Introduction: Journal Club with Lecia V Sequist, MD, MPH

DR LOVE: Good afternoon, everyone. I’m Neil Love from Research To Practice and welcome to Meet The Professor, as today we talk about the management of non-small cell lung cancer in patients with EGFR tumor mutations with Dr Lecia Sequist from the Massachusetts General Hospital Cancer Center in Boston.

We have a great faculty for this series. And later on, we’ll show you the results of a survey we did of the faculty of their usual treatment practices. As always, if you have any questions or cases you’d like to run by Dr Sequist, just type them into the chat room and we’ll talk about as many of these as we have time.

If you could please complete the pre and post-meeting survey that we pop up to you, we would really appreciate it. It really helps us to get data. It even helps us get funding for projects like this.

If you’re into audio programs, we know a lot of people end up listening to our webinars, check out our Oncology Today podcast series, including a recent program with Drs Bradley and Spigel on unresectable Stage III non-small cell.

We do webinars all the time. Tomorrow, we’ll be working with Dr Pegram on our HER2-positive breast cancer series which we’re about to launch. And then the next week, we’ll be working with a great faculty as a spin-off of the SOHO meeting focusing on patients with myelodysplastic syndrome. Some new agents coming out there. And also, ones we’re using in other places, particularly venetoclax/HMA. We’re doing another SOHO-related symposium on the 13^th. And this is going to focus on diffuse large B-cell, everything from upfront treatment, the POLARIX study, to the use of CAR T in relapsed disease.

But today, we’re here to talk about non-small cell lung cancer targeted therapy. We have a whole other series on targeted therapy outside of EGFR, but we decided to do an entire series just on EGFR. As always, we have a bunch of docs who are going to be presenting cases today.  

And here’s where we’re heading. We’re going to start out talking about some of the papers Dr Sequist has done. Then, we’ll jump into the case presentations. Then, we’ll go through the faculty survey. Then, we’ll come back and do some other journal club papers with Dr Sequist. And then, the fourth module really is for reference purposes. We love to suggest papers for you to look into.

And first, I kind of want to start out with something spontaneous here, Lecia. So I want to ask a question to the audience. I didn’t know exactly how to frame this question. But my question to you is whether you agree or disagree with this statement or maybe you’re not sure. There are patients — here’s what I’m going to say. Here’s the statement. There are patients with metastatic non-small cell lung cancer who had EGFR tumor mutations, activating mutations, who have high PD-1 levels who have, may have, and there are patients like this, that’s what I’m saying, you tell me whether you agree or not, a robust response to single agent PD-1. Do you agree with that statement? Do you think there are people out there who respond to PD-1 alone who also have EGFR tumor mutations? And I can see there’s a consensus in the audience. Actually, they’re completely split. But this is really, it came out of a conversation I actually had this morning. I recorded a great session with your colleague from the West Coast, Dr Wakelee. We were talking about, actually, early-stage disease, as you can imagine. And we were talking about the fact that these adjuvant trials, you see some benefit from IO in EGFR patients. And then she made that statement “I’ve seen patients with high PD-1 where I give them pembrolizumab or whatever, you know, IO and they have great responses”. And I’m like I’m not sure I’ve heard that, but I’m working with Lecia later and she’s the one who kind of started all this, I think, like 5 or 6 years ago about IOs and targeted therapy. So any thoughts? Is EGFR really completely resistant to IO? Do you not use it, Lecia?

DR SEQUIST: In oncology, you never say never. So I don’t doubt that there are some patients out there, a handful, that have had some amazing responses. I haven’t had the privilege of seeing them or meeting them myself. I really haven’t seen what I would consider to be convincing benefit in EGFR patients to single agent PD-1 inhibition. But I don’t doubt that it’s possible. It’s just not likely, in my experience.

DR LOVE: Yeah. What a challenging situation. Of course, IOs can have toxicity, for sure. Actually, she presented a case who had dermatomyositis from an IO which I had never even heard of before. In any event, let’s just go into some of the papers that you wrote. And, again, a lot of times, we put great papers in that the faculty does really, to get you to read it. We’re not going to review all of it. And this is one of the best review articles I’ve ever read, Lecia. What a great paper in Lancet on lung cancer. And I know this was sort of a group effort. Justin Gainor from your place was involved. He was on this series before. But I’m curious if you have any reflections on this paper, and on kind of the positioning of lung cancer, this is the Lancet, not Lancet Oncology, positioning of lung cancer to the primary care people, and particularly the issue of screening which you, I know, addressed in this paper. And also, you were commenting on the issue of screening in patients who are nonsmokers which I never even thought about. Any comments?

DR SEQUIST: Well I think it’s really important to educate the public, both primary care physicians, but even just the general public, about lung cancer because as we all know as oncologists, it’s changed so much, at lightning speed. And there are still a lot of people out there who just view it as an immediate death sentence and can only happen to heavy smokers. And there’s just a lot of education that needs to be communicated about lung cancer that can help decrease the stigma around lung cancer that has historically clouded our field. I think lung cancer screening is also a really important topic, especially for primary care doctors because they’re usually at the forefront of referring people for screening. And lung cancer screening is, really, I would say it’s the most effective screening test we have when you look at the number needed to screen in order to save one life. It’s way more efficient at saving lives than mammography or colonoscopy. So it’s our #1 screening test, but yet people aren’t getting it. And it’s a big problem that education can be one part of fixing, but we need more than that. Policy, implications. But even if we were screening 100% of people who were eligible for screening by their smoking history, we would still miss lung cancers because we know that people get lung cancer with a low, a remote, or a never smoking past. So one of the things that my research is focusing on these days is trying to figure out how can we come up with tools to screen people for lung cancer that don’t meet the current screening criteria. Should we be using CAT scans? Are there different tools? Blood biomarkers? Other kinds of artificial intelligence? New technologies.

DR LOVE: So another topic or paper you wrote or were on that I want to just bring up in terms of the issue here which is long-term survival in non-small cell. And not just about this paper, but more the overall global situation right now. Because we’re starting to hear about 5-year survivals of patients with metastatic lung cancer. I think we started hearing it with targeted therapy. And now, we’re hearing it with IOs, particularly high PD-1. I hear numbers floating around like 20 to 30% of people alive with high PD-1 in 5 years. Any sort of global perspective, in general, about survival in non-small cell lung cancer, both as a result of targeted therapy as well as IOs?

DR SEQUIST: Yeah. It’s been — I think targeted therapy made a huge impact, but on a small portion of the overall patients. And immune therapy has made such a bigger impact on long-term survival simply because it applies to more patients. And lung cancer is so common. And even if only, you know, 10% of people that you treat with immune therapy will have that long-term benefit, that tail of the curve when you’re giving, is tens of thousands of people, your clinic is suddenly full of survivors which is amazing. I think we have to do a better job now. It’s on us that we have helped people live longer, we have to learn more about survival issues. A lot of times, survival issues and survivorship clinics are really focused on breast cancer and these other tumors that have had a lot more success in the past with keeping people alive. But now, with lung cancer, I think we have to think more about what our patients need. And also, be open to thinking about the kinds of toxicities that immune therapy might cause 5 years later. We’re just starting to see these things emerge. And it’s not always on people’s mind that it’s related to the immune therapy, especially if they haven’t had immune therapy in 3 or 4 years and they’ve just been on surveillance. I think we’ll find a lot of disease is actually related to the immune treatment.

DR LOVE: When you see a patient who presents first line for metastatic EGFR activating mutations that’s going to go on osimertinib, or for that matter, let’s say, for ALK, for example, same thing. In your mind, or if a patient asks you, what’s the likelihood that they’re going to be alive in 5 years?

DR SEQUIST: If they have ALK, I’d say it’s very high. It’s very high that more than likely, they’ll be alive in 5 years. EGFR, the median is still less than that. But there’s a, you know, there’s a 30% chance maybe that they’ll be alive in 5 years.

DR LOVE: Wow.

DR SEQUIST: What I do try to emphasize is that things are always changing. Five years ago, I don’t think osimertinib was approved yet 5 years ago or it was just around that time. And look how much has changed with the introduction of that drug for EGFR patients. So things change.

DR LOVE: Interesting. So one of the cases that we’re going to present to you today is a patient with an exon 20 insertion. And we’ll talk about that a little bit more. But I wanted you to comment on this paper that you did on that topic. I really love the graphics. I’m always looking for fancy looking graphics. Everybody ends up listening to our stuff. They never look at the slides. But some of these in this paper, I think, are really cool. And I love this sort of overview you put in there of the types of mutations that are seen and sort of where the EGFR fits in. And particularly, the issue of exon 20. Any comments?

DR SEQUIST: Yeah. Well the majority of the work on this review in Cancer Discovery was by Catherine Meador who is a new attending at MGH and someone to keep your eye on. She’s just an amazing super star. But yeah, exon 20 insertions in EGFR are increasingly important for oncologists to recognize because now, we have 2 approved drugs which we’re going to talk about, I’m sure. But I think these — depending on what kind of genetic report you get from your NGS, it can be tricky to figure out what is the EGFR mutation? It usually says in big letters that there’s an EGFR mutation, but then depending on the vendor, it may be kind of tricky to figure out what is the mutation. And we’re learning more and more now about nuances and the responses to different treatments. John Heymach had a great paper about a year ago now that really looked at the structure of, the shape of the different EGFR mutations and tried to break them into categories. And here are the category that responds to second gen drugs. And here’s the category that responds to third gen drugs. And it is getting very complicated within EGFR. And so having a reference handy that you can look to, to decipher your genetic report for your patient is increasingly important.

DR LOVE: Could you review, you know, like you’re walking down the hall with rounds and there’s no slides, like how you explain to your fellows sort of what an exon 20 insertion actually is, like what happens there?

DR SEQUIST: Well it’s very similar biologically to one of the more standard mutations in the sense that the signaling in the cell is very heavy on the EGFR. The cell gets addicted to the EGFR signal and very dependent on it. So in theory, the cell should be able to die, it’s like an Achilles heel, if you cut off the EGFR signal. The trouble has been that the shape of the exon 20 mutation doesn’t fit as nicely like a hand in a glove in the drugs. So the first drugs that came out with erlotinib and gefitinib and even osimertinib, doesn’t really fit on the exon 20 as well as it fits on, say, exon 19 deletion. So I think people have the clinical — the correct clinical impression that the drugs didn’t work, but it was more about the shape of the drug and the shape of the EGFR and not the biology which is very, very similar, the downstream biology is similar to all the other EGFR mutations. But now, we’re getting some more nuanced designer drugs that fit that pocket a little bit better.

DR LOVE: Really interesting. Yeah, because the word insertion kind of sounds like a different pathology. But as you’re describing it, it sounds a lot more similar to what we’ve been seeing. This is another paper I wanted to steer people to. This is really an awesome review paper. And really cool graphics. I’m not going to ask you to go through them. But just if you have any comments on the issue of liquid biopsy. Myths, misperceptions, the future of liquid biopsy, when people use it appropriately, inappropriately. Any general comments? I’ll kind of flip through these graphics just to get people interested in reading the paper.

DR SEQUIST: I think liquid biopsies have changed the way we practice oncology. I hope that people are using them to get genotyping on a larger proportion of their patients because in lung cancer, it’s critical to get genotyping. We just had a new drug approved this month for HER2 insertion mutation. So you’ve really got to find the mutation that your patient’s tumor has because now there’s, you know, I think we’re up to 9 different targeted therapies that they can — classes of targeted therapies that they can get in lung cancer. And the data from some of these real world databases continues to tell us that not all lung cancer patients are getting NGS. And we’re really missing out on an opportunity to give people the best treatments if we’re not genotyping them. So hopefully, liquid biopsies can help people get the answers.

DR LOVE: So one thing, there’s a paper we actually put in the slide deck, but I’m not sure we’re going to get to it. But I just thought maybe we could bring it up is, one thing I’ve seen in a couple papers that you’ve written, particularly in the issue of relapsed disease, so patients typically, for example, start osimertinib. We have a couple cases like that, then they progress. What do you do? But one of the things that you bring up which you can’t get with a liquid biopsy is the histology and histologic transformation. Can you comment on that, how often it occurs, and the clinical implications?

DR SEQUIST: It does occur in EGFR patients who become resistant to osimertinib or other TKIs. It’s definitely more of an issue at the relapse, like you’re saying. I think liquid biopsies are extremely good in a newly diagnosed patient first line setting. There’s not much that you would miss. But my recommendation still, if someone’s progressing on an EGFR TKI is to get a tissue biopsy if at all possible because you can’t see small cell transformation. If you do have NGS at baseline, depending on what your panel includes, sometimes it’s possible to identify those at risk for small cell transformation. They usually have an RB1 mutation at baseline and TP53 mutation, but not all NGS panels cover that. So if your assay doesn’t cover it, lack of finding it doesn’t mean anything. It just means it wasn’t tested.

DR LOVE: Another reason to get tissue is, you know, for the regular mutations that maybe you’re going to miss on liquid biopsy because you can see a false negative liquid biopsy.

DR SEQUIST: That’s right.

DR LOVE: So let’s jump into the real world, so to speak. Once we get into the real world, everything looks a lot different. Before we start with these cases, I saw a question in the — we got a lot of questions and cases in the chat room.

DR SEQUIST: Oh, awesome.

DR LOVE: But one in particular I was kind of curious about. So Hassan says, exon 21 mutant patients. I’ve never heard about this. But do you use ramucirumab and erlotinib combo where, according to him, there’s been — I’ve heard certainly of erlotinib and ramucirumab, but I didn’t know that there’s more benefit with exon 21. When we asked — I think the — we’re not going to show the slide in the survey where we said, do you ever consider EGFR + ramucirumab? And everybody says no. But you tell me. What about this person’s question about exon 21?

DR SEQUIST: Yeah. So the most common exon 21 mutation that we see is the L858R. So it is one of the more common ones and not everyone always refers to it as exon 21, but that’s where it’s located. I don’t use, outside of a clinical trial, I haven’t been using EGFR plus VEGF except for maybe some very specific situations, not in the frontline, but if people — one situation where I would often reach for it is with leptomeningeal disease at relapse because I have seen some patients benefit from that VEGF helping get into the CSF. But I haven’t — I don’t think I’ve ever used ramucirumab plus erlotinib in any patient.

DR LOVE: Interesting. All right.

Case: A woman in her early 70s with Stage IIB adenocarcinoma of the lung and an EGFR exon 19 mutation — Adam R Miller, MD

DR LOVE: Well let’s get into these cases. And actually, this first doc is actually from your place and has a really interesting case, Dr Miller. I think he’s at a satellite, MGH satellite, works out there. He gave us a whole bunch of great cases, but I really love this one because this was a lady who went to surgery, had Stage IIB disease, and came back and he talked to her about chemotherapy. Maybe, you’ve even heard of this patient or know her. And then as she was getting ready to get chemotherapy, her NGS comes back and she’s got an EGFR mutation. So it just kind of brings up the issue that I’ve been curious about ever since the ADAURA trial came up and I hear all the time from oncologists, do you need chemo? This is a situation where he’d already said she needed chemo and now she finds out, he finds out EGFR. Here’s the case.

DR MILLER: For a patient who is very interested in targeted therapies, osimertinib, but not very interested in chemotherapy, is that ever a consideration to just proceed with the osimertinib alone, or is it an absolute necessity to start with chemotherapy?

DR LOVE: How did this woman feel about taking chemo? She was, like, give me anything that will help? Or was she hesitant?

DR MILLER: She was definitely on board with it and that’s going to be our plan. I do think that could have made things a little more awkward or more difficult if we had known about that EGFR mutation first and before we had signed her up for chemotherapy. It’s a question that frequently comes up to me is, can we find one of those mutations and can I avoid the chemotherapy? Or even immunotherapy now? That’s a question that some of my patients have raised is, do I really need to do the chemotherapy, when they’re trying to avoid the chemotherapy option and try to focus just on that immunotherapy or targeted therapy just because it sounds much nicer, sounds newer, and maybe has less of the notoriety of chemotherapy.

DR LOVE: So this is the real world and lots of things go on in the real world in early-stage disease. Any thoughts?

DR SEQUIST: Yeah. Poor chemo. I don’t know why it has this bad notoriety, but it does.

DR LOVE: I know why.

DR SEQUIST: People just —

DR LOVE: I know why. It has a terrible hazard rate. That’s what the oncologists say. Yes, you’ve got survival, but compared to the hazard rate you see, for example, with osimertinib, it’s terrible. And obviously, people don’t like it. But anyhow. So the purists, all the investigators say, give the chemo. And then, the docs in practice go, I’m not so sure. What are your thoughts?

DR SEQUIST: That’s been my practice, is to give the chemo if I otherwise would. If they’ve got, especially if they have Stage II or Stage III, but even for Stage I’s that are large, greater than 4 cm, I still tend to recommend chemo. The ADAURA trial is difficult to interpret in this regard because it was optional and so it was up to the doc whether the patients got chemo or not before they then got randomized to the adjuvant osi or placebo. And when you look at the data that’s been presented about the chemo breakdown, yes, the osimertinib did help with disease-free survival whether or not people got chemo, but you can also tell just by comparing the chemo, the control arms, that the docs had a good sense of the prognosis of the patient. Because, like, for example, in the Stage III patients in ADAURA, most of them got chemo. Some of them didn’t, a minority didn’t. But those minority that didn’t get chemo, their survival was actually better on chemo/placebo than the ones — no, their survival was better without chemo than the ones who did get chemo. So the docs knew, okay, these are the bad actors, they need chemo. And these people have Stage III, but it’s just a minor Stage III, it’s not a high-risk Stage III, because the survival without chemo in that arm, that minority of patients, was really good. So it’s really hard to compare a group of good performance disease to bad performance disease. That trial is hard to interpret because it was optional and the docs did a good job of risk stratifying their patients.

DR LOVE: I’m just kind of curious, again, getting back to this longstanding issue of IOs in people with targetable mutations. If you have a patient who has a high PD-1 level, over 50%, and they have an EGFR tumor mutation, and maybe they’re a medical oncologist, and they say, I’d like you to give me an IO, how would you feel about that, adjuvant?

DR SEQUIST: Adjuvant? I would be worried about giving adjuvant immune therapy to an EGFR patient. I think while a small number of these patients were included in some of the trials like the IMpower, we really, it’s such a small number that we don’t have much confidence in whether there was a benefit. And extrapolating from patients with metastatic disease like we touched on earlier, I’m not convinced that there is activity of these agents, especially single monotherapy in this type of tumor. But worse, in the adjuvant case, if they do recur, you may be stripping them of the ability to get a TKI later because of the pneumonitis risk.

DR LOVE: And, of course, that comes up in a locally advanced situation where you give durvalumab and then they relapse. And we’ll talk about that in a second.

Case: A man in his late 70s with metastatic adenocarcinoma of the lung and an EGFR L858R mutation develops hemoptysis from an “escape lesion” on osimertinib — Priya Rudolph, MD, PhD

DR LOVE: Here’s another case. This is a patient with metastatic disease getting first line osimertinib for an L858R mutant tumor. And the patient had a great response, did really well on osimertinib, but there was one lesion in the lung that didn’t respond. In fact, it seemed to be actually increasing slightly. And then, the patient started to develop hemoptysis. Here’s the case.

DR RUDOLPH: 77-year-old never smoker. He’s a retired math professor, very active. He routinely walks about 5 miles a day. He presented with new onset dyspnea on exertion, dry cough, poor appetite and drenching night sweats. Based upon his aggressive presentation, I started him on treatment with carboplatin, paclitaxel, and etoposide, sort of a broad-based CA of unknown primary regimen. I sent off NGS testing on the inguinal lymph node which was biopsied and came back with EGFR L858R mutation. I decided to continue the chemotherapy regimen for 4 total cycles, especially noticing that he had a remarkable improvement in his symptoms even after 1 cycle of chemotherapy. Subsequently switch over to osimertinib. At this point, he was back to normal life but had an increase in size of this 1 particular mass in the right upper lobe. He started developing hemoptysis. I referred him for SBRT to that 1 isolated lung lesion. And my questions are, have people seen hemoptysis with osimertinib? On the package insert, there’s mention of epistaxis, not necessarily hemoptysis. Given his hemoptysis, would they consider switching him to afatinib instead of osimertinib?

DR LOVE: So I should’ve mentioned that initially, it wasn’t clear where this was coming from. So she initially thought it was unknown origin and then got back the EGFR. Any thoughts about the case?

DR SEQUIST: Yeah. It’s kind of an example of how helpful NGS testing can be sometimes when you’re not sure where the tumor is originating from based on immunohistochemistry but then you get a very distinctive mutation. It sounds like luckily, the patient had been responding to general chemotherapy too, as EGFR mutant tumors often do. But NGS is often helpful for cases like this.

I’m not aware of any direct connection between osimertinib and hemoptysis. Now osimertinib can cause low platelets. So I don’t know what this patient’s platelet count was, but maybe if there was some kind of anatomic predisposition, just having low platelets was kind of enough to tip the scale. The platelets on osimertinib generally are in the kind of 80,000 to 90,000 range. They don’t tend to drop down into the 10,000 range. So it’s usually not clinically significant, but I think radiation is the right thing to do. There’s a lot of at least retrospective data suggesting that if patients have locally ablative treatment to that one area of progression, radiation is usually the way to go. But surgery has been studied as well that they can get quite a bit more milage off their TKI. So I think SPRT for both the hemoptysis and the unilateral progression is a good idea.

DR LOVE: Yeah. I was thinking even if the patient didn’t have hemoptysis, it might have been a reasonable strategy just as an escape lesion.

DR SEQUIST: That’s right.

Case: A man in his early 70s with metastatic adenocarcinoma of the lung (PD-L1 high) and an EGFR L858R mutation experiences disease progression on pembrolizumab — Sandip Patel, MD

DR LOVE: So this is a 2-parter, this next case. I’m curious what you would do in this situation which I think may be not rare. One of the issues we’ve been talking a lot about the last couple years because it just seems like it would be common and very important is, what do you do with a patient who needs to be treated right away where you can’t wait for the NGS because they’re sick? And a lot of times, these patients are going to get chemo until you see — even if they’re a nonsmoker, you got to see what’s going on. And then the question is, do you add an IO? And it particularly is an issue when you see obviously somebody with a high PD-1. And what we’ve been hearing from investigators is wait even if the PD-1 is high, particularly for a nonsmoker, until you see the NGS and then if it’s negative, okay.

This is kind of a play on that same scenario. The patient was a 72-year-old man but he was initially treated by another oncologist. And the PD-1 came back high, it was over 50%. The oncologist, actually, there wasn’t a genomic assay done. I don’t know if it would’ve been done or not, but the oncologist treated the patient with pembro. And the patient clinically progressed and then came to Dr Patel for a second opinion. He did liquid biopsy, L858R. Here’s part 1 in terms of his situation and what he was thinking. And I’m curious how you would think it through.

DR PATEL: So the patient unfortunately had progression on their first scan. They were feeling worse, their cough was worse, having worsening pain. So the patient was referred to my clinic. I ordered a cell-free DNA test at this juncture and we found this EGFR L858R mutation. So at this juncture, we have a patient who has been treated with pembrolizumab previously, but now their best therapy is an EGFR inhibitor. What would be your next course of action in this scenario?

DR LOVE: At that point how much disease did he have and how sick was he?

DR PATEL: He was pretty sick. His pain med requirement had effectively doubled in the past 2 months, from painful with bone metastases. The liver metastasis was causing him issues, and his cough was getting worse.

DR LOVE: So I’m wondering if you’ve faced this situation as a second opinion. But any thoughts?

DR SEQUIST: I have. And I think, especially when pembrolizumab first came out and was approved and nivolumab 5 years or maybe a little more than that now, this was very common as I think people were excited about these new drugs and they got that high PD-L1 and just jump on it. And these situations are tough, especially when the patient is just progressing through it very quickly, you really wish that NGS had at least been sent already so that you would have this information. But sounds like Dr Patel got it, got the information really quickly. And I think now the conundrum is, what’s the chance of toxicity if I go ahead and start an EGFR TKI? The chance of response is high, same as it would be if it was the first treatment started. But what’s the competing risk of pneumonitis? And it looks like that might be highest with osimertinib, maybe a little bit less with some of the older EGFR TKIs.  

DR LOVE: What do you think you’d do?

DR SEQUIST: I have seen patients like this before and I will usually try some chemotherapy first to try and let that immune checkpoint inhibitor kind of washout. It has a really long half-life. So I would say I’ve often started with chemo, but it’s hard to stand in someone else’s shoes. I know these are hard conversations.

DR LOVE: And as always, in hard conversations, it’s always helpful if you have a participating patient and this patient was all over it, very interested in the whole situation. And what happened, amazingly, he actually started the patient on osimertinib, gave the patient a pulse oximeter, prescription for steroids, and told him to go to the ER if he got hypoxic or short of breath. So pretty interesting, but well-informed strategy made with the patient. Here’s what happened.

DR PATEL: We had the lengthy discussion around we’re between a rock and a hard place here together. And the patient opted for osimertinib. I sent him home with a pulse oximeter and he actually did get pneumonitis, but it was steroid responsive. And we held the osimertinib, finished a steroid taper. At this point he was feeling better because his cancer had shrunk substantially, and then it would be a good question for the investigators, what do you do next in this scenario? He had about a 70% shrinkage of his cancer.

DR LOVE: Wow.

DR PATEL: And so really nice response. He was almost off his pain meds completely until the pneumonitis hit him. And so really kind of a major benefit. We opted to do stereotactic radiotherapy to the 2 remaining sites of disease. And he was able to go about 6 months before new lesions emerged, which kind of forced our hand in what we wanted to do next.

DR LOVE: So what did you do?

DR PATEL: He wanted to resume the osimertinib because he didn’t want to be in the place he was when he first started in terms of pain meds and how he was feeling. Radiation would not be sufficient to handle the distribution of disease he had at that juncture. And he resumed osimertinib, and luckily he had no recurrent pneumonitis. And he, in fact, also remains on osimertinib to this day.

DR SEQUIST: That’s great.

DR LOVE: So like 18 months later, so amazing case. I’m not saying this is what people ought to do or not. I was going to make this a 3-parter and ask you what you would do at the point that he was progressing. Where it was kind of like similar to what you were saying about chemo, that by using the radiation it gave him more time, so wait until he has started the osimertinib. Any other thoughts about this wild case?

DR SEQUIST: No. It’s a great case, Sandip. And I think it does seem from the anecdotes, but there’s no big series of exactly what to do. There’s certainly no perspective trial about what to do for these EGFR patients that have been exposed to checkpoint inhibition. But it does seem like time is helpful. And so once the patient got pneumonitis, by being able to do some radiation and stay off of any systemic treatment, sounds like really helped reduce the risk of getting pneumonitis again. So that’s a great job.

DR LOVE: Yeah. The art of oncology.

Case: A woman in her mid 60s with metastatic adenocarcinoma of the lung with an EGFR exon 20 insertion with multiple brain and bone metastases (PD-L1 <1%) — Justin Peter Favaro, MD, PhD

DR LOVE: Okay. Here’s our exon 20 insertion case from Dr Favaro. This is a 65-year-old woman. She also has a very low PD-1 level and she has both systemic, bone, and brain mets. Here’s the case.

DR FAVARO: At the initial time of her staging, her PET scan showed she had a left lower lung neoplasm, hilar and mediastinal lymph nodes, widespread bone METs, and also, she had about 7 small brain metastases. The largest was about 7 cm. She had no neurologic symptoms. We have 2 approved agents for exon 20 insertion mutations, amivantamab and mobocertinib. The question is, which 1 of these 2 agents would be best to use up front if she has progression, especially considering that she does have brain metastases? The other question that came up at our tumor board presentation is what to do up front for exon 20 insertion mutations. What option is best for chemotherapy? Do you typically incorporate immunotherapy for these patients? And what about the incorporation of bevacizumab for these patients? So she had a PD-L1 less than 1%. What about the incorporation of bevacizumab in patients that have untreated asymptomatic brain metastases? Amivantamab is an IV monoclonal antibody. Mobocertinib is oral. What are their different toxicity profiles? This particular patient has untreated brain metastases that are responding to chemotherapy. Do 1 of the 2 exon 20 inhibitors, are they better for brain metastases?

DR LOVE: So let’s start out with first line therapy in metastatic disease. And I guess one question is, do you approach IOs the same way as you just described for EGFR activating mutations? For exon 20, you also avoid?

DR SEQUIST: I do, yeah. This is a great case because even though we have these 2 new approved drugs for EGFR exon 20, it’s important to remember they’re both approved in the second line setting after chemo, and for good reason. The response rates are generally a little bit lower than like we would see for targeted therapies like osimertinib or alectinib or others that are used in the frontline setting. So it’s for later for this patient and we have to come up with a first line regimen now. And I usually don’t do chemo/IO for patients with EGFR exon 20 because, both because of the toxicities for TKIs down the road, but also because I’m just not convinced there’s much activity from it.

So I think carbo/pemetrexed would be standard. If you wanted to — this patient does have multiple brain mets. If you wanted to do something that might be a little bit more active, give a little more oomph up to the brain, I think bevacizumab is a great idea. But I wouldn’t do immune therapy.

And then when they do progress in the future, I think, trying to figure out which of these 2 new drugs, they are very different, as Dr Favaro was saying. One’s an IV treatment, it’s given every 2 weeks. It’s pretty intense. One’s a pill that you take at home. They’re both moderately toxic. So both of them have a good amount of skin toxicity and GI toxicity. They’re not easy treatments, but they do have a good activity. Unfortunately, neither of them have great track records in the brain. So this is a real area of unmet need in EGFR exon 20 is to find drugs that get into the brain better.

And I would certainly think about a clinical trial for this patient, especially if there is one available that is thought to maybe be better in the brain. There’s several drugs that are under investigation. And the other thing that I have sometimes done for exon 20 patients who have brain mets is think about osimertinib. It’s not as active in exon 20 as it is in some of the others, but there was a trial that, for full disclosure I was a part of, but out of the ECOG group looking at double dose 160 mg of osimertinib in EGFR exon 20. And pretreated patients, the median progression free survival was about 9.7 months. So it has decent activity and it does get into the brain. So I have sometimes done that for patients like this that have a significant CNS burden.

DR LOVE: I was actually flashing on our webinar tomorrow with Dr Pegram where the issue of treating people with systemic therapy with brain mets and holding off on RT comes up in HER2-positive disease because you have tucatinib up there. And we’re going to talk about the fact that a lot of people apply the lung, I think people call it the lung model of using systemic therapy and holding radiation therapy. And one the things I’m — in an asymptomatic patient, particularly if they need whole brain radiation. And of the things I’m not clear about is, do you do that with all or do you consider that in all the targeted therapies? For example, exon 20, would you attempt to use either one of these drugs and not radiate in the hope that you would see a response? Or it’s so unlikely it’s better just to go ahead and radiate?

DR SEQUIST: Yeah. I think you have to consider each drug differently because even if they’re in the same class, they can have different penetration into the CNS. For EGFR exon 20, since none of the drugs are approved in frontline, usually when you’re thinking about choosing one of them, the patient’s already had a response in the brain to chemo, or you already decided to radiate it. But, yeah, I think there’s several potential interesting trials, but one of them is amivantamab combined with lazertinib because lazertinib is an EGFR inhibitor that doesn’t get into the brain very well. And I think you could use osimertinib too, it just happens to be that the company that develops amivantamab, their drug is lazertinib, so that’s a combo that they’re studying. But I think the concept is that we need a CNS penetrant TKI maybe with some of these monoclonal antibodies for exon 20.

DR LOVE: How do you determine what comes first? I can imagine maybe a lot of patients end up getting both drugs. But generally speaking, how do you think about which one to go first?

DR SEQUIST: I think a little bit depends on how far the patient lives from me. The amivantamab is pretty intense with an IV every 2 weeks. And so if a patient is traveling more than an hour, that gets harder. If they live closer, it’s more feasible. So that’s one way that I have chosen between the two.

I think for some patients, you also get a sense during first line chemo of how much do they call? How much do they report to you? My concern about any TKI that causes a lot of diarrhea at home like mobocertinib can, and others can too, like afatinib. Are they going to call me? Or by the time they call me, is their creatinine going to be 2.5 because they haven’t let me know about their diarrhea and their dehydration? So I try and see what I think the patient can tolerate best. Can they be communicative enough to do a harder oral regimen at home? Or do I need to see them a lot because I’m worried about them? That’s more of an IV treatment.

DR LOVE: Interesting.

Case: A woman in her mid 50s with metastatic adenocarcinoma of the lung and an EGFR mutation experiences disease progression after response to osimertinib x 3 years (PD-L1 TPS 80%) — Gigi Chen, MD

DR LOVE: So I want to ask you about this case. We’re getting a lot of questions in the chat room about management of patients who relapse on osimertinib, secondary mutations, et cetera. Here’s a case that’s along those lines and the patient has a high PD-1 level as well. Here’s Dr Chen.

DR CHEN: She’s actually now progressing fairly rapidly, so my thought is for people who have driver mutation, I think that the general thought is that they are not going to respond as well to the immunotherapy. So I was more leaning towards chemotherapy, such as carboplatin, pemetrexed, and bevacizumab. Or the question is carboplatin/paclitaxel/atezolizumab and bevacizumab, is that a good option for her at this time? Is there a role for use of a checkpoint inhibitor plus/minus chemotherapy in a patient who has a high PD-L1? Her disease is progressing fairly rapidly, and she’s symptomatic, so she’s okay with chemotherapy. I think certainly she wants the treatment that offers the best efficacy and tumor reduction at this time.

DR LOVE: Any thoughts?

DR SEQUIST: Well when an EGFR patient is progressing fairly rapidly on osimertinib or any TKI, you always have to think about could this be small cell transformation? It does — EGFR is the disease setting where we see this the most. There have been some very rare case reports of ALK patients or ROS patients that have had small cell transformation.

But in EGFR, we definitely see it, 10 or 15% of the patients who progress on osimertinib. So I think it’s worth, especially in a patient who is progressing quickly, to do a biopsy because if you find a small cell transformation, you may not be thinking about pemetrexed. They may have a better response to carbo/etoposide because of the small cell. So I would think about doing a biopsy. But if your biopsy shows adeno, then I think chemotherapy is the way to go. There are other things you can do with that biopsy. You can check for something targetable like MET amplification would be the most common one that would be found. But if nothing targetable is found, I think chemotherapy is the way to go. And then the question is, do you combine anything with it? Immune therapy? Continue the osi? Bevacizumab? There’s a lot of different options.

DR LOVE: So I want to jump into the survey because we had several questions about this scenario in the survey.

DR SEQUIST: Yeah.

DR LOVE: If we have time, we’ll come back to a couple more cases. So, again, just, you know, what do people do? It’s such a challenge when you have multiple evidence-based options. And we often see something like this which is a little bit of heterogeneity in what people do. So we said, you’ve got a patient with a Stage IB tumor, exon 19 deletion, high TPS and we see everything from — you and Dr Planchard — I would say most investigators would say chemo/osimertinib. But you also see osimertinib and no adjuvant therapy. If you — if these people came a second opinion from Dr Neal or Dr Jänne or Riely, what would you say about their thoughts?

DR SEQUIST: Well I think the patient that saw Dr Neal and Dr Spigel probably had Stage IB by virtue of visceral pleural invasion. Maybe it wasn’t a large tumor. And I’d be fine with osimertinib alone also in a patient that didn’t have a large tumor. But I usually do give chemo if they have a larger tumor.

DR LOVE: And, of course, when we put a Stage II case in, things get much more homogeneous in terms of chemo and osimertinib, at least from the investigators. We were talking a little bit about that.

I’m also curious about this, it seems like, age-old question, but it always seems to be changing, which is patients with locally advanced disease who are getting chemoradiation, durvalumab or osimertinib. In the beginning, I was hearing all the investigators saying durvalumab, durvalumab, we have the data. More recently, I’m hearing more people, including you, talking about EGFR. Any thoughts? And osimertinib, specifically.

DR SEQUIST: Yeah. So certainly, the PACIFIC study that looked at consolidation durvalumab did allow patients with EGFR mutations. We don’t know the mutation status of most of the patients in that trial. But just of the same theme that we’ve been hammering on, you know, the biology of the EGFR tumors doesn’t really seem to respond to the PD-L1. And, in fact, Dr Neal and myself and Dr Wakelee and some others wrote a paper looking retrospectively at patients from Stanford and MGH and Georgetown and a couple other sites about patients who had been treated with durvalumab and had a known EGFR mutation. And most of those patients did very poorly, either because their disease recurred during the middle of the durvalumab and/or they had toxicity when we then tried to do a TKI in the advanced setting. So I’m really hesitant about doing durvalumab when I know the patient has an EGFR mutation. But we’re waiting for the LAURA study which hopefully will answer this question with data, prospective data. It just hasn’t matured yet.

DR LOVE: So we were talking about looking for additional mutations in patients who relapse on osimertinib. And we presented this case to the faculty of a patient who had a MET amplification. And it looks like people are reaching for the newly approved METs drugs in general, most of the docs here. It doesn’t look like — Dr Planchard brings up savolitinib which is not approved. I’m curious. I know you’ve done some work on that. But any thoughts about managing it? And also, this issue of whether to continue the osimertinib. I’m hearing more and more about continuing osimertinib, either temporarily or indefinitely and it looks like most of the docs here say keep the osimertinib going and add MET. Is that — any thoughts?

DR SEQUIST: Yeah. Well for this case, I think with MET amplification as the resistance mechanism, there’s pretty good laboratory data from over 10 years ago. About 15 years ago, Jeff Engelman and Pasi Jänne published a paper in Science showing that MET amplification was a mechanism of resistance to the older drugs like erlotinib, gefitinib, and that those cancer cells didn’t respond to either an EGFR inhibitor or a MET inhibitor alone, but you put both on and they respond. And we’ve seen that now in clinical trials too. Clinical trials that tried to do just a MET inhibitor for these types of situations didn’t really work. And it wasn’t until the TATTON study which looked at the combo of both of them that we started to see responses. So yeah, that trial was with savolitinib that Dr Planchard had mentioned in his answer, but that’s not an approved drug. So if I have a patient with acquired MET amplification, I’ll keep the EGFR TKI going and add in a MET inhibitor which is either crizotinib or now, more likely capmatinib or tepotinib.

DR LOVE: So question from the chat room. We have a case, I’m not sure we’re going to get to it. There’s all these other EGFR mutations people ask about. So Aradam has a 60-year-old woman with a G719X EGFR mutation and wants to know is it better to give afatinib? Is that one of the afatinib mutations?

DR SEQUIST: It is one of the ones on the afatinib label. Remember that that label with a few of the rare mutations on afatinib, that data was from pre-osimertinib days. So it doesn’t necessarily mean that afatinib is better, but afatinib certainly works in patients with that mutation. I think osimertinib also works as well and is better tolerated. We don’t have head-to-head comparison in some of these mutations.

There is a pre-clinical paper, so take it with a grain of salt, but a very highly cited paper from John Heymach’s group at MD Anderson where they looked at the structure of these different EGFR mutations and tried to categorize them. And so that one, the G719, it falls into the category that they said has the highest, you know, the cell lines had the highest response to afatinib and other second gen drugs. But the cell lines don’t get diarrhea and rash and so we always have to balance like what’s the best in the cell line with what’s the best for patients overall. And the toxicity is definitely higher, but I think you could use either. You could probably get either approved, no problem with insurance and then just depending on the performance status of the patient. I would usually choose osi.

DR LOVE: Yeah. Really interesting also. This one here, I was like, did I miss this day in school, or what happened? Because we say, you have a patient who’s got an exon 19, brain mets, good response. I don’t know if the brain mets change anything. Good response to first line osimertinib, but then has disease progression, is switched to chemo. So everything fine so far. Would you keep the osimertinib going? And all of a sudden, it’s like HER2-positive breast cancer. Like, when did this happen? Any comments?

DR SEQUIST: Yeah.

DR LOVE: Where did this come from?

DR SEQUIST: The one difference between Dr Planchard and everyone else is, he doesn’t practice in the US. So I think in France and in many countries, you can’t continue the osimertinib. You just can’t have access to it. But in the US, it’s often done. It’s done so often that it’s to the point where we have a clinical trial now trying to show whether this has a benefit or not. And a lot of the US sites aren’t participating because they don’t have equipoise about this question. This is the COMPEL study which I think is really important to answer this question. But the reason why I think a lot of people are voting with their feet to continue the osimertinib is because the excellent CNS protection that osimertinib seems to give. And you see a couple of patients who when you stop the TKI, soon thereafter, the brain mets sort of come out. Your judgement is definitely affected by that for future patients.

DR LOVE: Well all I’m going to say is, very interesting. And I’m curious what people in practice think about this. A couple questions we asked about exon 20, we were talking about before. And you can see that nobody, well Dr Spigel potentially is interested in PD-1 as first line therapy. Dr Planchard, if he could, I don’t know if it’s — I doubt it’s approved, but would like to give it first line which I think is interesting. We actually said, in general, when would you offer it? And everybody says second line as you were just pointing out. This is interesting too in terms of whether people have a preference. You were talking about kind of, you know, like the IV thing and that otherwise similar and it kind of reflected on the fact that people seem really split about what comes first.

And then the other thing I was going to ask about, and I don’t know if you can comment also on what we just showed, but also the amivantamab/lazertinib. And lazertinib, I guess, sounds like it’s a lot like osimertinib, but it’s just different preparation, different company. But we said if you could, would you use it in patients like this? And most people say yes. What do we know about this combination in people progressing on osimertinib? You say you would use it if you could access it.

DR SEQUIST: Yeah. I think what we know about it is still from early trials, but we are seeing responses. We saw responses to amivantamab in many different types of acquired resistance. By different types, I mean known MET amplification, known C797 or no mutations identified. Some of these treatments like a MET inhibitor and a TKI will really only work in one molecular situation, but amivantamab seems to have activity across different situations. It’s just that the main liability with the amivantamab is it doesn’t really get into the CNS. So lazertinib combining with it, the point is to try and get into the CNS and provide some kind of CNS protection. And so we saw some early data at ASCO this year about that combo, but I think there’s many trials ongoing. I think we’ll have much more confidence about which patients are the ones to give ami/lazer soon.

DR LOVE: So let’s see if we can do one more case. But there is an interesting comment in the chat room. Actually, I was talking to Heather about this this morning. Poor Heather. She’s on the West Coast, she had to get up at 6:00 AM to do this thing. She was looking like she’s falling asleep there. But in any event. Neoadjuvant targeted therapy in EGFR mutant patients. I always thought that was a good idea, particularly with locally advanced. But, of course, now we’re seeing neoadjuvant IO. But what about neoadjuvant targeted therapy?

DR SEQUIST: I’ve done it. Well we had a trial actually. So my first experience was on a trial. This was when afatinib was the latest drug and we had neoadjuvant afatinib in EGFR mutant patients with Stage III disease. And a couple of patients on that trial who didn’t have operable disease at the beginning, converted to having — they had inoperable disease and then it became operable. But, in general, I’ve done it outside of a trial with multiple different driver mutations. I think it’s something — so far, I’ve mostly used it when they were inoperable and even the radiation field was kind of big. So we were trying to give enough shrinkage that we could at least do definitive chemoradiation with some safety. And I’ve been able to do that for many patients.

But I think another question, now that we’re living in this neoadjuvant age with the CheckMate 816 data is, even if someone is operable or even if someone is able to have a safe chemoradiation port, is there some benefit of trying to get this targeted agent in early to try and capture those micrometastatic cells? And is your chance of cure higher? I think it’s possible. And I think the surgeons are really — now that we have neoadjuvant immune therapy approved, I think there’ll be a lot more testing, doing genetic testing before anything happens for an early-stage patient. And that might give us the real window of entry that we need to be able to do targeted therapy neoadjuvant.

Case: A man in his mid 50s with adenocarcinoma of the lung and an EGFR exon 19 mutation with brain metastases and disease progression on both osimertinib and carboplatin/paclitaxel/pembrolizumab/bevacizumab (ROS fusion detected on RNA assay) — Namrata I Peswani, MD

DR LOVE: All right. Let’s see if we can squeeze in one more case. Again, in the real world, stuff comes up that is sometimes difficult to interpret. In this case it was some type of RNA assay. But in any event, this is a 50-year-old man with EGFR exon 19 mutant disease with brain mets. Has a response, but then progresses on osimertinib. And as you’ll hear, as the patient was about to — this doc wanted to use — I was going to ask you before what you thought about the carbo/paclitaxel/pembro/bevacizumab strategy. But they also found some type of ROS fusion that she has questions about.

DR PESWANI: He’s 50 years old. He’s an orthopedic physician assistant. Really nice guy. Never smoker. The DNA portion of the NGS testing did not show any mutations, but there was an addendum, which was the RNA report, and there was a ROS mutation on that. And I wasn’t sure what to make of that. And there’s now more data coming out about trying a higher dose, the 160 mg of osimertinib if patients progress, if that would have been a better next step instead of switching to the quadruple chemotherapy, especially because that would have had better brain penetration and potentially could have prevented him from getting new brain mets?

DR LOVE: And also, I would add how do you know whether it’s a mutation that’s going to respond to targeted therapy or not, a “driver” mutation?

DR SEQUIST: Yeah.

DR LOVE: Do you see ROS as an escape mechanism?

DR SEQUIST: There has been some anecdotal reports of that. I think as long as the original EGFR activating mutation was also still seen and then a new mutation on top of it, I would feel more confident that this was probably a true escape mechanism. And there have been some anecdotal reports, the group in UC Irvine had a nice paper where they talked about different combos that they’d given kind of off-label because escape mechanisms had been seen. So yeah, mixing ALK and EGFR or mixing ROS and EGFR, you know, these have been tried in small numbers of patients with some success. But we really don’t have a lot of data to hang our hat on.

The question of whether to use the quadruplet IMpower150 regimen, I think because my bias for EGFR patients that get resistant is to try and continue the EGFR TKI, I usually don’t add immune therapy. I think when you really look down into the nitty-gritty details of the IMpower150, the number of EGFR patients was extremely small and the benefit that was initially touted was not statistically significant at the end of the day. So I don’t really see a role for that regimen in an EGFR patient. I think we’ll have a lot better data from the KEYNOTE-789 study which is still pending, but this is a large, randomized trial that is just among EGFR patients. So we’ll have the power to really know chemo versus chemo/IO. I think it’ll be really helpful when it reads out.

DR LOVE: So am I thinking that you would consider like osimertinib plus a ROS drug? And which ROS drug?

DR SEQUIST: Yeah. So if there really was an acquired ROS1 mutation, I have never personally done this yet in a patient, but I would consider a ROS drug. I’m not sure when that patient had brain mets, if it was before or after. But if they had known brain mets at the time, you might want to think of something like lorlatinib that gets into the brain. You’d want to see if there’s any safety data about giving osi with lorlatinib. It’s not something I’ve ever done, but it’s something you could consider, especially if there’s any published case reports. At least you have some idea of how at least one patient did. A lot of times, a case report is needed to get it approved by insurance.

DR LOVE: So just one more question from the chat room. When I saw this, I’m like, no, we’re talking about EGFR here, this isn’t going to be relevant. But now, it turns out like it is relevant.

So this is from Daniel. 26-year-old patient with ROS-positive non-small cell treated with entrectinib, developed V-tach storm after 2 weeks. Workup concerning for myocarditis. Any experience with myocarditis or cardiotoxicity from entrectinib?

DR SEQUIST: I do not have experience. I have only given entrectinib a handful of times myself. But I think other TKIs have caused cardiac toxicity and it’s certainly something you would want to work with a cardiologist. I’d be hesitant to give the same drug again after something like that. It sounds really —

DR LOVE: Well that’s — yeah. It sounds — maybe chemo. Well anyhow. Lecia, thank you so much for sharing your experience and wisdom with us today. Audience, thank you for attending. Come on back tomorrow night. We’ll see what Dr Pegram has to say about HER2-low and all the other wild things going on in HER2-postive breast cancer. Be safe, stay well and have a great night. Thanks so much, Lecia.

DR SEQUIST: Thank you.