Introduction

DR LOVE: Good afternoon, everyone. I’m Neil Love from Research To Practice and welcome back to “What I Tell My Patients.” As right now we’re going to focus on the management of non-small cell lung cancer and specifically those patients with an EGFR tumor mutation.

We have a great faculty today and as always we have two nurse practitioners and two medical oncologists on the panel and we’ll be talking about non-small cell lung cancer in targeted therapy and this specific type of targeted therapy. As always, we’ll be talking about some nonapproved indications of agents and regimens. Check out the package insert for more information.

For the clinicians in the room, you have iPads that have all the slides, a survey and ability to ask questions. Same functions for the many people, hey out there in the Zoom world and the chat room as well. We have a 1-minute pre- and postmeeting survey for you to take on the iPad or in the chat room. If you take that, you’ll get a lot more out of this meeting here today.

We also are recording all the programs we’re doing here at ONS. This is our 6^th program, out of 10, that we’re doing here today. We’re covering a variety of topics but we’re also thematically focused really just on taking care of patients. We’re making rounds with 40 of the top people in the field and really thrilled to have such a great faculty here working with us this week. But in addition to the 40 people we have here live, there are also 8 other nurses, which we’ve worked with in the past but we were unable to sort of make it work to get them here this year. And so I spent about an hour with each one of them, chatting with them not so much about the type of cancers they treat but more about oncology nursing in general. We ended up posting this content on the web. You can see the link. We’re just going to show 2. We produced 85 short-form videos, 90 seconds or less. We’re going to show you 2 of them, but there are another 83 at this web link if you want to check it out. We’re curious what to do with this content but we’re going to integrate it a little bit into the meeting here today where we are going to focus on targeted therapy. Mainly we’re going to focus on so-called classic, the classic type of tumor mutation, but we’re going to get into the details as we go through this in a second.

But first, just to take a little bit of a deep breath and kind of a step back and, Marianne, Amy Goodrich is a nurse practitioner we’ve worked with many, many times from Hopkins. She takes care of patients with lymphoma and CLL. We couldn’t work it out to get her at the meeting here last night but we chatted with her. And one of the things she was commenting on, well, we asked all the nurses about, was clinical trial participation. I love that story you told us in the faculty room, the case of the patient who went on a trial. We’ll get to that towards the end. But here’s Ms Goodrich with her thoughts about really the advantages to the patient of participating in clinical trials.

MS GOODRICH: We talk to patients about clinical trials all the time and I try to stress to patients, “Okay, you have disease X, and 5 years ago you could not have gotten this drug that you’ve already received,” right? So reminding them of the therapies that they have received that just a few short years ago were not FDA approved and were only available on clinical trials. And really we are very honest with patients that really 10 or 15 or 20 years ago clinical trials, most of them were not fruitful, but we’ve learned so much about the biology of just about every disease that that has really changed. And there are a lot of drugs that are more effective than anything we’re giving and that the only way you can access those are on clinical trials. So I think the whole face of clinical trials has changed because of the molecular focus and the drugs that are getting developed are really just so effective.

DR LOVE: I think, Marianne, another kind of message we’re trying to get out there is it’s one thing if you’re in a tertiary center and there are a million trials around you and it’s another thing if you’re in the community setting and maybe not that many trials but we need to let patients know they’re out there and they can access these trials from anywhere theoretically. Any thoughts about Amy’s thoughts? And just where clinical trials you think fits in with lung cancer nowadays?

MS DAVIES: So certainly, I think when we first started and when I first started with lung cancer, more than 25 years ago now, most of our clinical trials were very broad, kind of catchment kind of trials and so it wasn’t personalized. And now when we’re doing trials, we’re really looking at that patient’s molecular profile. What kind of tissue do they have? What is the actual specific disease they have? And the trials are built that really are very personalized. So it really speaks to the very specific mutations that those patients have in many cases. That’s not maybe the case for maybe some of the Phase I trials but so you feel like you have a better chance of having an opportunity to receive a drug that has more potential to have benefit in your very specific kind of cancer and so we try to explain that to patients when they are exploring different clinical trials now.

DR LOVE: I’m curious, Jillian, the kinds of reactions you get from patients when you bring up the issue of clinical trials. Do you generally get a positive reaction? Are there people who are concerned? They don’t want to be guinea pigs? How do people react when you bring up this issue?

MS THOMPSON: So we have mixed reviews, and I think it really depends on what people know about clinical trials themselves. Some people have that old thought process of you’re going to be a guinea pig and those are the ones that you have to spend some time with to really explain that this may be an option for you to get a therapy that could be of benefit to you that wouldn’t be available otherwise. And so I do see a mixed bag of that. We do have some people that come very educated that know about clinical trials and can tell you exactly what is available and are looking for that. So you really do cater it to the individual. But it’s very important that we make sure that we’re educating people so that they understand what clinical trials are and really understanding that they have the option, it’s an additional option for treatment, but they also have the option, if they’re uncomfortable at any point, to get off trial. So we always want to make people feel like it is their choice so they have that autonomy.

DR LOVE: So we’re going to now turn and focus on this specific issue and I was asking the faculty if anybody knew Dr Tom Lynch. He’s currently the head of the Fred Hutch Center in Washington. Alex, you said you had some contact with him in your fellowship?

DR SPIRA: My partner used to be very good friends with him and they used to play football together in college — sorry, medical school, and did a lot of drinking together as well.

The Importance of EGFR Testing in Non-Small Cell Lung Cancer (NSCLC)

DR LOVE: Well anyhow, I’ve got a great Tom Lynch story for you, really sets up what this is all about. So this is 20 years ago, 2004, and Tom, I think at that point, I think he was at MGH, and he was in Miami, which is where we’re located, and I said, “Well let’s try to figure out, let’s interview him. Let’s see if we can figure out a way to talk to him.” So we sat down and talked to him and I did an interview for educational purposes. And at that time there was a drug called gefitinib out there and I saw in his CV that he had done some papers on these Lazarus-like responses to gefitinib. So most people didn’t really benefit by it but a fraction of these patients it seemed like it was nonsmokers, nobody really understood it. So I said, “Tom, do you have any idea about why it is that these people respond?” And Tom, who is of Irish descent incidentally, his face got completely red and he said, “I can’t tell you.” I go, “Okay.” And then the next day I saw him on Good Morning America because he had discovered the EGFR mutation and that was the reason these people were responding. So Alex, that’s my Tom Lynch story and that really launched really the area of targeted therapy for solid tumors. At that point, we had CML, you know very successful targeted therapy, but Alex, at that point was when things really took off. So can you kind of give them sort of a 60-second summary of how we went from here to there in terms of targeted therapy? I just pulled up all the orals that were just posted this morning for the ASCO meeting and there are some really cool papers coming out. Where have we come and where are we now, Alex?

DR SPIRA: So it is amazing because somehow I went from being young, I actually published one of the papers with Tom years ago, way, way back when, to the new generation that can’t understand a time where we didn’t understand EGFR mutations. I’m sure that’s how you feel Helena, right?

DR YU: Yeah.

DR SPIRA: It was an era before but that’s my generation and your generation, Neil. But we’ve really come an amazingly long way. First, we had multiple generations of EGFR inhibitors and now, not only do we have first-generation, we have lots of second-generation choices. We’ll talk a little bit of amivantamab today. There are other exon 20 drugs. There is now chemotherapy given along with it. So it’s changed the field so dramatically. We now have second- and third-line trials that are driven by moleculars and, of course, we’re not only talking about EGFR, there are 9 or 10 genetic aberrations you have to think about. It’s made our field challenging as an oncologist because now to do clinical trials if you want to have something for everybody you have to have 10 clinical trials versus 1, which is an issue in and of itself. But it’s changed the field so dramatically that this is what we think about in terms of lung cancer treatment. It’s about tissue and molecular testing and getting those results back. Thankfully for many of us the incidence of smoking has gone down dramatically. So in many clinics, mine and I’m sure yours, we find actionable mutations in the majority of patients. It’s no longer just something you think about anecdotally. When I started, we were in an area where there were a lot of veterans and military and factory workers and it’s changed to professionals over time so we have a very, very low incidence of tobacco use. So almost everybody we see has a genetic mutation so it’s part and parcel of what we have. And that’s how do you think about it? How do you test for it? Do you check for second-line? And with the advances in computer technology, we’re now going to have 2 or 3 different options to think about as well. So it's not, what you do second-line, which of these options is better, which is incredibly complicated. It’s great, it’s much more complicated, but it’s why I went into oncology.

DR LOVE: So Helena, the smoking thing was also really interesting. We couldn’t understand it. Why was it nonsmokers were getting these EGFR mutations? And I can remember kind of looking out at an audience and thinking to myself after that that there were probably a ton of people who smoked and who never got this because it took us awhile to figure out what was really going on. So can you kind of explain the connection between nonsmoking and EGFR? Where these mutations are? Because these are mutations in the tumor. So this is not a genetic mutation. This is just in the tumor. Can you kind of tell the story?

DR YU: Yeah. So what I tell patients when they come to me newly diagnosed and they’re a never smoker, 1 out of 7 lung cancers, newly diagnosed lung cancers, are from a person who’s never touched a cigarette. And I think that number will continue to rise. When we think about sort of causal mutations, I tell people it’s nothing that you did or didn’t do. This is, as Neil said, a mutation that turned on in the cancer and is what drives the cancer to grow, but it’s not a hereditary mutation. Nothing you got from your parents. Nothing you pass down to children. I think that does provide a degree of relief for patients.

The Role of Osimertinib in Managing Localized and Locally Advanced NSCLC with an EGFR Mutation

DR LOVE: So I want us to kind of get into some cases and see how this actually plays out in clinical practice. We could spend the entire day talking about targeted therapy because as Alex mentioned there are 9 or 10 other targets. We’ll allude to a few of them here. They’ve now moved down from metastatic disease into the adjuvant setting. First, we had osimertinib and now we have alectinib. But let’s just talk about how this plays out in practice. Marianne, you actually have 2 patients you were telling us about in the faculty room. Can you kind of give us the bottom line of kind of what happened there? Because I think they’re kind of typical of what happens today as opposed — you imagine somebody coming in 10 years ago and getting chemo and not doing very well compared to these stories.

MS DAVIES: Great. So thank you. I do have 2 cases that are a little distinct but one of the common threads I think they have is that there really was a lot of shared decision making. A lot of cooperation between the provider and the entire team and the patient and their family in treatment selection, and I think that’s something that we’ll see in all of our cases today. So my first person was a woman in her 60s, a nonsmoker. She had recently returned from a trip. So she came in with leg swelling and dyspnea and a cough and so our first concern was did she have a pulmonary embolus from travel. And so a CT scan was obtained and she did have a left upper lobe mass and some bilateral lymph node involvement. So she had a CT-guided biopsy but the pathology came back and said, quantity insufficient. So they didn’t get enough tissue. And we always say in our field all the time, tissue is the issue. You have to get tissue of some sort so that you can do the appropriate molecular testing. And she was so anxious. She was like, “I don’t want to wait.” We did a liquid circulating DNA, a liquid biopsy, a blood test to see what her profile was, but that was going to take a bit of time. And actually her first workup was done at another facility where they had to send out the biopsy so it could have taken as long as 10 days. And she was so anxious and she did not want to wait for the results to come back and she was like, “Please, just start chemo, start something right away.” And we really had to spend time talking with her saying, “Listen, you’re a nonsmoker. Like the chances of you having an activating driver mutation are really high here. You have no other risk factors so please, please let’s wait.” And so that shared decision-making and that counseling with her was significantly important. And the liquid biopsy did come back and she did have an EGFR mutation at exon 19. I think we’ll probably get into the different exons a little bit later, but it was important for us to know the specific kind of EGFR mutation. So not only was it EGFR, but now we know more and more about the different exons that are affected because that will help us pick treatment. And so she actually was able to be started on osimertinib and had a dramatic response. So she had very diffusely metastatic disease, had a dramatic response, and I think very grateful that we were able to have her feel comfortable enough waiting that period of 10 days before she got started.

Another patient, a little bit different of a presentation, but she was a woman in her later 50s, early 60s, very active, working full-time, traveling, had this extensive social network and adult children and grandchildren, et cetera that she wanted to see. But interestingly enough, she was somebody who earlier on, several years prior, had had breast cancer, a localized breast cancer, and had received adjuvant chemotherapy and did not do well on the chemotherapy. Had a lot of side effects and she just almost had like PTSD kind of reflection on that and so she wanted to avoid any chemotherapy as long as she could. So fortunately, she did have an EGFR mutation and we were able to offer her targeted therapy, and she had one of the activating mutations, L858R, which is a subtype of that EGFR. She started the osimertinib and she also has had a great response. She’s actually been on it for a bit of time now and done well with pretty tolerable side effects.

DR LOVE: I’m curious, Jillian, what you do see, particularly in people who are able like many of these patients to take these drugs for a long period of time, the typical types of side effects and issues you see with osimertinib?

MS THOMPSON: Right. So with osimertinib typically we see more in the beginning of treatment. We may see things like diarrhea, rash, things like that. We notice that some of the later effects are happening more like the nails, paronychia, the splitting of nails and things like that. There are some rare cases where we have patients that may have a more longer course of the diarrhea, rash, typically become more mild over time. So that’s something that’s very important is monitoring those toxicities and managing them well because ultimately this is a better tolerated drug as long as you’re managing those toxicities and that’s what we want. When we think about treating our patients, we want to maximize the benefit. We want them to have full productive lives and being able to carry on with their regular lives with something like a pill that can be easily managed.

DR LOVE: So Alex, we want to move in a second into localized disease, adjuvant, also post chemoradiation therapy. But one other thing I want to just bring out here is the issue with a patient who needs to be treated right away before you get, you know, it takes a few days usually to get the results back. We mentioned liquid biopsy that comes back quicker than the tissue. But either the patient is so nervous they can’t wait or they may be so sick, they’re in the ICU, they’ve got tamponade, whatever, you just can’t wait. But the one thing that we’ve kind of learned about is maybe to hold off. Most of these people are going to get immunotherapy as well, right? Well, typically lung cancer chemo would be with immunotherapy. But we learned a different thing about these patients in terms of not only that they don’t benefit by immunotherapy, but if you start immunotherapy and then you find out they have EGFR mutation you may have a problem with toxicity, more toxicity from the osimertinib. So can you kind of explain that deal?

DR SPIRA: Yeah. So what we’ve learned really through retrospective studies is that when you give immunotherapy followed by targeted therapy within a relatively short window, probably about up to 2 to 3 months when most patients receive this, the increased risk of toxicity, particularly pulmonary toxicity, is real. I think it’s around a third of patients, give or take, have grade 3 toxicity, which is requiring steroids often usually in the hospital. So it’s a real number. So I think we’ve done a pretty good job as a field of educating physicians, nurses, APPs, regarding the importance of holding off on the immunotherapy, really in anybody but especially patients at high chance of having an EGFR mutation such as a nonsmoker. If something happens, it’s not the end of the world. I think you counsel your patients. You go over all that. And the reality is that two-thirds of patients will do fine. Most of those patients, even if they have a grade 3 toxicity, almost all of them got better. You obviously try and avoid it. But it’s very important to remember that — I tell everybody there’s no emergency in giving somebody a single dose of immunotherapy. They can all wait. If it’s an emergency, give them chemotherapy first.

DR LOVE: Right. And so as we were talking about typically in oncology we find things that work in late-line metastatic setting, then we move it into earlier metastatic disease, then down to often locally advanced localized disease and then even into the adjuvant setting. Many solid tumors this week that we’re talking about follow that approach. But Marianne, one of the things that’s different, and Alex is about to present a patient who had adjuvant osimertinib, is when you use adjuvant some of these people are already cured. So whatever risk you’re introducing some of these people are getting a therapy and they’re already cured and we don’t know who they are. Any thoughts about how people process adjuvant therapy, Marianne?

MS DAVIES: So I think that’s certainly across all of our patients when you talk about adjuvant therapy. So they’ve had their surgery, they’re resected, presumably they are disease-free at that time and so to give adjuvant therapy is associated with a risk factor. Any of the drugs that we give, whether it’s targeted therapies or antibodies or chemotherapy, there is a risk of those side effects. And with some of the agents that we use, there is a potential for even some long-term or even permanent side effects. So patients really need to be educated about that risk factor and we talk about, what is the benefit? What is the long-term outcome or the potential for a progression-free survival and overall survival by taking this adjuvant therapy? So helping them to explain that there could be kind of aberrant cells and some remaining cancer cells that we just don’t have the ability to detect on our current scans. And so this is kind of our insurance policy to kind of wash out those extra — give them a little, buy them extra time if there were any of those aberrant cells.

DR LOVE: And in particular for a long time now cisplatin-based adjuvant chemotherapy has been used in non-small cell lung cancer, not the easiest experience to go through, and pretty minimal benefit. It’s there. It’s statistically significant but not so much, Helena, and yet the trials that came in on osimertinib adjuvantly the patient could have adjuvant chemo or not. A lot of docs and patients looked at that and said, “I’m getting this huge benefit out of an oral drug that’s not toxic. Why should I take cisplatin for a couple of extra points?” What’s happened in terms of — earlier on I was seeing the general oncologists not using chemo but the researchers still were because that’s what the trials did. Are you giving chemo to these patients?

DR YU: Yeah, I think just, you know, while we were preparing, I think Alex and I disagreed there. I mean I think even, I mean osimertinib is a landmark kind of treatment option for early-stage disease but even with that you still don’t cure most people with early-stage disease. And so for me, it’s every little added benefit I can give these patients because this is the only time that cure is in the options, right? And so I feel like I would want to do everything I could for my patients. If there’s that little added benefit, I discuss that with them. And that’s focusing on higher risk, so like stage IIB, stage III where you really want to give them whatever you can give them.

DR LOVE: Again, shared decision-making. This is really the patient’s decision whether they want to do this or not, not ours, it’s theirs. They’re the ones who’re going to go through it. So let’s hear how this played out with this patient, Alex.

DR SPIRA: Yeah, so it’s a very straightforward case. It’s a 60-ish-year old woman, good family support, a couple of kids, a few years older than me, presented with stage 2 non-small cell lung cancer, underwent —

DR LOVE: Non-small cell? I mean, nonsmoker?

DR SPIRA: Nonsmoker. Nonsmoker.

DR LOVE: How was it picked up?

DR SPIRA: I’m sorry?

DR LOVE: How was it picked up? Was she screened or —

DR SPIRA: Cough.

DR LOVE: Cough.

DR SPIRA: No reason to screen in a nonsmoker.

DR LOVE: Right.

DR SPIRA: So she underwent resection and came to us stage II resected disease and found to have an EGFR mutation. So the question is, where do you go from here in terms of adjuvant therapy? Clearly at that point we knew about adjuvant osimertinib and that was on the table. The real question was the addition of chemotherapy, typically cisplatin-based at that time. So we had made the decision, as would everybody, I’m sure, to give osimertinib. But what do you do about the chemotherapy part? And I think a couple of decisions. One is, you know, it’s always the cisplatin versus carboplatin debate, which you probably have had in many of these. I think you give the cisplatin. I admit I probably swayed the patient a little bit. I’m also from the era — I remember when the first study was called the IALT study, which again antedates a lot of people. It came out, I think, in 2004 or late 2003 of adjuvant platinum-based therapy. They actually used cisplatin/vinorelbine was the big one that was used, if you can believe that. And the overall survival improvement was measured in single digits. And maybe I’m biased by that but again you talk about the benefits of chemotherapy, which is probably in the 4 to 10% range clearly overshadowed by EGFR-based therapy. The randomized study of osimertinib versus osimertinib with chemo has not been done, right? So patients on the original adjuvant study were allowed to get adjuvant chemotherapy if the physician wanted but a lot of people did not do that. So in my mind, given all that, we decided together that we would not give adjuvant chemo, although that was my swaying them a little bit to get there, which is I think what the oncologist’s job is, right? It’s not just our job to read the facts. Our job is to tell them what we would recommend but leaving it open.

DR LOVE: I was just sort of fantasizing, you know, patients all the time say, “What would you do if it were you?” So I was kind of fantasizing if that patient said to you and to Helena, “What would you do?” I’m kind of guessing what the answer would be.

DR SPIRA: I think the question was not exactly that, but it’s what do you think I should do?

DR LOVE: That’s another way to do it.

DR SPIRA: And it’s also, you know, when you’re recommending — if you have to recommend for chemotherapy that’s a much bigger step. It’s very easy to recommend against chemotherapy because it’s going to be a lot easier. So it’s a little bit easier to sell than upselling the chemotherapy part.

DR LOVE: One of the questions that was out there is whether or not in the long run these people would live longer. Maybe they could just not take adjuvant therapy. It has such a great effect when you use it in metastatic disease, maybe it would be better to just wait but you can see this paper came out last year showing they actually live longer, which nobody was really sure — and significantly longer. We’ve been talking about hazard rates so here again is a typical survival curve. So the top one in red is the patients who got osimertinib. Underneath the people got placebo. And you can see at 5 years at any point in time hazard rate 0.49, so that’s about 50%. So any patient at that point in time whether it’s 16 months later or 2 months later, their chance of being free of relapse is 50% or better. Not an absolute benefit, relative 50%. And so that’s the benefit people have to consider when they’re trying to decide whether they’re going to invest their time and resources in this. And again, pretty significant benefit, at least at this point.

Here's another thing, actually this is what happens in oncology. The way we learn about new trials is the first thing is they put out a press release. So as soon as they see that a trial is positive even before they can report it they just need to let the public know for a variety of reasons. So we saw this in February that this study that looked at using osimertinib in locally advanced disease. So we were just talking about locally advanced this morning. I can’t even remember what we were doing, but, in any event, we were talking — oh yeah, head and neck cancer. Okay. So, but, in any event, it looks, Helena, like and actually we just checked the ASCO paper, the schedule came out this morning. There are only 4 papers in the ASCO meeting that are called plenary. This is the big session they have on the best papers of the whole meeting, all of oncology, 2 are lung cancer this year. So one is this, which you guys are going to explain, but I’m just going to mention the other one because maybe we can talk about it at the end. I love this. This came out at MGH, well, I don’t know about this paper, comparative effectiveness trial of early palliative care delivered via telehealth versus in-person among patients with advanced lung cancer. So they had demonstrated it, starting palliative care at diagnosis to try to help with symptoms, et cetera. These people lived longer. So now this is a big paper they’re doing that they’re trying to do it with telehealth. Helena, that makes so much sense. I mean, I guess there are confidentiality issues. I don’t know if everybody would be comfortable, but theoretically you should be able to access so many more people. Any observations before you get into this stuff?

DR YU: Yeah, I mean, I think it’s the people who might have more difficulty coming into clinic and people who aren’t mobile that need that supportive care. So I think this is huge and it fits with what we do. Like I have my nurse call my patients to check in. I think the more that you’re on top of symptoms, the quicker you can respond and try to help people feel better.

DR LOVE: Do you think that that paper affected the way people take care of lung cancer? I mean just the fact that palliative care helped — as a matter of fact I remember Tom Lynch at the time said if this was a drug we’d be giving it.

DR YU: Yes.

DR LOVE: So do you think people have picked up on it, Jillian?

MS THOMPSON: Well, the institution I’m at, Georgetown, and actually our palliative care team has a telehealth focused program and they are doing something similar and it’s actually been very helpful to us because we work collaboratively together. Because in the midst of all that we’re doing, sometimes it’s difficult to be able to manage the aspects that come along with palliative care. So I think that there definitely is a benefit in doing that and time will tell. The program is fairly early, but I think time will tell how well it works to have that opportunity to do it in that way.

DR LOVE: I’m curious about your thoughts, Marianne? It’s not just palliative care, it’s the idea behind like, what are you doing there? And why is it that they’re living longer? Are they taking better care of themselves? Are they less depressed? Any thoughts?

MS DAVIES: So I think it’s a combination. So I’m not surprised that the paper came out of MGH first of all because that work was done several years ago to show that even in face-to-face palliative care introduced at the start of diagnosis improved overall survival in our patients with metastatic non-small cell lung cancer. And so I think probably what helped move that along is the pandemic. We were forced to use telehealth to meet these patient’s needs. And so now the study is showing that. I think it’s particularly advantageous for our patients that have these EGFR mutations because, in general, if they’re really doing well at home, they don’t have to come into the clinic as often. We can sometimes see them like once a month, and if they’re doing well maybe every couple of months because they’re really handling and living with and surviving with their cancer, but they need that extra layer of support. So having somebody check-in to make sure their emotional needs are met and making sure that the other side effects are identified early and that they’re managed, then we can successfully keep them on the therapy potentially for longer with better outcomes. So it really kind of makes sense having that extra layer of support to keep people living in their life and not having to make it all about coming into the clinic all the time to get that extra support.

DR LOVE: So this paper really reflects a lot of what we’re going to talk about and again this is going to be one of the big papers of the year that’s going to be presented. So, Helena, and we were talking about the fact that for some reason patients who have EGFR mutations they may have a high PD-1 level but they don’t tend to benefit from immunotherapy and we don’t really know why. So a few years ago, and we were talking about this morning with head and neck, because the first time we saw this strategy was in lung where you have locally advanced disease, not amenable to surgery but treatable and with some people with long-term response a significant number. And the first trial to show immunotherapy can be helpful after chemoradiation was in lung cancer, the PACIFIC trial. Big benefit in these patients by giving immunotherapy after chemoradiation. Not so much clear that that was going to happen with the EGFR or other targetable patients. They didn’t have that many patients in there. Subsequently a lot of work was done and now we have this paper essentially, I guess, with substituting osimertinib for immunotherapy.

DR YU: Yeah, I mean, I think it makes sense because we think of stage III obviously as an extension of the surgically resected IB2 and 3 so if we saw such a marked disease-free survival and overall survival benefit in the surgical setting it just makes sense that we would see that benefit here. And I think when we saw that PACIFIC study, the one subgroup where we look at different subgroups in a clinical trial to see if there are certain patient populations that might benefit more or less, one of the ones that could have went towards placebo in the PACIFIC trial was patients with EGFR mutations. So that was always a question and this study clearly definitively answered that. That rather than durvalumab immunotherapy we should be giving osimertinib.

Established First-Line Therapy for Metastatic NSCLC with an EGFR Mutation

DR LOVE: So let’s go on now and move forward into metastatic disease. I think that this paper that we just talked about is maybe not only going to change management of patients with EGFR mutations, Alex, but all the other — I don’t know, are we going to be able to do a trial in all these other mutations? Or do you think people are maybe going to just start applying this strategy?

DR SPIRA: I think people are going to start applying the strategy. I mean it’s kind of tried and true right now, and I think it’s where we are and that’s where the field is taking us.

DR LOVE: It also gets into this question of how much clinical research information do you need in order for the FDA to approve it or for us to be able to recommend it. You can imagine all kinds of things, but we want to get these therapies to patients as well. Let’s talk about disease in the metastatic setting and sort of similar story in terms of how effective it is but here in the metastatic setting you have another very important consideration and again we were talking about this Wednesday night in breast cancer, it’s a theme throughout many tumors, brain mets. So Marianne, can you comment a little bit about kind of where brain mets fit into the picture of lung cancer in general but particularly in these EGFR patients? Generally, when you see brain mets, the first thing people think about is radiation, either stereotactic if there are a few small ones or whole brain, which, of course, people want to avoid because of potential toxicity. So can you kind of tell what happened and talk about what happened over the last 5 or 10 years in terms of people with targetable mutations and brain mets.

MS DAVIES: So what we have seen in most of the trials with people that have actionable mutations and particular EGFR is that taking a drug such as osimertinib it has really good blood/brain barrier penetration. And so for patients let’s say that have either really mildly symptomatic brain mets or asymptomatic brain mets, meaning maybe it was found because you were doing the whole workup. You did the whole CAT scan and then, just to do your due diligence to see what level of disease they had, you did an MRI of the brain and you found what they call incidental. It just happened to be there, asymptomatic, meaning no neurologic findings. And so if that patient has that mutation, we can actually see excellent responses in the brain with the osimertinib with that penetration. And so that you can actually then really save that patient from having to through something such as the Gamma Knife radiosurgery or that targeted stereotactic radiosurgery with the potential side effects that go along with that. So it’s really again revolutionized how we treat these patients. We don’t have to run right to radiation and we can still see good, really durable long-lasting outcomes and response in the brain.

DR LOVE: It’s interesting, Wednesday night here when we were doing a breast cancer session, we were talking about how brain mets are managed in non-small cell lung cancer and they were just beginning to think about the possibility. I mean, it was kind of scary there in the beginning. People that typically go right to the radiation department and you’re giving them prescriptions for a pill, it’s kind of scary but it seemed like it worked, Helena. Now almost pretty much standard of care. What are the situations where you go to the radiation? How much symptoms do they have to have before you’ve got to radiate?

DR YU: I mean, that’s a shared decision-making with the radiation oncologist. I think usually it’s a certain size, like if it’s above 2 cm, if it’s in a location that’s really important like brain stem where if it grows a little bit there’s going to be a big neurologic issue. If somebody has had a seizure. So those are what kind of prompt us. But anything that’s less than 1 cm and largely asymptomatic, we always defer and just give the TKI.

DR LOVE: When you start osimertinib on a patient whose got a bunch of brain mets are you expecting they’re going to shrink?

DR YU: Yeah, I am. I mean the intracranial response rate or shrinkage rate is the same in the brain as it is in the body. So we have a very good chance of those brain mets responding.

DR LOVE: I’ll say this took a while to sink in because it was so different. But let’s hear about how it played out. Alex, 45-year-old man. I guess these people tend to be younger.

DR SPIRA: Yeah, so I had a 45-year-old gentleman, perfectly healthy, couple young kids at home, presented with I think cough or symptoms and had a chest x-ray that kind of led him to us. Maybe had a few neurologic symptoms, hard to kind of tell and tease out because we obviously knew what was going on. But he was otherwise doing well. Nonsmoker. Long story. Stage IV disease. Had a couple of bone mets and had a few brain metastases, the largest of which was 1.5 cm. Maybe a little bit of swelling there. Maybe a little bit symptomatic. Kind of hard to tell. One of these things, if you pressed him, he may have been — obviously, we’re asking, are you having any symptoms? And obviously, pressed with the question is, how do you proceed? Do you give him osimertinib as front-line therapy or do we ask our radiation oncology colleagues what to do? I made the decision with him to defer on radiation. Gave him a little bit of steroids. He got better and he currently has an ongoing response now at about a year or so and actually doing very well.

DR LOVE: What’s his life situation?

DR SPIRA: Married. White-collar employee. A couple of kids at home. Very good support.

Newly Approved and Promising Investigational Approaches to First-Line Therapy for Metastatic NSCLC with an EGFR Mutation

DR LOVE: Interesting. So let’s hear about a couple of other cases. Marianne, you have a 52-year-old surgeon, which caught my interest, anytime healthcare professionals are the patient. Can you talk about what happened with him?

MS DAVIES: Sure, so this gentleman is a 52-year-old nonsmoker. Very, very active, is a skier and just very active lifestyle with 2 young children at home as well, but again he’s a general surgeon. He had an orthopedic injury and was going in for a chest x-ray for the surgery screening and found incidental metastatic non-small cell lung cancer and had a biopsy and he was EGFR positive. And so there was a lot of shared decision making in this case. He wanted to obviously do everything possible to be very aggressive because his children are small, but you’re weighing that with, so do we do osimertinib on its own or do we combine that with chemotherapy? Actually, recently a study came out called the FLAURA2 study, which showed that with the combination of the osimertinib and the chemotherapy increases progression-free survival by about 8 months. And so he was like, “I want to do everything I can. However, with the caveat that —” so the chemotherapy arm was cisplatin, pemetrexed and osimertinib and we all know that cisplatin has got that risk of peripheral neuropathy. And he’s like, “I’m a surgeon and I ski and I really don’t want to risk having that neuropathy impacting my career and my hobbies.” And so kind of negotiated or had that shared decision making and so the decision was to give carboplatin, pemetrexed and osimertinib. Typically, those platinum-based regimens you do 4 cycles of that combination and then you go onto the maintenance arm, which is the pemetrexed and the osimertinib. So at this point the patient has had a fabulous, fabulous response. They finished the 4 cycles of the full combination and now on the maintenance therapy and doing very well. Has continued to be very active doing, well right now we’re not in ski season, but being very active with his children and able to work and really minimal toxicity profile that’s associated with it. So I think you have to just understand your patient and understand what their goals of care are and making those decisions and what their lifestyle is and all the impact. Had he been a person let’s say who’s 80 years old who had chronic kidney injury and had already peripheral neuropathy and had other medical conditions then you might say, “Okay, maybe that’s a patient that we can say let’s just do osimertinib on its own. Like maybe we shouldn’t be giving you chemotherapy.” But again, that’s all that shared decision making and balancing that with the risk profile.

DR LOVE: So one of the themes we deal with over the years at ONS and every single one of the 8 nurses in this supplemental program comments on it is patients with minor children or grandchildren. Just kind of curious how that dynamic played out with this patient who even though he has a disease that is very treatable, it’s not curable.

MS DAVIES: Well, for this particular patient with children are younger and doing well. But I was sharing another case with you earlier today that a patient with stage IV disease had children that one of daughters, 3 kids, but one of his kids was about 13 years of age and really struggled emotionally. Was not doing well in school, was having kind of self-destructive behaviors. So it really took a lot of work on the part of our nurses and our triage nurses and our social worker and really the whole team to help provide some additional support for that family to not only help the patient get through but also helped the family members in trying to identify resources in the community so that you can help that child to really adapt and really be able to live with the fact that her father had this life-threatening illness and how is she going to carry on. So it was really very emotionally charged for the entire team wanting to make sure that you kept that family as whole and as healthy together as possible.

DR LOVE: We have a couple of other patients here that we’re going to present with small children. Actually, tomorrow night when we talk about colon cancer, some of the videos are going to relate to these types of challenging scenarios. So the surgeon, his kids were younger, 4 or 5, and too young to understand?

MS DAVIES: They were too young.

DR LOVE: At that age do you start talking to the kids do you think they can begin to comprehend what’s going on?

MS DAVIES: Typically more of the middle school. As soon as they have kind of that intellectual capacity to start processing and they’re more on the internet so they’re doing some exploring on their own as well and Googling so they’re saying, “Oh my goodness, my parent has stage IV non-small cell lung cancer.” And so they may have the ability to look up things and see that information but not the sophistication to understand the nuances of the subtle other types like those that are molecular driven lung cancer. So I think we just have to it just really reenforces that we need to understand what the patients are experiencing. So this particular patient, the surgeon, his children were too young. He had a really excellent, excellent support system and was able to really help with those young children. But others don’t maybe have that, and so we need to just keep that in mind because that impacts the patient’s ability to even be compliant with or adherent to their treatment regimens if they’re really challenged.

DR LOVE: I’m trying to think if we’ve done a program before just on EGFR because I’m looking at all — this looks like a breast cancer series of ages. Everybody’s under 50. We did a thing on Wednesday night. All the patients were under 50 in breast cancer and then here it is in lung cancer. They’re all under — I mean I’m not saying everybody, obviously you can be older, but Helena you have a 46-year-old woman, young kids, brain mets.

DR YU: Yes. Same thing except this time the patient really presented fulminantly. So she had a pericardial effusion, so fluid around her heart, that was preventing her heart from beating appropriately. She had to get that fluid drained. She was in the ICU. She was on high-level oxygen support, so really sick when I met her, and so she was willing to sort of do whatever I suggested in terms of managing her care and getting her feeling better. So she is someone with the brain mets, very high burden of disease. She ended up having an EGFR mutation so we did do the osimertinib and the chemotherapy, as you’ve heard about just recently, and she did really well. And this is an interesting case because she did so well and she became pretty close to baseline after the first 6 months of treatment. But then with pemetrexed, we sometimes see longer term toxicities where we can have swelling in the legs or redness of the legs, the kidney function can start to decline and the creatinine creeps up. So we had to take off the chemotherapy and that actually was really hard for her because I think just having that control of my disease being controlled and now you’re taking away something that might be what was helping my disease. So that took a lot of counseling, but she is still doing well on osimertinib.

DR LOVE: So I was imaging what it was like the day she walked into clinic feeling completely fine. When you reflect back on her with cardiac tamponade and the question that I ask all of these nurses, isn’t oncology depressing? I mean yes this is a very challenging, horrible situation but this lady has an opportunity for hopefully awhile to have a normal life.

DR YU: That is the Lazarus effect that you mentioned, right, Neil? I think the fact that you can get people so sick and so quickly get them feeling better. It’s pretty amazing.

Common Toxicities Associated with Amivantamab

DR LOVE: So let’s move on to some of the things that are new and one in particular very, very interesting drug, Alex. We’re hearing about bispecifics all over the place in lymphoma, myeloma. We were talking about that — is this Friday? I guess it was last night — we spent an hour on bispecifics but these are immune bispecifics. But this is different. Can you explain first of all what a bispecific is and what amivantamab is?

DR SPIRA: So amivantamab is a bispecific and that basically means it has 2 heads. So an antibody has 2 things shaped like a “V” at the top part and here’s a great picture, thanks Neil, and you can see most of them are similar so they’re usually a blue and a blue or a green and a green. This has a blue and a green. And these are now, again I’m dating myself, but you know making antibodies 25 years ago was an incredible task, now you can make millions of these in any which way combination. So the original idea, very simple, was to develop a new antibody against EGFR. We know that one of the major mechanisms of resistance in patients with EGFR mutations is to develop MET overexpression or secondary mutation. So fast-forwarding a step, they made an antibody that would hit both, EGFR and MET. The first development of these EGFR antibodies was for amivantamab and approval was actually in exon 20 insertions.

DR LOVE: That’s a different type of EGFR?

DR SPIRA: Different type of EGFR.

DR LOVE: We’re going to talk about that in a minute.

DR SPIRA: Yeah, and very simply, it was easier because there was nothing approved. So that was an easy thing to do. Nothing approved and it got its first approval in that. Of course, there are many, many more patients with the typical EGFR activating mutations, exon 19 and 21 are the common ones we’ve alluded to today, but in essence this is a new way of attacking EGFR. It has a couple different mechanisms of action I won’t go into. Very fancy slide there on the right. But it was really designed to overcome EGFR resistance and being studied in many different ways. First, post EGFR therapy and now in lieu of EGFR therapy in the front-line setting as well. Of course, one of the things you have in the slide, lazertinib. Lazertinib is a TKI, very similar to osimertinib but the idea right now is not only can you use this as a way to overcome resistance but also what happens when you combine it with lazertinib as well, so combining with a TKI. So lots of different ways of applying this as you can imagine.

DR LOVE: So Helena, maybe you can talk a little bit about some of the data but also what this actually is. These other bispecifics are much more common out there right now. One part grabs the tumor with the target and the other grabs an immune cell to try to bring them together. This thing is getting 2 parts of the same cell.

DR YU: Yeah, so we’re going to talk about antibody-drug conjugates later, which is kind of like antibodies 2.0. But yeah, exactly, I think that we know that MET and EGFR are often together on the cell surface and so combining one antibody that targets both is really going to kind of extra home in on these EGFR-mutant lung cancer cells.

DR LOVE: So this is a paper presented last fall at the ESMO meeting in Madrid combining these two agents. So again remember lazertinib is very, very similar to osimertinib so you’re kind of getting a double attack on the cell. But where we talk about the data just kind of curious, Jillian, what’s been your experience in terms of tolerability with ami?

MS THOMPSON: So people typically are tolerating it well. Now, the one thing that we do know is typically in the beginning the first cycle infusion reaction so it is divided dose. Typically we get them over that. They do pretty well. Commonly what I’ve seen is rash, some swelling have been the most common side effects. Most of our patients, it’s usually mild and tolerable with minimal intervention. So it is something that we’ve been successful in using.

DR LOVE: So this study, randomized patients they got either osimertinib or lazertinib, which is very similar, but plus amivantamab. Before you go into what they saw there, Helena, can you just globally compare the experience that a patient would go through on each one of these arms?

DR YU: Yeah, one thing that I don’t think we said outright is that amivantamab and most antibodies and antibody-drug conjugates are intravenous therapies and so that is a big difference for the patients, right? The TKIs are pills that you take every day at home but these are medicines that actually upfront people have to come in quite frequently for. It’s weekly for 4 weeks and then it’s every other week. Marianne mentioned the infusion reaction, which is, I think, unique with that but that’s the main difference, IV versus oral.

DR LOVE: Can you talk about exactly what they saw, Alex, in terms of the tolerability profile and where you think this is heading?

DR SPIRA: So we’ve already had approvals for this so there were really no surprises here in terms of tolerability. So the biggest side effects you see from amivantamab are related to the EGFR therapy so paronychia, rash, diarrhea, acne rash, you can see them all here, a little bit of stomatitis. Very similar to cetuximab if you want to take from our colorectal cancer colleagues. But these are the things we typically see with cetuximab. Of note and just as a complete aside, not really, you know, there are a lot of theories as to why cetuximab doesn’t really work for these patient population but it really has never shown activity and it kind of fell off the radar screen although again similar MOA just in terms of the EGFR. Another matter in the side effects as well, because this is a bispecific and hits MET, almost any molecule that hits MET, including if you look at the other MET compounds, tepotinib or capmatinib, can cause edema and hypoalbuminemia. So that’s what you really see when you’re giving it here. And as you can see with MARIPOSA, the study clearly showed improved outcomes, progression-free survival. We’ll probably see improvements in overall survival. The curves were close. With time I think we’ll get there. And the ultimate question is a couple of things is very similar to when you’re giving platinum-based therapy with osimertinib we know it works better but is this for everyone? Much like your surgical case. Should everybody be getting advancement of therapy? And now we’re likely going to have 3 choices, chemo/ami and amivantamab/lazertinib as well as osimertinib by itself. And the fundamental question is, it is worthwhile to give everybody the increased toxicity and of course increased challenges of IV drugs? Is there a select set of population and, of course, your study, Helena, looking at patients that may not respond as well and then adding things on. So you ask, Neil, about where do I think things are going to go and what do I think? It is as I say complicated and I think there’s going to be a lot of debates at these events and other events as to whom should get what and hopefully we’ll be able to figure it out. We would love to offer, like your surgical case, better outcomes to patients but is that for everybody? That goes into are you a 75-year-old person that lives alone and lives an hour away from clinic versus a 35-year-old patient that’ll say, “Just give me anything, Doc. I don’t care about side effects.”

DR LOVE: I was thinking about that surgeon, Helena. Do you think if you had no problem accessing it, if you explain the risks and benefits, would you say, I think this might be a little bit better?

DR YU: Yeah, I think that — they haven’t been compared head-to-head in terms of chemotherapy and osimertinib and the MARIPOSA, the amivantamab and lazertinib, so I think it’s kind of talking to your patient about what side — like if someone really doesn’t want neuropathy but then maybe the ami/lazer combo makes more sense, but if someone has a job where people are looking at them all the time they might not want the rash. So I think you have to sort of think about what is most important for your patient to make that decision.

DR LOVE: Do you think your surgeon would have wanted it? The combination?

MS DAVIES: I think if it were offered, probably. I think he would have selected that, but keeping in mind it is a pretty demanding regimen in the beginning as well as has been pointed out. It’s 2 days in a row the 1^st week and then weekly for the first 4 weeks and then every other week, 5^th week and then every other week. So the chemotherapy arm that he was on was treatment once every 3 weeks. So I think that might have played into his decision-making as well.

DR LOVE: Yeah, we presented a case a couple of weeks ago, a breast cancer patient who went through everything, neratinib even, and Joyce O’Shaughnessy the first thing she said is, did she have kids, which she did. Because she said people who have kids they just drop it. They’re going to do everything they can. I’m sure that’s not a hard and fast rule. But let’s just talk a little bit again about what happens when people get the ami, as we call it. So, Jillian, you have a 67-year-old woman who actually responded briefly to ami/lazertinib. How did she tolerate it? How did she do on the therapy?

MS THOMPSON: She actually tolerated things pretty well. There didn’t seem to be a significant difference of the combination of the amivantamab with the lazertinib as far as like it being elevated. Now this clinical trial included chemotherapy so they also had some of the chemotherapy side effects. But overall tolerated it well, and did have, it was about a 7-month period of response before progression. So we look at it from that standpoint. It gave us additional options of treatment and it was 7 months where the patient was doing relatively well and having this additional option of therapy.

The Current and Future Management of Progressive NSCLC with an EGFR Mutation

DR LOVE: So we sort of alluded to the fact that even people who do relapse after receiving either osimertinib or this newer combination of ami/lazertinib are going to develop progressive disease but, Helena, what we’ve seen is there’re still some patients who are going to respond to targeted therapy. A lot of times we’ll do a liquid biopsy to see if there are any mutations that have developed while the patient might have been on osimertinib for 3 or 4 years, et cetera. But then we start thinking about what’s next. And also in view of the fact that we think they’re not going to respond well to IOs so immunotherapy. So how do we think through the next line?

DR YU: Yeah, so when someone is progressing on osimertinib or a combination with osimertinib first if it is oligoprogression, where there’s only 1 or 2 sites that are growing, and the rest of the disease is stable, I always try to treat that, you know, the growing lesions, and continue the osimertinib for as long as possible. And about a 3rd of patients that is a reasonable viable option for them. When somebody is clearly progressing, I do like to do a tumor tissue biopsy after osimertinib. We see different types of resistance mechanisms. One rare one that we see about 15% of the time is the change in histology where a tumor can be adenocarcinoma and it actually completely changes to a small cell or squamous cell. If you’ve seen it it’s pretty dramatic and you’ll remember it, but that needs to be treated differently and you can only see that on a tumor tissue biopsy. And then we send off mutation testing. And sometimes we can find things like MET amplification where we can add in a MET inhibitor. Usually I tell my patients we do the biopsy, it’s only about a quarter of the time where that changes our management but that’s still enough to want to do that. And then there are some novel therapies including amivantamab and also some antibody-drug conjugates that patients can choose from after osimertinib.

DR LOVE: So in terms of amivantamab first of all, Alex, I’d love to hear about your 63-year-old woman who first got osimertinib then ami/lazertinib. If you can discuss her. I will mention though, Marianne, this is interesting here. There are like 6 or 7 major papers on ami at ASCO, but here’s the one I think is interesting, subQ ami. I did not know that. Do you know that?

MS DAVIES: Well, I did know it only because of recently —

DR LOVE: How do you think that’s going to affect things?

MS DAVIES: I think it’s going — so I’m really curious about the side-effect profile it’s associated with that I haven’t really read the data on that yet. But certainly —

DR LOVE: It hasn’t been presented yet.

MS DAVIES: So I just think as somebody who helps run an infusion center, like, we have a hard time getting all our patients in that need to be in for infusions. And when you look at the demands for amivantamab, like, 2 days in a row and then weekly it’s like really, you know, sometimes the infusion center can be kind of squeezed tight. And it’s like, where do we fit these patients in, especially since the first 2 days are quite long, lengthy days? So if we can somehow give this in a subcutaneous way and the patient’s in and out of clinic, oh my gosh, that is practice changing. It has so many downstream benefits for the patient, for the staff, for all of you. And so I’m really hoping that the side-effect profile is going to be just as impressive.

DR LOVE: Yeah, whenever I hear about subQ stuff, the first thing I think about is daratumumab in myeloma. Because these people would be in the clinic like all day long and now it’s just like they’re in and out and it’s completely different. So Alex, what happened with this patient who got ami/lazertinib?

DR SPIRA: Yeah, so this is a 70, a little older patient than some of the other ones, not 50, I think 63 here, who was on osimertinib for a while and had progression of disease. We talked about oligoradiation and clinical studies. To be candid, I can’t remember which clinical study because we’ve got a bunch of them, but the patient got lazertinib and amivantamab at that time and had a response. It was not a huge response, but the patient clearly responded for a while. Was on it for about 6 to 8 months and subsequently, unfortunately, like most of our patients, did progress and ended up going on another clinical trial at that point. He did pretty well. He did have the major side effects that we’ve alluded to today. Day 1 he had a mild infusion reaction that we managed. If you haven’t seen it, it can be pretty pronounced that first day as long as you’re comfortable in managing it. Patients do fine, but it can be pretty scary if you’re new to it. Had a little bit of rash and skin changes. We did require some monitoring that did change his life a little bit, but he actually did very well for quite some time on the combination.

DR LOVE: So we also want to talk about another entry into the field. We were talking about this. I can’t even remember, let me see, HER3, where were we talking about HER3? Do you remember? Some other cancer. I’ll think about it in a second. But in any event, targeting HER3 interestingly in lung cancer as well. So Helena, can you talk a little bit about what patritumab is and also what antibody-drug conjugate is? Oh yeah, breast and lung we were talking about it.

DR YU: Yeah, so antibody-drug conjugates when I talk to my patients I tell them that this is really a hybrid between chemotherapy and targeted therapy, because it has an antibody, that is the targeted therapy portion that’s linked to a payload, which is a molecule of chemotherapy and so it sort of delivers that chemotherapy much more specifically to the cancer cells of interest. HER3 is part of the EGFR sort of HER family of proteins and we know that HER3 protein expression is pretty universal in EGFR mutant lung cancers and that’s why they chose to look at HER3 DXd, this antibody-drug conjugate, in this population. And so it was first looked at post osimertinib, post chemotherapy and did show significant benefit for patients in terms of shrinkage and disease control in that setting.

Tolerability and Other Practical Considerations with HER3-DXd

DR LOVE: So Alex, can you talk a little bit — now I remember we did an entire symposium last night on antibody-drug conjugates and we were talking about this as well. This is such a fascinating, you know, we were talking about this last night, fascinating but rapidly evolving field. You’re seeing immunotherapy come in, but at the same time you’re seeing antibody-drug conjugates. We were talking last night about all the different places in cancer right now where ADCs are used, everything from diffuse large B-cell lymphoma, you know, obviously breast cancer, multiple ADCs. Alex, what’s the idea behind an ADC?

DR SPIRA: So I think they’re phenomenal drugs. It’s amazing because you can take any target and any, I hate the word warhead, but that’s the chemo, it’s called the warhead with this linker protein and you can have a million different combinations. And there are a million different combinations out there right now. They are not completely benign drugs. The yin is that they work well and they target things very well. The yang, and depending on the analogy you use and the one I like, is chemo on a stick. So there is chemotherapy here with it as well. And many of the patients have chemotherapy-based side effects. The way that I think they kind of work is you have the antibody, you have the warhead, the chemo part, that’s the target, but then you have this linker and nothing in life is perfect. You need to have the chemotherapy released at some point so the linker has to break down and it can break down in the bloodstream and bottom line is the efficacy is how well it sticks and how little gets broken down in the blood. So you can have chemotherapy-related side effects. You can get alopecia, you get diarrhea, you get neutropenia. There is a very fine line of dose levels. There is not a broad therapeutic index so you have to be very mindful and although most of them are weight-based you can get into trouble with that. They have other things. For example, a common warhead is something called MMAE, which is similar to what’s involved in paclitaxel so you can get neuropathy. Many of them can affect the eye so you can get corneal abrasions and redness. They are great drugs. They’re going to change what we do right now. There are so many in clinical trial, I don’t think anybody could count, but they are real drugs with real toxicity.

DR LOVE: So — and actually we talked a lot yesterday about another topic we’re not going to talk about today, although it is pretty related, which is trastuzumab/deruxtecan, another antibody-drug conjugate that targets HER2 and, Helena, there, of course, we just saw a pan tumor approval. So any patient with a solid tumor who’s run out of options potentially if they have HER2 positivity, and you may only see it in 5% of cases, but any solid tumor they’re eligible to receive T-DXd. Again sort of same second name is HER3 T-DXd. And one of the concerns, Helena, although particularly T-DXd seems to be very effective and very long responses it has a unique toxicity that’s of great concern, particularly in lung cancer patients, which is interstitial lung disease. So I’m curious (a) what your experience is with T-DXd but more importantly also patritumab do you see ILD?

DR YU: Yeah, that’s a great point. I think our patients with lung cancer already have cough and dyspnea and sometimes need oxygen, so it’s hard to tell or diagnose pneumonitis compared to breast cancer and other cancer where you don’t see pulmonary symptoms. So we say that interstitial lung disease or pneumonitis is a class effect for kind of ADCs in general but specifically with that DXd, that deruxtecan backbone, there’s a large range though. With T-DXd, it’s up to 20% of patients get pneumonitis. With HER3 DXd, it’s about 5%. But I think for all of these you have to have your radar — if you’re not telling your patients what to potentially expect, they’re not going to tell you about it. The number one thing to treat this pneumonitis, of course, is stop the drug and then treat with steroids.

DR LOVE: Right, and we were saying at this point, and I’ll just repeat it, there may be people who were here yesterday when we made this point. But you see a patient who’s run out of options and they’re thinking of holding off on therapy or sending them to hospice who has a solid tumor of any type, make sure there’s a HER2 assay on the chart that’s negative because if it’s positive they may have this option and again we see pretty interesting responses. Let’s talk about how the ADCs sort of play out clinically and actually, Helena, I think you have a patient who got patritumab. Did I ever tell you my nickname for patritumab?

DR YU: What is it?

DR LOVE: Because I think that now they’re calling it HER3 DXd. I call it trasthreezumab. A little joke.

DR SPIRA: How long did it take you to come up with that one?

DR LOVE: That’s the only joke I’ve ever made in oncology in my entire life. All right, well, let’s see how this plays out in practice. Oh Marianne has a case but let’s hear about your case first, Helena?

DR YU: I think one highlight for this case is we didn’t talk about it much but there are atypical EGFR mutations, so those are like EGFR exon 18 mutations, which are like 709 or 719. You might see something like S768I. The tough part is for the ami/lazer approvals for HER3 DX-d it’s really only going to be for exon 19 deletion and L858R. And so there are these other mutations that have the same biology but they’re just not allowed on these clinical trials and might not have access to these drugs once they’re approved. So I think that’s a big point. But this patient of mine had an atypical, I think she had an S768I and an exon 18 mutation, and so we already knew that HER3 DX-d was active and they opened a cohort for these atypical mutations and so she was allowed to join at that point and so we just jump at the chance of having more options for these patients. And she did well. She tolerated the drug well. She did have some alopecia. She did have cytopenias, and I think needed growth factor support for a few of the beginning cycles and then she responded for about 6 or 7 months and then ended up coming off but it was a good option for her and again it was one of those she went through all of the standard chemotherapies and right as this cohort was opening it was an opportunity for her.

DR LOVE: So another ASCO paper, ami and lazertinib in atypical EGFR mutated non-small cell lung cancer. That’ll be interesting. I’m curious, Alex, when you have these unusual mutations there’s — there was another TKI I think that was used that had a lot of toxicity. How would you decide between ami/lazer and osimertinib? Incidentally, Helena, I see you have a paper ami/lazertinib related to CNS disease. Does it work in the brain? I guess it should, right?

DR YU: Yeah, it does —

DR LOVE: So Alex. I’m sorry. Go ahead. Do you want —

DR YU: I was just going to highlight that I think we know that half these people with EGFR mutant lung cancer do develop brain metastases and I’m sure if you’ve ever tried to enroll someone on a study, active brain mets or leptomeningeal disease are automatic exclusion criteria. So part of why we did the study was, can we focus on this high-risk population that needs new options and try something that’s available to others? And so that was part of I think the success of the study is that we were able to enroll and it did work.

DR LOVE: I’m looking forward to seeing that paper to see how — it’s like the new approach in terms of CNS. So Alex, again, you have these rare, unusual EGFR mutations. You can’t do like a study that easily on them. How do you decide?

DR SPIRA: You know, it’s interesting. They’re tough though because if you ask 100 oncologists, they’ll give you 110 different answers. The approved drug for the atypicals, the most common one is the exon 18 ones but there’s a smattering of others. There’s actually afatinib, which is the drug I hate to give. If you’ve ever given it — it’s still approved and it’s still out there and many oncologists give it. I don’t know your feelings on it, Helena, but it’s a very, very rough drug. The starting dose is incredibly toxic. I dose level -1. I can’t even remember the dose off the top of my head because I don’t give it anymore. I want to say it’s supposed to start at 45 and I start at 30 or 30 and go down. But I just don’t like giving the drug. A lot of people use osimertinib really off-label and it’s a little distressing because we’ve known about these mutations for a very long time and what should be very easy to do a basic clinical study — in fact, the approval of afatinib, I actually had to look up because we’re involved in another study, is actually based upon a retrospective analysis of 2 old studies called the LUX-Lung group for afatinib. And it’s really a retrospective analysis that they threw everything in and said it kind of worked and it got approved. So I’m all for developing new drugs. We know that these atypicals probably do not do as well as the exon 19s and 21s so there is an unmet need. We don’t know are these going to be any better than the other ones because the ongoing studies aren’t really randomized, but we do need more choices for our patients initially. And common sense being we know that these drugs are going to work. They work across the board. There’s no mechanistic rationale why they shouldn’t work. The trials need to be done and at some point we do need to figure out, which one is better for our patients.

DR LOVE: Yeah, that idea of a pan tumor approval again it just came out. There’s only a couple in oncology, pembrolizumab is another example. It’s kind of an interesting situation because if you’re going to apply it to rare tumors, here you’re talking about rare situations, it’s going to be challenging to do a study on every single cancer. So to be able to sit down and say there’s enough evidence that if you see this, even though we haven’t tested it in that cancer, considering the risks it’s worth taking a shot at. So, Marianne, let’s hear about your 46-year-old man. When I heard this case I was thinking, this is a great example of what we were talking about in the beginning, the potential advantages of clinical trial participation to patients.

MS DAVIES: So this 46-year-old I started to talk to you about earlier on in terms of his daughter, he was actually diagnosed a little over 4 years ago and he was at another facility about an hour away from an academic medical center. And children were younger, so under the age of 10 at that particular time. He was the stay-at-home dad and his wife had kind of a really unpredictable work schedule. And so though it was suggested that he do a clinical trial, he really declined at that time because he wanted to keep functioning at home, caring for his kids. And so at that time, he was placed on osimertinib and he actually did well for about 3 years. He did really, really well with a very tolerable side-effect profile. He was able to be very active like on the side he was an athletic trainer, he coached his kid’s soccer teams and that kind of thing. He’s always out and about. But when he did have progression, again it was offered clinical trial and he again declined because he still was so invested in not traveling and not having to take any additional extra appointments and all of that that goes along with the clinical trials. So the decision by that treating team was to switch him to erlotinib, which is a first-generation TKI, and so he did okay for about a little under a year.

And then at that point, when he progressed and he was more symptomatic, so he didn’t have as much activity with coaching the soccer team or his athletic training, just didn’t have the muscle strength, et cetera, he finally said, “and my kids are a little bit older now,” they’re older than 10 in general and his wife’s job became a little bit more predictable, he was like, “This is now the time I’ve got to start looking at alternative treatment regimens.” So then came to our facility looking for a clinical trial with the goals of care to say “I want to maintain my lifestyle and have minimal impacts.” So he was enrolled in a clinical trial with the HER3 antibody-drug conjugate, which, of course, again is going to be given intravenously. Well actually the trial at the time was randomizing either to monotherapy or combination with the osimertinib and because he had been treated with osimertinib a couple of years ago, he was actually going to just get the single-drug agent. So he was started on that and actually had a really good improvement in his symptoms. His dyspnea was less. He was able to get back there on the soccer field and do the things that were really important to him. He had about 6, 7 months of really good quality of life, improved symptoms and then some of the symptoms started coming back and he said to me, “I know my disease is growing. I kind of have that feeling. I can just tell. Like my muscles don’t feel as strong. I can’t run quite as far. I don’t have the same stamina.” And sure enough, on the next scans he did have progression. At that time, we didn’t have a clinical trial specifically that targeted, that would really meet his profile, so we referred him to another academic center. So it’s kind of interesting he was now willing to certainly travel anywhere because he really wanted to make sure he did everything he could to be available for his family and have a longer life. So he went on another clinical trial at another facility and he was on that for about the same amount of time, 6, 7 months. Initially had improvement and then progressed and unfortunately, he did pass away in this past year.

DR LOVE: Do you think when he and his family look back on it they feel good about having entered these trials? Do you think it was the benefit they got? We talk about the benefits in a palliative situation. The patient’s having different goals in that situation, what value they might put on that, what value he put on spending 6 or 7 months feeling better with his kids, with the students that he works with. Any thoughts?

MS DAVIES: So I think for him he had done so well on the oral TKIs that they almost could forget that he had lung cancer and they really didn’t have to have it be such an impact on their life, but when it started to progress, the family kind of really had an opportunity to prepare and think about, “Okay, how do I get my family setup so that they can financially be successful. And what are the resources and support systems they need in place so that in the event I do pass away, how are they going to really get through this?” So I think he was very grateful to have an opportunity on both of those trials to get several months of benefit where he could be very active with his family, create new memories, and also put structure in place to help assure that they would be successful when he did pass and have the resources. So I think they were very, very grateful to have that opportunity and be able to have that time together.

DR LOVE: What was it like for you to take care of him and deal with his family?

MS DAVIES: It’s always I think really emotional. I’ve been taking care of lung cancer patients for well more than 20 years and on one hand it’s really super exciting to see all the benefits that we’ve had and all the advances but it is obviously it just grips your heart when you see somebody that’s got young children that you say it shouldn’t happen. Like how do you get through it? And so you have to, you know, what are our resources then? How do we emotionally get through that? And I think that everybody in this room certainly probably feels that you spend a lot of time with those patients in the infusion center and you probably hear a whole lot more stories than I do as the nurse practitioner. I’m sure you hear a lot more and get even closer. And so you have to have some way to have some emotional resilience and some kind of support system so that you can have a reason to get up in the morning and keep helping more people. And sometimes it’s harder than others and some people, I think when you have a patient that’s either close to your age or you can relate to that family situation, it’s just it really kind of cuts close to home. But again making sure you, everybody here, all of us have good support network and resources so that we can be motivated to keep going on.

DR LOVE: So let’s talk about another patient and also, Jillian, any thoughts about this idea of treatment in the palliative situation? This classic situation where you’re able to give a well-tolerated agent, you can’t cure the patient but the patient feels better for a period of time. Do you feel a sense of gratification as a nurse in that situation?

MS THOMPSON: Absolutely. When I think about, I’m aging myself too, of how long I’ve treated lung cancer patients, I remember early on there weren’t the options. There really wasn’t a lot of options. Once you exhausted chemotherapy, there wasn’t much to do. So I think when we have the opportunity to first of all think ahead. Something the physician that I work with that I really appreciate, they were always from the beginning saying, what is our next option? So we’re always prepared in the event that there is progression because we know that these metastatic patients that we’re not able to cure them. So I think that when we’re able to already have something in place and we’re communicating that early, it gives them a sense of relief because they’re coming in and saying, “Okay, what’s next?” They’re already thinking about how can we continue to fight this disease, which I think all of us are hoping now we can see as being, treating more of a chronic disease as opposed to previous there was that limit with the toxicity related to the chemotherapy and the limit of how beneficial it could be.

Treatment for Metastatic NSCLC with EGFR Exon 20 Insertion Mutations

DR LOVE: So let’s talk about exon 20 insertion mutations. Helena, can you kind of explain what that is? We were talking about unusual mutations but this is a qualitatively different story.

DR YU: Yeah, this might be even tougher because when you see like a next generation sequencing molecular report, they all look different. But usually now they give you a summary statement, this is an exon 20 insertion. And so those are different because they’re activating. They cause cancer but they’re not sensitizing to the standard EGFR inhibitors like osimertinib. So up until just a few years ago, we had really no targeted options for these patients and so it was always hard to say, “You’re a never smoker, you’re going to have a mutation” and then have to come back to them and say, “Well, you have an EGFR, but it’s not that one.” So that was always challenging, but I think now probably a few years ago amivantamab was approved for this group. It was actually initially approved in the second-line setting after chemotherapy. So we start chemotherapy for these patients and then would sequence to amivantamab and now there is data of combining and you’ll see this as a theme combining chemotherapy with amivantamab in the first-line setting.

DR LOVE: So I want to talk a little bit more about exon 20. Alex, can you kind of comment a little bit about how you think through the management of these patients? We talked about the fact that with the classical EGFR mutations, we start with targeted therapy and chemotherapy comes later. How about with these exon 20 patients?

DR SPIRA: Yeah, so the caveat of what I’m about to say is things are probably going to change dramatically over the next 6 to 12 months, which is great. So we think about it a little bit differently. So amivantamab as I alluded to before, Neil, was approved a couple of years ago now, I’m getting forgetful, for second-line therapy. The response rates in the second-line setting were good, not as great as we would love to see for a targetable mutation. So the decision made going forward is to bring this into the front-line setting and comparing in the PAPILLON study chemotherapy versus chemotherapy with amivantamab. Long story short, the survival and overall outcomes were better and now in the front-line setting the standard of care is chemotherapy with amivantamab. It’s a little bit different than we usually try to think because there’s no data currently of targeted therapy in the front-line setting, which is what we all want, right? I mean our patients for practical reasons as well as the reality is nobody likes that chemotherapy word. So they all want to get a targeted therapy in the front-line. So right now we’re currently left with the PAPILLON study and for most people in the front-line setting, borrowing very few examples, the standard of care is and will remain platinum-based therapy with amivantamab. We do expect some other molecules, some small molecule TKIs, to hopefully read out and hit the clinic in the next 12 to 36 months that may change this, but right now it’s chemotherapy with amivantamab in the front-line setting. So Helena, can you tell us about your 74-year-old lady who got amivantamab for exon 20.

DR YU: Yeah, this was one of those cases where she was like an elderly grandma matriarch, had lots of family that came with her, and this was a tough one because she didn’t really want chemo and they were excited about this EGFR mutation and then I had to tell them it’s a different kind and that she did need chemo. So I think the options were chemo at the time or best supportive care so her family did convince her to move forward with the chemo and then after a certain degree, I think it was about a year, she progressed and then we did the amivantamab. She was excited about this being a targeted therapy but then it still has the infusions, it has toxicity, but she did well. I think she had some skin toxicity. You can get a scalp rash so she had that, had to cut her hair short and then had some nail issues. But I think she is still on it and it’s been about 8 months. So doing okay.

DR LOVE: Interesting. So I want to finish out and get some thoughts from you all about another issue. Incidentally, I guess we did have a TKI, a small molecule before for exon 20, mobocertinib, but that is no longer available. When that was there, Helena, which one were you using? That was oral.

DR YU: Yeah, that was a patient decision thing where I told patients, “We have amivantamab, which is probably slightly more effective, but it’s an intravenous drug, but then there’s mobocertinib, which is an oral drug and has more GI toxicity.” And so it really was discussing with the patient sort of what their values were. But you can see that was a drug that got accelerated approval, but then they needed to do a study to confirm benefit. And that confirmatory study really didn’t demonstrate benefit, and so obviously it was removed from the market.

DR LOVE: And just another graph to take a look at. We’ve been looking at hazard rates and, you know, a lot of the trials the hazard rates are like 0.7, 0.65, which means not as much benefit because remember it’s minus 100, here again hazard rate of 0.4. So any particular point in time, 60% fewer recurrences by using a targeted approach, and we’ve been talking about the tolerability and again it’ll be really interesting to see what happens with the subQ formulation. So particularly relevant to that last case that Marianne presented of the saga and tragic ending, here are some thoughts from one of the other nurses. Interestingly, we showed another video of Ms Glennie last night and actually after graduating nursing school at the age of 22, she decided to work in a bone marrow transplant oncology unit and had some very disturbing experiences there and burned out cold, and discussed it last night. If you weren’t here, it’s all posted on the web. But here she is back in oncology and incidentally I asked her why did she decide to go back to oncology after going through all that and things happen for a reason. It was the only job she could get and she ended up loving it again. Anyhow, here are her thoughts. She talked about that last night a bit. Here are her thoughts about having to go through an experience as Marianne described of a patient passing away.

MS GLENNIE: I’m a sort of I suppose verbal communal processor and so I have my colleagues at work, my husband, bless him, is not in healthcare, and so isn’t always the best sounding board for those scenarios just because he doesn’t quite know how to deal with it either, and so I have found folks within the oncology community that I can process some of my own feelings of grief because you take care of patients for months or years pretty intensively and those bonds and relationships are very real. And I think that the grief and the trauma that we experience as clinicians is very real. Just because we were not directly involved in that patient’s life prior to their diagnosis, doesn’t mean that we were not deeply involved and an important part of their life even if it was towards the end. So I do find that I try to allow myself those feelings. If I box them up, they’re going to come out later and we are only human and so I do what I can to kind of process with the community that I have.

DR LOVE: Any thoughts, Marianne?

MS DAVIES: No, I think it was very well spoken. Keeping it in doesn’t really get — it’s kind of a cumulative effect, a cumulative loss of the patients, so being able to process with those that you work with that have an understanding of what you’re feeling. And I think it doesn’t make me any less motivated and excited about being in this field because I just think it’s such a special relationship we have with our patients. We get to really be a part of their life at one of the most critical times in their life and we get, you know, that’s like a blessing for us to get to help the family and process through that time but again we have to keep ourselves healthy and resilient so that we can keep doing that for all of our patients and not just a few select ones that we particularly form attachments to.

DR LOVE: I just got inspired so I’m going to have to spring something on you that we’ve done for many years, but I think it would just — one of the group of people we think a lot about, we know there are people here new to oncology, there are people in this room and watching who are thinking about going into oncology and again every single one of you has been asked, isn’t it depressing? And what we’ve asked people over the years is, what is it that keeps you going and allows you to do this? The one thing was doing stuff outside of the hospital, outside of the clinic. So for many years when we would start our symposia here, we would introduce the faculty and they would show pictures of what they did to get away from it. So how about if we do a quick down the line, what do you do to get away from your job, Alex?

DR SPIRA: Spend time with family, spend time with my dog who I love more than my kids and they know that. If anybody knows me on Facebook there are more pictures of my dog than my kids.

DR LOVE: Yeah, I can relate.

DR SPIRA: His name is Cosmo and he’s a golden retriever.

DR YU: My two kids and then I actually really like watching football and Formula 1, so sports.

MS DAVIES: Wow.

DR SPIRA: Formula 1?

DR LOVE: Football?

DR YU: Yeah.

DR SPIRA: Really?

DR YU: Yeah. We can talk about it later.

DR LOVE: What do you think about the Jets?

DR YU: Huh?

DR LOVE: Are you optimistic about the Jets?

DR YU: Oh no, I’m a Bills fan.

DR LOVE: Oh.

DR YU: I’m sorry.

DR SPIRA: She’s optimistic that the Jets are going to suck.

DR LOVE: Marianne?

MS DAVIES: Well, my kids are older now and I’m excited that I’m going to be a grandma soon so I can’t wait for that. And what I’ve done over the years something is I race sailboats in Long Island Sound, so typically a couple of nights a week and on weekends for regattas and you get out there and obviously you’re not making any money, we’re not like America’s Cup or winning any big trophies, but it’s just a really good way to be physical and be outside and get some fresh air.

DR LOVE: Jillian?

MS THOMPSON: Well, I have a 7-month-old now so I love spending my time with him. But the other thing I do is paint by number. It is relaxing, it’s enjoyable and you feel accomplished when you have this beautiful picture afterwards, so…

DR LOVE: Well, Marianne, I completely second your grandkids kind of strategy. I’ve got a bunch of them but a 4-year-old and a 2-week-old and it’s pretty interesting. So anyhow, thank you so much. Audience, thank you for attending. Come on back tonight, ovarian cancer.