, you know, NGS leads to the greatest sensitivity or pickup rate for all of these and, you know, in particular doubles the number of exon 20 insertion mutations that you can find.
ROSS CAMIDGE: Yeah, one of the things that, and Alex and I have talked about this before and he kind of hinted at it, is when you get these next-generation sequencing reports, you know, can the average guy reading it, you know, know that it’s an exon 20 insertion? I mean, one of the things I sometimes see is as a specific exon 20 insertion, which is a duplication, and you get this list of code numbers and it just says DUP in the middle of it. So I don’t know, does your report, I mean, how much are they digested when they come to you, Natasha?
NATASHA LEIGHL: So you bring up such a great point, you know, that the classic sort of HGVS nomenclature is impossible for clinicians to understand. You know, even a KRAS-G12C mutation doesn’t look like KRAS-G12C. And so I think it’s so important to, with reporting, that people get together locally and really make sure that the lab that you use is also using some of the, you know, I don’t want to say colloquial nomenclature, but things that clinicians understand that–
ROSS CAMIDGE: Like a dumbed down nomenclature.
NATASHA LEIGHL: Right, so T790M, for example, you know, you call it T790M, exon 20 insertion mutation, and then also sensitizing, you know. So the other day I got an email from a colleague and she said, you know, she said, I don’t really understand what this mutation is or whether I should treat with it. And it was actually an exon 19 deletion. So it’s so important to have that last piece of translation, that annotation part that says, you know, this is sensitizing to a TKI, or this is resistant, or there’s this new class of drugs. And so in my clinic, you know, when the report doesn’t make sense, we go to OncoKB or get to ClinVar, you know, there are a lot of different websites you can go to. Or we just call the lab. But yeah, I agree that kind of translating it into clinical speak is so important.
ROSS CAMIDGE: You know, it’s interesting because there’s that move, and I can’t remember what, you know, kind of plain speaking for sort of communicating to patients, you know, and yet, you know, we don’t have this in these molecular records. I think there’s a gap in the market there.
NATASHA LEIGHL: Fully agree! I think we need to understand the test that we are using and also how the report is done, and fully read. We need to use a common language, a common nomenclature here. Because, as I said, many times we have some problems to understand the reports we are reading. So fully agree with your thoughts.
ALEXANDER SPIRA: The reports are terrible. I mean, I’ll be blunt ’cause they don’t really, you know, especially in the United States, we use a couple of the commercial NGSS, at least here. And sometimes they are vague. Sometimes they tell you things. Sometimes they, you know, are mistaken. I mean, I’ve seen many with just mistakes. They’ve gotten better over the last couple of years, you know, couple of years ago they would have EGFR mutation, exon 20, and talk about osimertinib, which we know doesn’t really work very well. But yet it’s on there. And they need to be simpler, right? I mean, those of us on this call are thoracic oncologists, and I hope we know more than a lot of the other oncologists, but appearing oncologist, seeing a few patients a year, it’s really hard to digest it. I mean, what do you do? Go to up-to-date? No, you really want it out there, two sentences, this is the drug that I want, and then learn it. I mean, I would love to tell you that it should be that easy, but oncology has become very complicated. That’s why we’re having this meeting today, but it would be helpful if it was just clearer and to the point, which drugs work, which lines of therapy are there, and just end the discussion. But it’s far more complicated on these reports than it needs to be.
ROSS CAMIDGE: Yeah, one of the things, you know, if we take the NCCN as one example, you know, it has a tendency to be this broad church which lists all possible options. And then they hit on the idea that they would list preferred, but then they list five things as preferred. And you go, you know, you’re a bunch of experts, give us an opinion! You know.
SECTION 2: 1L treatment approaches: TKIs, toxicities, chemo, and the role of IO?
ROSS CAMIDGE: But let’s talk about that! So we’re moving from, you’ve done the test, you get this result, you know, what are they gonna treat these people with? Maybe we can try and start to use, amongst these structures that we’ve got, you know, the structures of grouping these mutations, what you would start with. And let’s start Rosario. So how would you choose what you’re gonna treat these people with?
ROSARIO GARCIA CAMPELO: Okay so, we usually try to include all these patients in clinical trials. In case we cannot include those patients, our standard of care in a common and sensitizing mutation is osimertinib. I guess that’s basically the vast majority of the countries. And in those common mutations we try to figure out the sensitivity to afatinib or osimertinib. This is basically what we’re using these uncommon mutations. And then we have the group of exon 20 insertions. In first-line setting we try to do these patients in clinical trials since we have the opportunity to offer a targeted agent. And in case we can’t, platinum-based chemotherapy is our preferred first-line option. We can discuss, I guess, the role of chemo plus immuno in this setting, but to tell you the truth, this is something that we usually don’t do in our daily clinical practice. I know the rest of you.
ROSS CAMIDGE: Well, you know, let me get to that in just a second. So let me just push you one thing. So you said for the uncommon mutations, you said osimertinib or afatinib. Which?
ROSARIO GARCIA CAMPELO: Yeah.
ROSS CAMIDGE: Which do you do and why?
ROSARIO GARCIA CAMPELO: Well the vast majority of evidence we have is with afatinib, but the truth is that, talking about toxicity, you balance the evidence that is not so extense. And the toxicity, I usually prefer to use osimertinib to tell you the truth. Because in that balance, this is my preferred option.
ROSS CAMIDGE: Yeah, I mean, if I remember enough, I don’t know what it is by the EMA. I think afatinib is the only one that actually has a license that specifies the uncommon mutation. But yeah, I think in my practice, I would probably tend to use osimertinib as my first-line choice for tolerability.
ROSS CAMIDGE: You know. Sorry.
NATASHA LEIGHL: Places like Canada, sorry, you know, we are limited in what’s approved. So for us it’s afatinib, but I certainly agree, you know, both with Ross and Rosario that, you know, it would be great to have a less toxic TKI, and there’ve been some nice data. I know James Dan presented some nice data recently suggesting that OSI, you know, has very good activity as well. So I’d love to see a drug approval with that drug as well.
ROSS CAMIDGE: Yeah. Have you seen the data on neratinib and G791X? I mean, that’s also interesting.
ALEXANDER SPIRA: Yeah.
NATASHA LEIGHL: Yeah, I mean, it’s very, it looks very promising, you know, I think Leisha published some data, first-line actually, with great response rates some time ago. I think it was like 75% or three or four patients responded. And then in the pretreated setting, I think Jonathan Rees presented some nice data, sorry, Johnathan Goldsmith placed some nice data looking at pretreated patients. I think the response rate was about 40%. So, you know, it looks great. One of the challenges with some of these drugs, of course, with neratinib of course is the diarrhea, right? You need prophylactic antidiarrheals. And so, you know, there are some ongoing studies with that. Certainly very promising and, you know, potentially more promising than subsequent chemo, but toxicity remains a challenge, you know. It was just so a drug like osimertinib or something more specific remains very attractive.
ALEXANDER SPIRA: You know, it’s interesting you mentioned both the neratinib in your question, Ross, what to do with an exon 18. And it’s pretty impressive. I mean, most of us as oncologists, especially thoracic oncologist, can tell you what we would do for anybody with an exon 21 or 19. But if you ask 50 thoracic oncologists, what would you do for an exon 18? Half would give afatinib because it’s on the label for the atypical. I apologize, for the uncommon mutations, including that. But their other half that would give us osimertinib. And I mean, you’re at camp. I mean afatinib is a tough drug. I mean, it is something that is not that easy to give. And I’ve given neratinib as part of a clinical study, and that’s even harder. And it just points to the lack of data and lack of consistency as well for something that should be so simple, right? I mean, it should be like, you have an exon 18 or G79X, what do 100 medical oncologists give? And it’s not that easy an answer.
ROSS CAMIDGE: Sure, it’s funny ’cause you say neratinib is harder. I actually think diarrhea is easier to manage than the skin side effects. It’s like afatinib hits your skin, and neratinib gives you diarrhea. ‘Cause I mean, I guess it’s a personal choice, but you know, I think, you know, you look the same, and you take Imodium, and you know.
ALEXANDER SPIRA: Which grade three/four toxicity would you rather have?
ROSS CAMIDGE: I know we’ve plenty. Which would you rather have? I get that. So let’s go back to the Rosario’s thing. So there was this kind of retro move a few years ago about the value of adding in chemotherapy to your first-line EGFR TKI. And the studies were mostly done with, I think, gefitinib. There was a Japanese study and an Indian study. You know, it’s interesting. It seemed to produce slightly higher response rates, slightly longer progression-free survival, and surprisingly longer overall survival. I think it’s being explored in bigger studies in the west, but is anyone doing it outside of a study?
ROSARIO GARCIA CAMPELO: Not in my case. To tell you the truth. No. And again, I’m looking for the final results for these disparities, but the balance efficacy-toxicity, I think we need to take that into account when we have to do this decision. But not in my practice today.
ROSS CAMIDGE: Yeah, I mean, even if there was a PFS advantage, you’d still say, well, couldn’t I just give the chemotherapy later? I mean, if there’s an overall survival advantage, you always got to say, is this just, you know, access to it in some of the places where they’ve done the trial when they do? I think the study is FLAURA 2? Does that sound about right?
ROSARIO GARCIA CAMPELO: Yes, FLAURA 2.
ROSS CAMIDGE: Are you guys enrolling to that one?
ROSARIO GARCIA CAMPELO: Not.
ROSS CAMIDGE: Natasha is nodding.
NATASHA LEIGHL: Yeah, so we are, and it’s certainly not a strategy we use off-label or outside the trial, you know. I think accruals is almost done. You know, even more than that study, the study that I love is that one designed by Helena Yu where you get a month of osimertinib. They do a plasma ctDNA assay. If it’s fallen, you know, you stay on osi, come off the trial. But if it hasn’t fallen, you get randomized to ad chemo or continue. And so, you know, I love a study like that ’cause that really speaks to me as a clinician, right? If the osi is not working, those are the people you want to pull out for an intensified approach. And I apologize for the background emergency noise over here.
ROSS CAMIDGE: It’s the real world, you know.
NATASHA LEIGHL: Yes, absolutely!
ALEXANDER SPIRA: At least we know there’s a doctor on site!
ROSS CAMIDGE: It might be a fire truck, that’s the problem. So, let me ask one other, so we’ve kind of touched on it. So with the, you know, we talked about afatinib, we talked about neratinib, talked about osimertinib. For the EGFR exon 20 insertions, you know, we have these new drugs. Alex suggests that we have amivantamab, and then we have mobocertinib in the U.S. But the efficacy doesn’t blow it out of the water. The response rate is running, you know, high twenties, you know, high 30% response rate. Is that enough that, if you had access to those drugs, you would give that to someone first-line? Or is it, you know, so much more palatable than chemotherapy that you just try it and see? I mean.
ALEXANDER SPIRA: So I think, and we can all take turns, obviously, you know, I think number one is the labels in second-line which makes it an easy discussion. Certainly Natasha said, you know, in Canada they guide it by label, which means you probably can’t use it in second-line, which makes it an easy decision. I don’t know what it’s like for Rosario. Here I usually aim for something like that. I try and hold on the FDA guidelines, which means I do give people first, although we do, as I’m sure many of us to have a clinical study, you know. If you’ve given the drugs and, you know, their relatively rare indications, they’re not, you know, the toxicity is probably not substantially better than chemo if you really look at it. You do have the rash. You do have the diarrhea. I don’t know which one you’d rather have, Ross. But they both have toxicity. They both have toxicity. That is real. And so, in my mind, I’m currently following and just giving people chemotherapy first if they’re not going to enroll on a clinical study. The response rates are less. I mean, depending on how you look between 28 and 40% on the two studies. Depending on which cohort, and you’re looking at central or investigative review, which is less than carbo-pem plus or minus pembro in the frontline setting. So, you know, granted that second and third line and beyond, so you’d expect that. I will say, my only comment is everybody was a little disappointed because we’re so used to RET, and MET, and EGFR response rates are like 80%. People go, well this is not that good. I mean, considering you had nothing in the second-line setting, I think it’s great. We need to take a little step back, but I think there is room for improvement there, and I give people chemo.
ROSS CAMIDGE: So let me ask you that. So you kind of dodged the issue a little bit. So do you give them chemo, or chemo-IO knowing that they have an exon 25?
ALEXANDER SPIRA: Oh, interesting question! So I’ll get out there first. You can differentiate me. I just give people chemo. I am a firm believer in that, you know, with a targetable mutation, there is little data that a drug-like immunotherapy improves outcomes based upon a mechanism of action. So I just get people carboplatin, pemetrexed, and without it. I’m also a little concerned about pneumonitis afterwards, although that didn’t really bear out in some of the mobocertinib data. Maybe I’m wrong. And I know, in fact, I had a second opinion on a patient the other day, and they very rightfully said they were gonna give carbo-pem pembro in this line setting. And I couldn’t disagree with them. But I’m sure we’re all a little bit different on that.
ROSS CAMIDGE: So Natasha, if you have to go by the letter of the law in Canada, do you have to give carbo-pem pembro?
NATASHA LEIGHL: No. So the good thing is, you don’t have to give anything expensive that you don’t want to in Canada.
ROSARIO GARCIA CAMPELO: Same here!
NATASHA LEIGHL: Quickly with chemo-IO, I agree completely with Alex, you know, I think it’s so important that, you know, you focus on chemotherapy. I think checkpoint inhibitors really don’t work as well in this population. You know, I have to laugh because we actually published a series where we had six patients with exon 20 insertions, and three of them responded to single-agent checkpoint inhibitors. But I think, you know, when you put that in the mix of all the other studies out there, response rate’s much lower. I agree with chemo first in Europe and, you know, Charo, you can tell us what you do in Spain, but you know, I know some people use chemotherapy plus bevacizumab, but you know, certainly in Canada it would be chemotherapy first and then these new treatments. And when you look at the trials moving to first-line, you know, the amivantamab strategy is to add to chemo, and the mobocertinib strategy is either or. And, you know, when you sort of think about it, like, if you’re just as good, you would probably use mobo first-line if that study were sort of similar or equivalent. And similarly, if the MM batch MAP plus chemo study showed that one is clearly better, you know, you would use that. But I love the idea of a targeted first paradigm. I just don’t know if we’re going to get there in the exon 20 insertions.
ROSS CAMIDGE: All right, so Rosario, let me, you can address both what you would do in Europe in terms of chemo.
ROSARIO GARCIA CAMPELO: Yes, we have the–
ROSS CAMIDGE: But I also want you to address, you know, predicting in the future, that mobi versus chemo, or chemo plus or minus ami. Which one are you gonna put your money on?
ROSARIO GARCIA CAMPELO: Okay, let me just look in the future! You want me to look just for–
ROSS CAMIDGE: Yeah, yeah, that’s what I want, yeah!
ROSARIO GARCIA CAMPELO: That’s nice. It’s always easy to talk about the future. Today, looking at the data we have in pre distributed population, I guess that the combination approach is going to be more effective. I am taking part in both trials and, that’s a guess, that the combination approach has more sense. So this is my lecture to the future!
ROSS CAMIDGE: Oh I totally agree! I mean, let’s be honest here, you know, don’t you think that a drug with a 28% response rate going head-to-head against first-line chemo doesn’t sound like a really smart idea?
ROSARIO GARCIA CAMPELO: Yeah, I think we need to raise the bar. Okay? We are talking about personalized approach, and we are talking about first-line setting. So let’s not be happy with this 30% response rate. And we are missing also some details regarding brain efficacy. We know that these patients have brain mets, have the risk of developing brain mets. So I think today with the information I have, I prefer the combination strategy approach. Yeah.
ROSS CAMIDGE: And then, just to tie out the other question. So if you’re starting with chemo in the real world here, do you give chemo or chemo-IO?
ROSARIO GARCIA CAMPELO: Okay, in our country, basically the vast majority of us, we are doing conventional platinum-based chemotherapy, usually pemetrexed-based chemotherapy. And we have these discussions sometimes regarding if clinical factors, like smoking habits, can influence the decision of having immuno or not. In my practice I usually skip the immuno. I just do conventional chemotherapy. But we have this discussion to tell you the truth. The colleagues in the country, sometimes people think that chemo immune can be an option for this patient. I don’t truly believe that we have enough data to support this decision.
SECTION 3: Brain efficacy of TKIs and treating bone metastases
ROSS CAMIDGE: So I’m gonna pick up on one of the other things you said. So you mentioned brain efficacy. So either if we have these clinical trials where these are going, moving into the first-line, or the patient has developed new brain metastases when you’re coming to them in the second-line. My understanding is neither of the two licensed drugs, ami or mobi, really has that much activity in the brain. So how comfortable are you about either trying it? And then at the same question, are you comfortable trying it when we’re talking about some of the more common mutations and we’re using osimertinib or something? So Alex, do you want to comment on that? Oh, let me do Alex and I’ll work my way back.
ROSARIO GARCIA CAMPELO: No, no, no, no! Please please, Alex, go! Go Alex!
ALEXANDER SPIRA: I can’t interrupt ahead of time!
ROSARIO GARCIA CAMPELO: No, no, go ahead!
ALEXANDER SPIRA: So how comfortable I am. So that is my biggest concern, so the brain is that my biggest concern. And having participated on the studies, I will tell you that that’s where all my patients had trouble ultimately. So it’s a problem. And we’ve also gotten very used to the fact that targeted therapies, by and large, do get into the brain very well. So I think this was a little bit of a kick in the you know what, because we were all kind of hoping and expecting the small molecules, but again, hearkens back to the day of erlotinib, which didn’t really have much CNS penetration as well. So I still use the drugs. I try and come up with alternative approaches, like SRS, crossing my fingers and digging my head in the sand, and hoping the brain mets don’t grow very much, or other things during that time. But it’s a tough situation, especially in the second-line scenario as well with no easy answer.
ROSS CAMIDGE: So if I had new brain metastases, with an EGFR exon 20 insertion, and I was, you know, eligible for one of these drugs because of line of therapy or trial, would you require me to have the brain metastases treated before you went on? Or would you just watch them closely?
ALEXANDER SPIRA: I just watch them closely because, I mean, if you’re really looking for the outside of a clinical trial setting, if you’re really looking at the second-line scenario, I don’t think we have much of a better option. Right? I mean, typically we can do the docetaxel, assuming they got the usual drugs first without a lot of drugs with CNS penetration. So I would do a little bit of watchful waiting and crossing my fingers, and just close-monitoring for those patients. I admit there’s not an easy solution to that.
ROSS CAMIDGE: Would anyone do anything different?
NATASHA LEIGHL: I mean, I guess the only thing I’d add, I mean, I agree with Alex and, like, I think, you know, that’s not a decision as medical oncologists that we make by ourselves, right? Like, you want to get input from the multidisciplinary team, you want to know how big it is or how many, you know. Whether it’s in an eloquent area, and so. But what I, you know, once you get that sign off, I agree, you know. I’m really interested in the data from the newer compounds, the Collin compound, the TZT, you know, these have some CNS activity, and I think, you know, what I want to see even more is sort of activity in sequencing, right? So we know that mobocertinib could be quite active in TKI pretreated patients. Alex, you actually had a really nice presentation that brought light on that. But you know, what about activity after amivantamab or vice versa? How are we gonna sequence these? And then I think it’s gonna be, how do we pick the best TKI as part of that treatment journey? And then we kind of have to figure out sequence.
ALEXANDER SPIRA: Yeah, and again, Ross, I will tell you, if a patient had one or two brain mets, I probably would do SRS, but I think I was operating on the assumption that it was, you know, multiple brain mets, not really a candidate and thinking about whole brain or something like that. But I actually, I mean, I was a little enticed by some of the newer data for the DCD drug, which says it may have a little bit of CNS penetration, although it’s super early on, but again, a little bit unclear. I think even poziotinib maybe did have a little bit of brain data, which is a little enticing as well, getting back to a little bit more toxic TKIs as well. But again, you know, so many of these patients are outside of clinical study, and many clinical studies are a little bit reluctant to put these patients on right now because you want to show there’s stomach activity first.
ROSS CAMIDGE: Well, I would take exception to the fact that we’ve got that much CNS data, even on these new drugs. So what they’ve tended to show is preclinical data, and you go, that’s great! You know, so far so good. But almost all of the studies have said you either have to have absent or treated brain metastases to get in, and showing, you know, RPFS is the same if you do or don’t have baseline brain metastases. It tells you absolutely nothing until you have untreated measurable brain metastases in these studies. And none of them have presented that data as yet that I’m aware of.
NATASHA LEIGHL: Yeah, I think there are a couple of sort of anecdotes, but I agree with you Ross, like, that’s the key thing, right? None of this PFS with or without. You have to show the actual intercranial activity and that kind of speaks to all the great work you’ve done looking at RANO and different criteria. I think there are a few reports now. What strikes me so interesting is you would expect that high-dose osimertinib, 160 milligrams, we’d already have reports of CNS activity, and yet both of the studies that have been reported don’t make any mention of that. So I don’t know if it’s that, you know, we didn’t have the right patients or they haven’t looked at that yet, but I was actually kind of disappointed. I really had high hopes for high-dose osimertinib and exon 20 insertions, but between sort of the U.S. study, and the recent Dutch study, you know, that PFS, I think for that duration of response is quite short. And I think it’s different from the currently approved agents.
ROSS CAMIDGE: Yeah, I mean, the high-dose osimertinib, again, sometimes, you know, in the real world we do things because we only have certain tools in the toolbox. You know, if you think about osimertinib as a primarily EGFR wild-type sparing agent, it’s the one that’s least likely to work on exon 20, ’cause the structure of the kinase is so similar. So I think, you know, if you’re trapped on a desert island and you only have osimertinib, you try it. I don’t know I’d put a lot of faith in it, but yeah.
ROSS CAMIDGE: You know, I think what we’ve touched on is that the brain is gonna be this incredibly important battleground for these new drugs to really, you know, differentiate themselves. Rosario, did you have something to add on this? The other one I wanted to say, because I wanted to complete this is, for if you had an EGFR common mutation, or an uncommon mutation, would you trust the osimertinib work in the brain?
ROSARIO GARCIA CAMPELO: Okay, I think I fully agree, I think that the brain here is a key element for decisions in the near future. I’m going to differentiate those new ideas that we have from the ground. And regarding the role of common mutations, I have many laps with these exon 20 insertions on the role of local therapies with osimertinib. I really trust the efficacy of the drug at the brain level, and usually it’s my first option. If I cannot do SRS, I try to avoid the whole radiotherapy and use osi first. I think you can trust the potency of the agent at the brain level. I have less experience with uncommon mutation on the brain, but given the fact the data is not so abundant, I will say that I would do the same.
ROSS CAMIDGE: If you had just one lesion in the brain, and it was a common mutation, would you give SRS, or you would just try the drug?
ROSARIO GARCIA CAMPELO: That’s a great question, Ross.
ROSS CAMIDGE: Give a great answer!
ROSARIO GARCIA CAMPELO: Okay! What I do is I do SRS and then osimertinib, yes.
ROSS CAMIDGE: So, isn’t that–
NATASHA LEIGHL: So we have a trial! Oh, sorry, Ross. We have a trial. Actually, Ross, you know Cheryl Ho quite well, I think.
ROSS CAMIDGE: I think I do, yeah, yeah.
NATASHA LEIGHL: Yeah, Cheryl’s got this trial where if we have patients with brain mets and common sensitizing mutations, we randomize that to get the SRS upfront and go in osi or they just start with osi. So, you know, we’re hoping, I mean, obviously it’s just a small trial, but we’re hoping to get a signal. But I agree with Charo, you know, that the retrospective data looks so good you kind of wonder, but the clinician in me, the medical oncologist in me always tries drug first to whenever I can get away with it. I believe it even if uncommon.
ROSS CAMIDGE: In Cheryl’s study, when do they rescan for the people who are just trying to drug?
NATASHA LEIGHL: I believe, well, I’ll have to double check, but I believe the MRs are between six and eight.
ROSS CAMIDGE: So you don’t do an… Well, we may have just lost Natasha. But one of the big debates is if you’re trying a drug to work in the brain, should you do an earlier brain scan than you would normally do just in case? Like at three weeks or sometime.
ALEXANDER SPIRA: You know what? It was just one comment that I think this is kudos to you is that, you know, so many of these studies don’t allow these two or five, or even one centimeter brain mets from enrolling on study. Weeks. And then what ends up happening is you do a study, you show that it works, and then you wonder about the next gen. Do you have CNS activity? I mean, you’re published in the ALK world, all the CNS activity which was done early on. And I think now there should be an expectation of any clinical study. You know, we should be looking at this earlier on, so we’re not asking the question three years, or four years later. What is the real activity? And you’re going by the anecdotal report from Colorado, from Memorial, from Princess Margaret, saying I had these patients. We need to be getting these questions and data much earlier on in the studies. And kudos, you know, mobocertinib, the clinical study it had, you can see in the slides, has like 10 different cohorts. And many of them asked that question very early on. It was a negative study, or negative data, but it’s super helpful because it helps you figure out how to help manage these patients rather than us just all kind of asking each other, hey, do you have any brain mets that work?
ROSS CAMIDGE: Yeah! And it also helps. I mean, adding that CNS cohort into the mobocertinib study was also designed to say, the company can then figure out the safest way to develop their drug early on. But because CNS was obviously an overt liability, you know, they could then address that in future studies. I’ve got one other thing, since we were talking about brain, I’m gonna do a side move here. What about bone metastases? So a lot of EGFR mutants across these things have bone metastases. Do you give bone-strengthening agents? Or do you rely on the TKI? Or does it depend on the EGFR mutation you’re talking about? Rosario, I’m gonna throw this one to you.
ROSARIO GARCIA CAMPELO: Yeah, I usually rely on the EGFR TKI I’m using. Overall, when we talk about EFR common mutation this is my practice.
ROSS CAMIDGE: What would you do with an exon 20, though?
ROSARIO GARCIA CAMPELO: Oh, again that question. Since it’s not, the agents we have so far are not so active, I think I try to combine both.
ROSS CAMIDGE: Yeah. I’d probably be the same. Alex, what do you do?
ALEXANDER SPIRA: I, for the bone mets, I kind of look at the burden of disease, and kind of see how much they’re going on. I mean, I’ve also, you know, it only takes one case of osteonecrosis of the jaw with bisphosphonates, and you’d go, oh shoot, did the patient really need that lesion? So I go more by the burden of disease and risk per fracture ’cause these patients do respond very well.
ROSS CAMIDGE: Yeah, I would say for the common mutations, and even maybe just for the uncommon ones, I’d probably only use the bisphosphonates with the XGEVAs of this world if they’re progressing in the bone on the TKI and I can’t control it in other ways, you know. Because I’ve seen one case of osteonecrosis of the jaw and. that was one too many.
ALEXANDER SPIRA: Yeah, and you know, as I said, you know, for most of the responses while the bone heals up, you’re kinda like, did I really need to do it for that one particular lesion? And you’re right. That one ONJ is just tough.
SECTION 4: Re-biopy on progression and future directions
ROSS CAMIDGE: We are doing great, by the way. One question I want to ask is, you put people on these targeted therapies, and again, we go to our three categories, common, uncommon and exon 20, and then they initially responded and then they progress, let’s say within the body. Do you rebiopsy? And if you do, what do you test it for?
ROSARIO GARCIA CAMPELO: Should I start?
ROSS CAMIDGE: Yeah, go for it.
ROSARIO GARCIA CAMPELO: Okay. Usually, we try to rebiopsy. To that rebiopsy. It’s not always easy. Different reasons as you already know. But this is what we try to do. And we try to look for different resistance mechanisms. We have different trials, we try to put these patients on the trials according to resistance mechanisms. And in case we don’t have any trial, or the patient doesn’t want any trial, we offer those patients conventional chemo. But we try to do rebiopsy. First because most of the trials require this rebiopsy. In case we cannot get the tumor tissue, we usually do a liquid biopsy. Yeah.
ROSS CAMIDGE: If you get a tissue biopsy, what do you test it for? Do you just do next generation sequencing? Do you do–
ROSARIO GARCIA CAMPELO: We do, we do next generation, and hoping to find any resistance mechanisms we can target. Yeah.
ROSS CAMIDGE: I mean, my understanding is, you know, for example, like progression on osimertinib with the common ones. We in Colorado used to talk about doing a kind of resistance panel, and then we rejected that, because essentially you have to look for everything because you can get an L, or a–
ROSARIO GARCIA CAMPELO: Yeah, an alpha, RET, or whatever. Yeah, whatever!
ROSS CAMIDGE: Alex, what do you do? I mean, you’re in the community.
ALEXANDER SPIRA: So I always laugh. So I do a lot more biopsies at tumor boards than I do in real life. Number one, right? You know, and actually I think, we just lost Natasha, but I used that exact same line. We just did another one of these recently. So I, you know, I try and find clinical trials for these patients. And most of the clinical trials are agnostic. You know, we have some, I’ll give you, you know, with amivantamab, in combination with osimertinib. Now look at all types. We get that as part of the clinical study as well. I actually ended up doing a standard of care more liquid biopsies, because as you think about the real time here, you know, somebody comes in with progression, I try and propose them another option or clinical study, and by the time you get some of that, you know, by the time you get a biopsy, you get the NGS panel back it’s a month, right? I mean, getting a biopsy, at least here is another week or two to get scheduled and then they get them an NGS assay. So the liquid biopsy comes back pretty soon. And I admit it’s not perfect, but it often provides you almost as much information right now. So in general, I’m doing that, but they’re getting their tumor biopsy, hopefully as part of a clinical study, and we’re using the boat together. That was a lawyer answer where I dodged the question a little bit.
ROSS CAMIDGE: Yeah, there was absolutely no details in there whatsoever. So one of the things I was astonished by was that the NCCN guidelines have no mention about rebiopsy or progression. The only mention about rebiopsy across any of the molecular drivers is if you started, if you had a common mutation, you started on erlotinib, and then you have to see if you’ve got T790M. And it’s like, dude, we are in, you know, in 2021, why is it not in there?
ALEXANDER SPIRA: But I think last, I mean, the reality is that if you look at what’s the standard of care, the standard of care is chemo at that point. I mean, clinical trials is a standard of care, but I don’t think there’s anything on NCCN guidelines right now. Correct me if I’m wrong. That, you know, you should give, if you have a specific mutation right now, and we all agree, we should find something, and find a clinical study, or do something that’s out of the box. Right? I mean, we, as the rest of oncologists agree with that, but the reason it’s not on there, I don’t think there’s anything truly actionable with an approved drug. Right?
ROSS CAMIDGE: That’s the thing.
ROSARIO GARCIA CAMPELO: Fully agree, but I think that the message we have to send to the community, to the young people who start the ER, is that we still try to get this molecular information, and try to get a clinical trial. I know that it’s not a standard of care. I understand that pretty well. But I think that the message here is go for that rebiopsy. I fully agree with Alex. Time. Sometimes we cannot wait for this rebiopsy for the results, but if you can do it, I think that the message should be do it.
ROSS CAMIDGE: Yeah, I mean, the strategy I have is, you know, there’s no drug rep out there telling you that you have to find met amplification and add in a met inhibitor. That’s not a licensed indication. But again, if it was your mom or your dad, then you would want to know this. Even so you could go find the right trial!
ROSARIO GARCIA CAMPELO: Absolutely. Fully agree.
NATASHA LEIGHL: I agree too, and I think in Canada, how we get away with at least the rebiopsy part. Sorry, I’m back from that. The no communication zone. Is to rule out small cell transformation, right? And then if we have the ability to do NGS, we go from there. But I completely agree with you, Ross. That, you know, streaming patients towards. ‘Cause now there are all these different options, right? There’s C797S-directed trials, met-directed trials, sort of emergent fusion-directed trials. And then of course, everybody else with these great antibody drug conjugates. So I agree. I think it’s such an important thing to offer patients. And, you know, clinically we get away by saying, oh yeah, we have to rule out small cell transformation, or squamous! Squamous transformation.
ROSS CAMIDGE: So in the last minute or so that we’ve got, since you mentioned trials, I’m gonna give you enough rope to hang yourself with. So out of all of the trials going on in the EGFR’s mutant space, tell me one that you think you’re really excited about, and one that you think you wouldn’t put a patient on ’cause it’s a stupid idea. Recognize–
ALEXANDER SPIRA: I’ll go first! I’ll go ask you for a turn!
ROSS CAMIDGE: Okay, yeah.
ALEXANDER SPIRA: So I like that patritumab, the HER3 study only because it’s demonstrated some promising data, right? I mean, it’s already got some impressive response rates that’s been published. So I like that.
ROSS CAMIDGE: So that’s the ADC, just to expand on that.
ALEXANDER SPIRA: Thank you. That’s the ADC against HER3. So it’s a little bit of change in concept, right? It has to do with the dimerization of EGFR with the different compounds. So you got to think about it conceptually differently than what we’re used to. Right? You think about EGFR, you just think about EGFR. But what I like about it is that they’ve already shown some very promising data and that study will hopefully be accrued in the next few months. So to me, that’s the most exciting one that’s out there. I’m glad I got to go first because that was the–
ROSS CAMIDGE: You’re not off the hook yet, Alex. Tell me one trial that if I offered it to your center, you would turn it down.
ALEXANDER SPIRA: I pass for now.
ROSS CAMIDGE: Oh, come on! Like, you don’t want to burn any bridges? In the immunotherapy study in EGFR mutant lung cancer. Excited about that?
ALEXANDER SPIRA: So I am, so that’s a great, thank you Ross. So I am very much anti-immunotherapy. I firmly believe that. Just because, you know, the scientific doesn’t make a bout of sense of it, but I’m always brought back to the IMpower150 data, which we’re not gonna talk about today, which shows that when you combine bevacizumab and immunotherapy, it probably does work a little bit with a taxane-based therapy. And I struggled with that mentally all the time. And I actually don’t use it because I still struggle with that scientifically. As to why, I also struggle with the rationale of VEGF inhibitors, because conceptually, I just don’t get it. So I would turn a immunotherapy study down.
ROSS CAMIDGE: Okay, Rosario.
ALEXANDER SPIRA: Thanks for the help.
ROSS CAMIDGE: Yeah, you’re welcome.
ROSARIO GARCIA CAMPELO: Okay.
ROSS CAMIDGE: Rosario.
ROSARIO GARCIA CAMPELO: Yeah. So talking about the common mutations, I think the MARIPOSA trial can give us important information in the role of lung–
ROSS CAMIDGE: Explain what that one is.
ROSARIO GARCIA CAMPELO: Okay, that one is testing the role of osimertinib first-line setting. We already know the role. And the combination approach, with a tyrosine kinase inhibitor, third generation, will start the new process and leave that out. I think that is a strategy that can have some specific role. And we have to see those patients with concomitant alterations. That is something we didn’t reach today, but it’s important. We know that disagreed heterogeneity. What we talk about the EGFR mutant population and the new NGS technology has allowed us to see that this is not so simple as we thought at the very beginning. So I think that the combination of strategies may have a role, not for every single patient, but at least we have some clue. And the trial, I couldn’t put any patients. You want me to say that?
ROSS CAMIDGE: I do.
ROSARIO GARCIA CAMPELO: Okay. I am not very excited for those trials who are combining, or introducing immuno in this scenario to tell you the truth.
ROSS CAMIDGE: Okay. All right. Natasha, ever the diplomat.
NATASHA LEIGHL: So, I agree with Rosario. I’m very excited about these, you know, combination, either the bipecifics like amivantamab and osimertinib. Also telisotuzumab right? Which is an ADC, but again, that sort of combined EGFR-MAP targeting. So I’m really excited about those, especially that subgroup of patients, you know, there was that nice subgroup analysis that was presented at ASCO, looking at MET IHC, positive tumors, and our patients like nine out of 10 of them had a response. And so, you know, can we look at those data with some of these other compounds and really sort of have a much more focused strategy of who gets what? The study that I guess I was most disappointed in, but maybe it’s not the fault of the drug, I think there was a study called HERTHENA which was looking in patients with HER2 IHC positive tumors after osimertinib met failure. And then I think they added a T-DM1. And so I was a bit disappointed in that. Now, you know, I think we could say we’re all disappointed in T-DM1 compared to, for example, trastuzumab deruxtecan. But in this EGFR space, you know, I was really disappointed that it really didn’t seem to have additional effect. And so was it that we didn’t choose the right biomarker, right? We used IHC and not amplification. Maybe that was it, but that’s the group where I’m sort of thinking, well, maybe I should put them on another study. I’m not as unenthusiastic about chemo-IO as my two friends here, but I won’t be surprised if those studies aren’t strikingly positive either.
ROSS CAMIDGE: Right, and I guess I’ll have to throw something in there too. So I think antibody drug conjugates are really interesting. I guess what I would be most excited about is them combining them together with a TKI, with some concern about pneumonitis risk. But you know, the whole idea about doing studies in oncogene-addicted, where you’re taking away the TKI and jumping onto something else would fall into the category of studies that I’m actually not interested in. You know, ones that are not really addressing the underlying biology of the disease. And when they are doing that, especially if there’s some kind of predictive biomarker, those are the ones I’m most excited about. Guys, I am gonna wrap this up. This is possibly the most fun teleconference I’ve had for a long time. I’m hope we get to do it again. Thank you!
ROSARIO GARCIA CAMPELO: Thank you so much, have a great day!