All right, good morning, everybody, and thank you for joining us for the first session of the day. My name is Jason Akulian. I'm an Associate Professor of Medicine and Section Chief of Interventional Pulmonology at the University of North Carolina at Chapel Hill. I'm gonna read a little bit of sort of the preamble of the Constitution as Chess would like me to for session notes. So welcome to session 2013, the window is open, Multidisciplinary Considerations in Lung Cancer. As a reminder, all sessions can be evaluated through the mobile app and or the online program. Please don't forget to evaluate the session, course, and faculty when it's done. If you have any poor ratings for me, just give them to Dr. Gilbert. Presenters are required to verbally disclose any or no financial relationships relevant to their presentations. All rights are reserved. The visual and audio content presented during this meeting is the exclusive property of Chess. No personal recordings of the content in this meeting are allowed. Please assist Chess staff by keeping the aisles and exits clear. Please silence all cell phones and pagers during the presentation. If you brought your pager, I'm very sorry. Please make room for attendees to have a seat by moving towards the center of the rows and leaving empty seats in the aisle for late comers. CME claiming will open Wednesday, October 11th at noon. We don't have any ARS, I think. Nobody has any ARS in their slides? Yep, so I will not read that piece. All right. With that said, I'm gonna kick this off. Just sort of give an outline and an overview of what multidisciplinary care and lung cancer might look like, what it is, what some of the pitfalls might be. So these are my financial disclosures. So we think about lung cancer, we see that the cost of lung cancer exceeds $12 billion in the United States, not to mention the rest of the world, right? So this is a major issue, we all know that. That's why we live in this space, not just for those reasons, but also for the health of our patients. ASCO, in the last couple of years, developed a value-based treatment paradigm scale by which it helped to help institutions and providers and patients understand kind of the value add of a new set of therapies or therapy. And within that, there are sort of three domains that they looked at, which was, what is the clinical benefit of the actual new treatment? And they termed that efficacy. What is the toxicity of it, right? So does toxicity outweigh benefit? And that's a safety signal. And then the overall cost, right? So does a single drop cost a million dollars and only give you a month worth of life? You know, that falls under efficacy. Along with that, ASCO and ESMO published this statement right here, which is that the optimal treatment of cancer is provided by a team that includes a multidisciplinary medical group that is composed of oncologists, both medical and surgical, radiation oncologists, palliative experts, oncology nurses, and social workers. They did leave out a couple of team members there, as we like to think of it, but I think it's important to understand that there has been this growing sense that it takes a village to take care of these patients, not just a single lone wolf paradigm. So we think about what's the best approach, right? So we think about all the different paradigms that exist within lung cancer, and that is a little bit of a small slide, but what I really wanted to illustrate was that there is increasing complexity within the different paradigms, right? And we're not just talking about sort of a one-size-fits-all approach to lung cancer, whether it's early stage or late stage, but there are nuances within each stage that drive some of our decision-making, and those decisions are made best within a multidisciplinary framework. We think about systematizing these approaches, right? We think about practice guidelines that exist, but oftentimes, practice guidelines are a little bit long of tooth, right? They don't necessarily keep up with the rate of innovation that's occurring within our space. We think about maximizing information, right? So how do we understand what's happening around us? How do we share that with our colleagues, and how do we share that with our patients in a way that's meaningful, and again, value-add to their overall decision-making, both as individuals, but as they're being guided by the medical team. And then minimizing patient morbidity, right? I mean, this is always about putting the patient at the center of things, right? So we're trying to improve and maximize their outcomes, but at the end of the day, what does that actually mean? And potentially, that may mean minimizing their morbidity, which may minimize their longevity, but may optimize their quality of life. So how do we make sense of all of this? You know, it gets even more complex in regards to, you know, when we start to think about all of the different targetable mutations that now exist. We're finding new ones almost annually, and drugs that go along with them. And so this complexity continues to grow in terms of how we push our patients down the pathway. Again, sort of harping on this idea of complexity, this is the timeline of targeted therapy. This is a really nice article that sort of laid out with the timing of how these drugs came to market. And as you see, you know, it's from 2003 all the way now to 2022, there's been this growth, and this doesn't even encapsulate all the different options that one has as a medical oncologist or as a care team to care for these patients. Largely, these decisions are driven by the mutations found within the tumor biopsy. But again, as you can see, there's starting to be this increase in complexity over time. When we think about there being complexity, I mean, let's talk about what we're seeing in chemotherapy. And now we have chemo and immunotherapy and immunotherapy standalone. Okay, so the complexity grows as ever present as our understanding of the biology of cancer grows and our ability to access patients in both invasive and minimally invasive ways. So now there's neoadjuvant, right? So this has been the sort of next iteration in how do we think about our patients and how do we take care of them. So this is one of the window trials that, this is the CHECKMATE 816 trial where they looked at giving patients nivolumab and chemotherapy versus just chemo alone and then surgery. So as a neoadjuvant window trial, and what they showed was really significant improvements in overall survival in these patients and in event-free survival. And so there's been a lot of excitement around this, but this sort of, again, lends to this level of complexity and how do we as a team of caretakers ensure that patients are not only provided this, but are put onto the pathway at the correct points. Again, this is another trial, this is the NATEM trial, basically showing very similar results in terms of survival. So when we think about multidisciplinary decision-making, we think about the advantages and the challenges, right? And most of, I think, we have a pretty good sense of what the advantages are and how it drives patient care to a better place. From a challenge perspective, though, we have to think about this from the perspective of the patients, the care team, and the community at large, right? So patients oftentimes have a difficult time grappling with the different options that they might have, right? And we are certainly in a paradigm in medicine where we're not being paternalistic about the way that we care for our patients, but they really rely on us to help them understand what their options are throughout their therapy and through the entire longitudinal course of their disease process. You know, there are times when you may end up with delays in care, whether that's because of operational issues within one's own institution or even patients, right? I mean, there's a real world outside of the clinic and outside of where you see your patients. When they go home, they have their own challenges. They may not have support networks that help them to facilitate the appropriate care that they need to get, that maybe we're trying to provide, but there are these barriers, and sometimes they're invisible barriers that we don't encounter until we actually see them, and they impact patient outcomes directly. And then for us as clinicians, I mean, so how do we take care of patients that oftentimes travel from far distances, right? So we have people who come routinely in North Carolina from two hours away. So I have this, I've, you know, rated everything in North Carolina by Akulian units, and so Akulian units, everything's two hours from everything else. And so if you're two Akulian units, you're four hours away, which means you're coming from Asheville to Chapel Hill, right, and if you're one Akulian unit, you're about two hours away. And so, you know, everything is sort of broken down into this time distance issue, right? The expertise may not lie in their communities such that they're able to actually get the care that we would encourage them to get and know they would have better outcomes with. So how do we surmount those issues within our multidisciplinary team that is really centered at large academic centers? How do we connect with other providers at these places? How do we form multidisciplinary provision of care at sort of the far-flung parts of our various empires or with our partner institutions? And then there's sort of this variance in therapeutic options, right? So there's a lot of data. There's a lot of window trials that are now actively being pursued. And so as these data's kind of drip, drip, drip out or are presented at large meetings, people get excited, but it adds, again, levels of complexity in terms of which do I apply in the appropriate setting for the appropriate patient. And so those are sort of the main issues when we think about challenges, and then there's sort of the financial cost of it. And that is not just how much does the drug cost, right? But again, going back to this question of if you have a patient that lives three hours away, getting them from their home to the MDC and getting them treated appropriately, that's a huge financial cost, oftentimes a burden for them. And sort of those are some of the issues that we have to sort of consider. When we think about decision making and how we do this, clinical reasoning is a cognitive process, right? We sit down, we think, we've been educated, we continue to try to educate ourselves. We come to meetings like this to try to learn something new. We read articles in our spare time. And it helps us to form more complex thoughts about how to take care of these complex patients. Typically or historically, that was an individual process, right? Where you'd have this sort of this lone wolf approach where there was the physician standing high on the hill with a beacon of light, and I'm gonna take care of all these people and I'm gonna do it all alone. We know that's not really possible anymore, right? And that you have this introduction of biases that have existed for many, many years, but have only been compounded upon, again, because of this growing complexity within medicine. When we think about what type of systemic biases that exist, I found a really nice interesting set of articles talking about groupthink. Groupthink is defined as when a group of individuals reaches a consensus without critical reasoning or evaluating the consequences of alternatives. And I think this is a real risk that we run within the multidisciplinary setting where somebody within the group or one or two individuals in the group can be viewed as the expert within a specific silo of the multidisciplinary team. And if they come in strong or hard with their opinion, others will sort of fall in line and agree with this because they're experts, you respect them, they're your colleague, you don't wanna be the person that steps out of line, and you sort of, you know, you accept these things. I think we have to make sure that we're gonna do this with a grain of salt. When we think about the different sort of pitfalls within groupthink, there are three types that have been previously defined. So the type one is the overestimation of the group. So, you know, we know everything, we can take care of everyone, and we know all the right answers all the time. And that becomes a problem because when we, that's sort of this hubris in medicine question. We sometimes need to slow down and understand that maybe we don't understand all the complexities of the disease process or of the patients themselves and sort of the barriers that may exist within their own personal existence. Closed-mindedness is another. So we rationalize things that are warnings, right? So we sort of, we see a warning flag in the distance and we sort of rationalize it away that that's okay, we can manage that later, or we sort of already understand that, so we'll grapple with that. But rather than, you know, sort of rationalizing these things, taking time to sort of peel them apart and understand will they become very large issues in the future is gonna be just very important. Stereotyping, right? So, you know, making sure that we don't vilify one another within the multidisciplinary setting, right? That we don't say, oh, that person, they always think about it this way, or, oh, they're always, you know, doubting the efficacy of, you know, surgery or immunotherapy or, you know, just they can't ever get to that nodule, you know, that kind of thing. So we have to understand that we all have expertise within the group and we have to draw upon that and appreciate that rather than sort of pound those individuals down like a hammer and a nail. Type three is pressuring towards uniformity, right? So there's definitely this theme, right? So self-censorship, I think, is a real issue, right, that we think about, right? So again, this idea that there's an expert, you sit next to them, you respect them as your colleague, they have a very strong opinion about something and you're just quiet because you feel like you don't wanna step on their toes, you don't wanna get outside of your lane. But again, within a healthy multidisciplinary consortium, you're gonna have that freedom of thought to be able to say, well, wait, wait, so, you know, help me understand this better. You know, help me understand where you're coming from, why you feel so strongly about that. Because there might be a different way and I sort of see it from this facet. Help me understand why maybe the facet I'm looking through isn't the right one or maybe I can change your opinion and it perhaps is. Again, allusions of unanimity, kind of the same idea that, you know, silence is agreement. That's always very dangerous when you assume that when people are quiet, they agree with you. So I'm assuming everyone in the audience right now is in full agreement with me. Direct pressure and then mind guards, right? So mind guards are those self-appointed members who shield a group from dissenting opinions, right? They're the people that kind of say, no, no, no, it's okay. You know, such and such knows the answer to that. We'll just move on. So how to avoid groupthink, right? So there should be leaders within these groups and it doesn't mean that, and leaders doesn't mean that they overrule everyone, right? Leaders means that they help people to form thoughts, they help to facilitate conversation and they help to be a critical evaluator within the overall paradigm. They shouldn't express their opinion when assigning a task to a group, right? They should hold back. They may have a very strong opinion, and it doesn't mean they can never share their opinion, but they probably shouldn't be the first one out of the gate. They should also be absent from many meetings, right? So a lot of this comes actually out of the private industry, right, and sort of how private industry deals with large group projects, right? And so leaders should let other people sort of run these things. Now in the MDC context, that's probably not something that we're gonna say, our medical oncologist has to step out of the door, and we're gonna talk about this and let them in later when we've decided what we wanna do. So that may not be as applicable in this situation, but effective alternatives should always be examined, right? We need some devil's advocacy in the room. Somebody to say, well, I totally hear what you're saying, and that's something that we certainly should consider, but what about this? And maybe that's 180 degrees different in terms of an idea. It's healthy to have those conversations. It's healthy to have healthy dissent, right? You don't wanna get angry at each other and start yelling at each other, but it's okay to say, well, again, I see this from a totally different angle. What if we approached it this way, right? And just to sort of make sure that everybody's on the same page, is using the same data, and is understanding the approach and the logistics behind taking care of these patients. So this is, again, a small sort of set of slides, but I wanted to really illustrate what this patient-centered care looks like, right? So again, you have this group of individuals who are all incredibly highly trained, and they all have their individual roles. It doesn't mean that they can't step out of those boxes, right, again, a healthy MDC context is one where we're all learning from each other, right? And over the course of years, we all become miniature experts within the other person's field, right? And that's important, because that, again, helps with that devil's advocacy. It helps with that, to avoid group think, and it helps to sort of form your own thoughts within an overall context of the group. This is actually holistic patient care, right? So we have patient care, and this is very, as you note, very medically oriented, right? These are all the people who are looking at the little bits of people, they're cutting the bits out of people, they're diagnosing the bits out of people, they're irradiating them, and they're giving them drugs, right? And so these are all very clinically oriented individuals within the MDC context, but when we think about holistic multidisciplinary care, we have to include palliative care, we have to include nurse specialists, physiotherapists, psychiatrists, patient advocates, right? We need all of these people within our group to think more broadly than what our standard context as physicians would be. And so to sort of get close to the end of this, to understand is to know what to do, right? It's sort of a famous line, and I think to understand is the real key to this, right? And that understanding, again, comes through the multidisciplinary exchange of knowledge between people in a safe space where one can challenge other people, but at the same time respect them and not have that devolve. And again, there's a famous Japanese proverb that the frog knows well nothing of the might of the ocean, right? And so again, everyone knows what their narrow area is, but if we start to understand and expand our mind, we can see more of this. And this is where I'm gonna sort of pivot over to my colleagues here on the podium. You know, how do we apply this framework within the neoadjuvant paradigm, right? Again, this is an area that I think a lot of people struggle with. We've struggled with it at our own institution in terms of how to set the pathway up, how to stay on the pathway, how to make sure that patients actually get the different steps of care that are probably most appropriate to them. Clearly, you're not gonna get 100% of them all the time, right, but setting a mark for yourself, something like 70 or 80% of cases that could potentially fall into the neoadjuvant paradigm is important. That's a metric that you can actually try to work towards as a group. So how do we get that tissue? Is there a best type of tissue? How do we ensure that patients stay on the pathway once they're on it or once we think they're supposed to be on it, right? How do we get them onto it and keep them on it? When do we time surgical intervention? How do we make sure that our surgeons are available and that they can actually get OR time? You know, how do they manage their own schedules and how do we help them to manage that as well? And what's the role for adjuvant therapy in this paradigm? So I just wanna say thank you and don't forget to evaluate the session. All right, so my name's Chris Gilbert. I'm from the Medical University of South Carolina. And I was asked to speak about the diagnostic considerations and specimen handling in resectable lung cancer. Oh, it looks like they dropped the disclosure slide. So I have no disclosures related to this topic. But so the objectives here are to evaluate the recently published neoadjuvant trials, which is the main reason that we're giving a talk like this, to review updated guidelines related to non-small cell lung cancer and to identify the subsequent impacts on diagnostic procedures in the initial lung cancer evaluation that I think many of us are often involved in. And so this trial, Jason already alluded to it, I'm sure, I bet in some form it was probably in all four of our presentations. Is- You and the checkmate eat 16 by the time you leave this room. That's right, exactly. And so that's kind of the whole reason that I think the paradigm has shifted. And this has brought a lot of attention to kind of this change and kind of the main reason that Jason kind of wanted to do this talk here. And so it's the checkmate A116 or it's neoadjuvant nivolumab plus chemotherapy in resectable lung cancer. And I'll try to quickly just go through it. Essentially, they took stage 1B through 3A. They had to be of good performance status and they could not have an ALK or an EGFR mutation. And it was a prospective open-label trial. This slide was already shown, but it showed a benefit including event-free survival that benefited the nivolumab limb. Now, this is another one that just came out. You can see the date, August 10th. This is, it's an interim analysis, but essentially it's probably showing the same thing that they use prembrolizumab. And they took, they did a little bit different. They took stage 2 and 3B. So they didn't do the 1Bs, like they did in the nivolumab one. And this was double-blinded. And at the interim analysis, they've shown some of the other endpoints, including event-free survival, major pathologic response, and complete resection have been improved. They don't have a significant overall survival benefit at the 25-month mark, but you can see it looks like it's probably gonna spread out. And it may be more significant when they're done. But like I said, this was an interim analysis. So again, probably more data that might favor this type of approach. So why did anybody even do this? Why does anybody care about immunotherapy? So the thoughts of giving immunotherapy preoperative, I'm sure our other two panelists are likely gonna talk about more as well. But from a lowly pulmonologist standpoint, these are kind of the hopes that they've talked about is trying to decrease the tumor size, improve the likelihood of complete resection, eliminate micrometastasis. And that last one I have here in the hope I think is the biggest one people are focused on is that they think that exposing people to the drug, while they still have tumor in them, will probably have a better response. Now there have been some concerns, including side effects from giving drugs before people go to the OR. Is there a delay then as a result of maybe side effects or just a delay in general? And does it result in a harder or more difficult operation? Now this is, so if you remember in the Checkmate trial, they excluded people that had a known EGFR or ALK mutation. And so there is only one trial that I'm aware of that looked at a pre-op EGFR mutant lung cancer. And it's a relatively small trial, took a long time and was pretty slow to recruit. They only have 30-some patients in each arm. In general, they did not find a significant overall survival benefit using Erlotinib. They did find a significant improved progression-free survival. There was a trend towards a five-year survival. There was lymph node downstaging, a good pathological response, and there was improved R0 resection rate. So again, some overall benefits when you look at kind of the whole thing, but when they're looking at the quote-unquote old standard of overall survival, it didn't meet that. So most of us are pulmonologists, so we don't technically treat people with lung cancer. So why do we care about any of this? So what do the guidelines say? So when we go back and look, and if we look at our older guidelines, which are now about 10 years old, actually, they referenced one trial 10 years ago that didn't show a benefit in regards to giving preoperative therapy for people that got lung cancer resections. And so most of our guidelines are still based on that in regards to the pulmonary and chest guidelines. And so we, in general, from the lung cancer and the pulmonologist standpoint, didn't think that this was a benefit. But again, this new trial has changed things. And now this is from the NCCN, so the National Cancer Comprehensive Network Guidelines. And so these are out as of this year. And you can see here now, again, anyone with stage 1B or higher, that first blue thing there, evaluate for preoperative therapy, or sorry, perioperative therapy. And the NCC recommendations now specifically include that anybody that has resectable, non-small cell lung cancer, that has a mass greater than four centimeters or has any nodes positive and do not have contraindications to immunotherapy, should strongly be considered for preoperative therapy. And so that's a change now. This gets to kind of the multidisciplinary discussion that Jason talked about. In general, as pulmonologists, or if there's any radiologists or anybody else that does a bunch of diagnostic work out there, most of our time is generally spent in that green area up there. And that's in general where we've worked for years. But we've started to shift our way now down into that red area a little bit, which is where the multidisciplinary discussion occurs. And we've become very involved in regards to the tissue confirmation and then the pathological evaluation. And you can notice that by going to any of these talks. And so whenever I give talks on lung cancer, this used to be my slide for EBUS, where we talked mainly about getting enough tissue for molecular testing. And now essentially it has kind of shifted. And now it's for almost any diagnostic procedure that we're doing. So even for people that we think have early stage cancer, if somebody had a small nodule, necessarily didn't have to worry too much about getting additional tissue for molecular testing in the past. But that's clearly changed at this point. And so now, again, no matter where you're going for lung cancer, for a diagnosis, you should really think about confirming the actual diagnosis. That's important. The second one then is confirming the subtype, which is also important. And then lastly, which was probably not as important in the past, but it's definitely now more important, is to make sure that you obtain enough tissue for further IHD and molecular marker testing. And again, most of us are probably pulmonologists here in this room, but you have to think about this even if you're not a pulmonologist. So if you send somebody for a adrenal nodule, and so you send them to IR or you send them to GI, it's the same thing. They need to be thinking about that. And then for the interventional radiologists, now if they're going after these small nodules, a centimeter or so nodule that's in the periphery, and you send them for a CT-guided biopsy, they need to be thinking about that now as we kind of move and this paradigm is shifted. So I put this up here. So this is an old guideline from the World Association of Bronchology. And the important parts I put up here are really the stuff in red. And that's mainly that when you're talking about specimen acquisition and handling, probably the two most important people that you need to talk to are your pathologists and your oncologist as well. So the pathology, there's no real great recommendations in regards to where or what we put stuff in. And I really consider it all to be local, meaning that you should really talk to your pathologist to figure out how they process specimens, what's the best way that they can get answers for you in regards to additional molecular testing when you're doing biopsies. This was a statement that we put out a few years ago. It doesn't actually really have too much in regards to kind of molecular testing for this topic. But what is important about this is this is somewhat almost kind of the first time that the College of American Pathologists clearly recognize and are willing to admit that cytology is a good specimen for doing molecular testing in our small biopsy specimens. And then the bunch of slides I have here next are really just trying to kind of confirm that and to at least show you guys that there is some evidence that that's true. And so this is a study that's 12 years old now, 13 years old, and suggesting that when they looked at all their FNAs and core biopsies, that both of them were essentially pretty much equivalent in regards to adequate for molecular testing. So their recommendation after their review was that you should really just consider what you're trying to do, what's the safest, and you don't necessarily have to do a core, but an FNA will likely get you the same amount of tissue. This is looking at EGFR and KRAS. Now again, when we're doing these early stage lung cancers that could potentially get immunotherapy, EGFR testing will be important. So can you get molecular testing by using cytology specimens? And the answer is, in general, yes. The insufficiency rate is fairly low for most of the specimens that get sent off for FNAs. This is another study from MD Anderson where they suggest that probably the cellular content, and this actually tends to become a theme if you look more and more into this, is that the cellular content related to FNAs tends to probably be better than some of the core needle samples. And so this may be a better specimen sample for us as we move down looking at additional testing for people for lung cancer. This was another one. This is just a bronchoscopy study that essentially they looked at all of their radial ultrasound and ENM bronchoscopies, and they essentially looked at their feasibility of genotyping, and essentially found that, in all honesty, probably the things that don't necessarily matter is the way that you get there or the tool that you use to get there, but it's really just that you actually got there and you got a specimen, and probably that somebody was thinking about getting a good specimen. But essentially it shows that you can order genotyping on most of these specimens, you're able to get answers, and you can still get PD-L1 testing as well. This is another one where they looked at transbronchial biopsies using radioprobe ultrasound, then they compared these to people that got resections. You can see on the bottom here that EGFR was, they had a fairly good concordance rate in regards to being detected in the biopsy specimen versus the resection specimen. It wasn't perfect, but it was pretty good, and ALK was also the same. So again, our biopsy specimens that we get from doing transbronchial biopsy and or cytology brush are generally able to give adequate specimens for what people end up ultimately having. This was another one, people used TBNA, they used transbronchial biopsy, again suggesting that EGFR, ALK, and PD-L1 were available from the specimens that were provided. This one, the main reason I brought this one up was that this is not one that I commonly think of. Normally when we're doing biopsies and trying to send stuff for molecular testing, most of us probably focus on TBNA and transbronchial biopsy, but here, this one shows that brush, so endobronchial brushing is actually a fairly feasible option to provide cellularity in order to send for molecular testing. So just something to let people know. This one also shows the same thing. Here they did, they had 97 endobronchial brush samples and their success rate was 99% in regards to getting next generation sequence testing. So again, it's not something that I commonly think about or would do, but it is available. You can also see that the DNA and RNA that they're able to get is somewhat similar to EVAs TBNA, which is one that all of us probably don't think twice about sending for additional molecular testing. And this was the same, this was, they used transbronchial biopsy forceps in this one instead of the brush, which was in the prior one. But again, they're just showing that you're able to get DNA and RNA that you can use then for testing from our sampling methods. This was a core needle biopsy and FNA. Now this was interesting because it's a little bit different than some of the other stuff that I had shown. They used 22 and 25 gauge needles and 18 and 22 for their cores. Their FNA and core biopsy was not as good as some of the other tests, other testing that's been reported. So you do, again, the main reason I brought this one up is you have to make sure that, again, everything still remains local when you think about things. And so you really have to be doing quality control and quality improvement to evaluate what you're doing and if there's ways to make things better. Maybe at this institution, sending people for core needle biopsies is not the best option. Maybe bronchoscopy would be a better option for some of these samples because they don't seem to be getting great results in regards to their molecular testing. But it's something that should be continuously evaluated and see if there are better options or other things that can be improved upon. One thing that they ended up doing is they found that by increasing their biopsy attempts by two, they slightly increased their yield. So that's what they ended up doing and that was their conclusion. But it's just something that, again, people that are doing these types of testing should be familiar with what their actual yields are. This was another one that just said that CT-guided biopsy worked as well. So what's in the future? So for right now, at least the way that the paradigm is set up is what we're supposed to be looking for, according to the NCCN, is anybody that has non-small cell lung cancer and potential resection candidate, we should be looking at EGFR, ALK, and PD-L1. So those are the tests that we're supposed to send for now. But just like the way EBIS was 10 to 15 years ago, where we were sending for just EGFR, ALK, now we're sending for a whole bunch of stuff and I bet these markers will probably change as well. So it's probably something that will continue to change as we move along and get more studies and more targetable mutations that show a favorable outcome in preoperative therapy. So conclusions. So recently published neoadjuvant trials are changing the previous treatment paradigms we used to have. The guidelines now recommended that all patients with non-small cell lung cancer be evaluated for preoperative therapy. And these changes do impact us, the people that are doing diagnostic workups. And again, no matter what stage you think the person has at this point, you should likely be thinking about getting enough tissue for additional testing. Cytology specimens do provide very good samples for this. So depending on how you sample, TBNA brush, what have you, if you want to do transbronchial biopsy, fine, but cytology is a very reasonable option. And again, wherever you're at, all care still remains local. And so you have to work within your system to how to best deliver care to your patients. Thank you. All right, guys. Thank you so much for having me. I'm Erin Gillaspie. I'm a thoracic surgeon. I need everyone to fasten your seatbelts. I'm gonna take you through a whirlwind review of everything going on in surgery. This is one of my incredible patients. She is a lung cancer survivor because of lung cancer screening. My credentials are actually changing upcoming. So if you have questions for me, you're gonna be able to reach me in a different location in a couple of weeks. These are my disclosures. And I'd also like to include that I actually might be a medical oncologist trapped in a surgeon's body. We are living, as you've heard, in an unprecedented era. It's such an exciting time in lung cancer, but it's also becoming more and more complicated. And as we're dealing with all of the information coming out, I'm gonna encourage you to be a little bit different than Ted Lasso. And I acknowledge this as a Walt Whitman quote. We need to be curious, but we also need to be judgmental as we're thinking about how we're going to apply all of this new data, all of these new trials that are coming out to our patients and how we're working people up and taking care of them. So I'm gonna kick us off in sort of different phases. First, we're gonna talk about the really early stage. So this is small tumors, tumors that are two centimeters or less. And we're seeing a stage shift. We're finding more of these people. And that's a testament to all of the lung cancer screening programs that we have. Really, really exciting. This is one of the most incredible trials that's been put together in surgery recently. This is a trial called CalGB140503. It was spearheaded by Dr. Al-Torki, and it took 15 years to get the answer to this. To give you just a tiny little bit of background, historically, we always did lobectomy for 100% of patients coming in with lung cancer unless they couldn't tolerate it for a physiologic reason, right? As we start getting better and better CT scans, better and better screening available kind of more broadly across the country, all of a sudden we're finding these tiny lesions and we're taking out lobes for these tiny lesions. And it was based on a trial that came out in 1995 by the Lung Cancer Study Group. And so with the advent of our better imaging, better technologies, we say, hey, we need to revisit this topic. And so what they did is they took tumors that were two centimeters or less and randomized them intraoperatively to either a lobar or sublobar or a section. Sublobar could be a wedge or segmentectomy. It's at the discretion of the surgeon. And then they followed these patients out for seven years looking at DFS and OS. Now you can see here the two different curves and specifically this trial was looking for non-inferiority, right? So we wanted to make sure that a sublobar resection was non-inferior to a lobectomy. On this kind of panel over A here on the left-hand side, you can see that the disease-free survival, those curves are right on top of each other. Next to that, you can see the overall survival curves right next to each other. So what do we conclude from this? Well, we conclude a couple different things. One, disease-free survival. Two, overall survival are non-inferior when we're doing resection, a sublobar resection for patients with tumors that are two centimeters or less, no negative proven pathologically at the time of resection. I will tell you what though, to me maybe the biggest, most fascinating, shocking piece that came out of this study was actually this. It was the patterns of recurrence. When you look at the two different subgroups of patients, not only were the patterns of recurrence the same, but they were both high, 35%. These are two centimeter tumors, 35% recurrence rate. And I think to me, this underscores the fact that there's a biology that we're dealing with. And I think it also helps to explain why we're seeing more and more of these wonderful therapies moving into earlier stage settings and working to try to identify which patients are gonna benefit the most so we can prevent these recurrences. So what's the treatment impact? Well, one, smaller treatments are being adopted. We're seeing more and more people doing sublobar resections, but there's a lot of questions that still remain. Do we need to stratify based on additional factors? Are there high-risk features that we need to think about where maybe these patients still need a lobectomy or a more aggressive lymphadenectomy? We need to continue gathering data on these patients to make sure we're doing the right things. Let's move quickly into adjuvant therapy. So we've seen a huge number of adjuvant treatment regimens read out, the first of which was Empower 010. And so we're taking completely resected tumors, 1B all the way up to 3A. And as a reminder, a lot of the analyses that are performed in these studies are actually focusing on the 2 and 3A groups. So when you look at the inclusion criteria, it's wider than a lot of the published and specific outcomes that are being followed, and I think that's really important as you're looking at and reading through these studies. So patients undergo a complete resection and then they're randomized to receive chemo plus IO or chemo plus best supportive care. We're using a lot of surrogate endpoints now as we're looking at these studies. They've performed really well in the late stage setting, so we're incorporating disease-free survival, progression-free survival, pathologic complete response, we'll touch on that in just a minute too, as some of our surrogate endpoints. And those are becoming our primary outcomes that we're looking at. So how did it go? Well, when we look at the evaluation group, stage two to 3A, for PD-L1 positive patients who are evaluated, we see a beautiful separation of curves here, hazard ratio of 0.66, crossing the statistical significance boundary around that 36-month mark. We get FDA approval for patients who are PD-L1 positive to be treated in the adjuvant setting after complete resection for patients who meet all of the kind of aforementioned criteria. But oh, pause things for just one second. So we keep following patients out, right? Remain curious, be judgmental. Overall survival didn't pan out as well as we thought it was going to. It was a little bit shocking when we all got this. Everybody was like super excited, right? We found something to give our patients in the adjuvant setting. Overall survival's not panning out quite as well. So what did everybody do? Well, we do what everybody does. We go into the subgroup analysis because we can't be that completely defeated. Somebody surely must have benefited, right? Well, it turns out there are some people who look like they're gonna have a little bit of a more of a benefit. So probably favoring our larger tumors, so certainly the 3A group, probably some of our twos, and people who are PD-L1 high, so greater than 50%. So I think this is really important and it kind of highlights the need to continue to redefine the subset of patients who are benefiting. More work needed, I think, to understand who benefits the most. Adora was sort of another landmark trial. Really, really exciting. There's a few trials that we have who have separations of curves as great as this. I'll show you on the next page. Very sort of similar criteria for inclusion, 1B all the way to 3A, great performance. That is completely resected. Two specific mutations, exon 19 deletion and LA58R mutation, that's important to know. There are more EGFR mutations than this. These are the two specific ones that this drug treats. Patients were followed up after randomization and here are our curves for our stage two and stage 3A patients. You can drive a truck through this. We hardly ever see curves like this and actually the interim analysis, the study was closed early allowing patients to go over to the opposite arm of treatment because it was such a dramatic difference in outcome. Why do I show this? I want this curve for my patients. This curve is better than the other curve, right? Okay, so where does this become really, really important for us? Well, it becomes important because we need to make sure we're getting our patients on the right therapies. So we look at overall survival. It stays statistically significant in our Adora for our stage two and stage 3A patients and even for our stage 1B to 3A patients when we're looking at our overall survival with hazard ratios of 0.49 respectively for the two groups. This was practice changing. So EGFR being a standard test that we need to perform on patients to be able to help get them on the right therapies. So what is the treatment impact as we think about these patients? Well, one, we need to be staging our patients appropriately, right? We need to be getting fully comprehensive nodal staging and we need to make sure that our patients are getting opportunities for treatments that they may benefit from. But importantly too, we need to be sending molecular and PD-L1 testing immediately after surgery for patients who haven't received neoadjuvant therapy because we need to make sure that we're getting them on the right treatments to be able to help get the best possible outcomes for them. If we miss a EGFR mutation and we give them immunotherapies at the end of the world, well, actually it might be for some patients. So LA58R mutations actually perform okay with immunotherapy. Not great, but exon 19 deletions, those are immunologically cold tumors. They do not respond well to immunotherapy. So now not only have we missed the opportunity to give them a better therapy, but we've given them something that doesn't work, that has a lot of side effects. 92% of people who get immunotherapy are gonna have some kind of side effect from it. Most of them manageable, most of them mild, but that's a big impact. That's something that we really need to be thinking about. We're all gonna talk about it. Everybody has to talk about it. You can't open a newspaper without hearing about CHECKMATE 816, huge landmark trial. I will tell you for us as surgeons, it made people really nervous at first because the only context we had for interacting with immunotherapy before surgery was in two settings. And it was single site progression or single site residual disease. And I will tell you when we got calls from oncology colleagues after two years of immunotherapy and then I said, can you take this guy to the OR? And we open up and we are literally chiseling through cement trying to find residual lesions. It was stressful. We did not want to be doing that on a day-to-day basis in our careers, right? But the good news is, is actually after a short amount of immunotherapy, it does not significantly impact our ability to do a very safe operation. And my focus as we talk a little bit about this CHECKMATE 816 trial is gonna be on the surgical outcomes and surgical considerations. As you heard, key eligibility criteria. So good performance, that is 1B all the way to 3A. Again, a lot of the analysis done on that 2 to 3A cohort. They ideally didn't want EGFR mutations. However, some patients were untested. And so they ended up being included. And that is described in the New England Journal paper. Couple key endpoints we're looking at. Path CR. Path CR has become a more common primary endpoint that we're looking at. Really important to think about. And as we continue to collect data, to use that as a surrogate marker for outcomes. So patients were randomized one-to-one. They got chemo I.O. versus chemo up front, followed by resection, followed by additional treatment at the discretion of the treating physician. And so that's where things get a little bit complicated with this trial. Ideally, surgery was supposed to happen within six weeks. So how did it go? Well, the good news is surgery was actually very feasible. So if we think about the surgical outcomes, first and foremost, we're not having massive delays in getting patients to the operating room, right? This was a big fear everybody had. We're gonna give them all this therapy. We can't get them to the operating room. No big difference between chemo alone versus chemo I.O. So that's great. Length of delay of surgery, very short. On the whole, again, equal between both arms. When we think about some of our surrogate markers for how easy surgery is to perform, couple things we think about. Time in the operating room. Now I will tell you, time was a little bit shorter for the chemo I.O. group. Am I gonna stand up here and tell you that I think immunotherapy makes my surgery easier? No. I think it just doesn't make it harder. That's what I would conclude from that data, okay? So don't go home saying, hey, it was shorter. Give them immunotherapies, it's gonna make everything easier. Surgical approach is really interesting, and this is where I think some of the data gets very misleading in presentations. Again, stay curious. So we hear all the time, as sort of one of the big conclusions of this study, is that fewer patients had a conversion from minimally invasive to open, and a higher percent of patients were able to have their surgery minimally invasively. Most of the patients in this study had an open surgery. 60% of patients had an open surgery. That is not how we generally practice these days. Most of our surgeries are being done minimally invasively. So this was a big departure, and I think that's important to know. Nobody knew what to expect. I will tell you in my practice day to day, I'm doing a lot of these surgeries minimally invasively. As we gain more experience, as we see kind of the tissue impact of the chemo I.O. up front, we're feeling a lot more confident doing these surgeries, but I think the big take-home point, very, very similar between the two groups, okay? Similar rates of thoracotomy, similar rates of minimally invasive, similar rates of minimally invasive to open conversions. Not very different between the two groups. Slightly higher rates of lobectomy in the chemo I.O. group, and I do actually think that's gonna pan out to be something fairly legitimate. We do see huge rates of reduction in disease with this combination, which is fantastic. Very similar rates of R0 resections. Paths here I'm gonna touch on very, very briefly. High, very high in our chemo I.O. arm. 24% versus 2.2%. We cannot tell this radiographically yet. We cannot tell this surgically yet. If you look at the radiographic response, 1% of patients had a radiographic complete pathologic response. At the time of surgery, when we're looking at the tissue, we cannot tell what is tumor versus what is just fibrosis, and so we tend to send higher numbers of frozen sections to try to help guide resection. It can be very complicated sometimes interpreting it in the O.R. Promising event-free survival. Great pathologic response across the subgroups. No question that we see side effects. Any therapy we give to a patient, whether it's surgery, whether it's a bronchoscopy, whether it's chemotherapy, immunotherapy, targeted therapies, or radiation has side effects. It's important to think about that and make sure anything we prescribe to a patient, the benefits are gonna outweigh the risks. Overall survival's still very, very immature, so stay tuned. Certainly the groups that are performing the best are pathologic complete response, both in the chemo and the chemo I.O. arms. More are coming soon. You saw a little preview of the Checkmate 671, which is the pembrolizumab, and we also have a gene coming down the pipelines. Those are both already starting to read out and getting presented at conferences. These are periadjuvant, so a dedicated neoadjuvant, followed by surgery, followed by a dedicated adjuvant arm. The reason this is important for us is it changes how we counsel our patients ahead of time. We have to set the right expectations to say, hey, you're gonna get a little bit more therapy. Treatment impact, we need better biopsies up front. We need to be able to do molecular and PD-L1 testing up front. We need to make sure we're getting the patients on the right treatment pathways. We need to make sure that we have really thorough staging for our patients, and we need to work very carefully early on in the patient's lung cancer pathway with our multidisciplinary teams. My last comment's just gonna be on quality. Quality is a necessity in everything that we do, and one of the places I think that we have failed in lung cancer surgery is with lymphadenectomy. In the Alchemist review, we found that only about 53% of patients get guideline-concordant lymphadenectomy at the time of their surgical resection. I find that embarrassing. We have to do better. I encourage every single one of you, look at your pathology reports. Make sure your patients are getting great surgery. Make sure they're getting an adequate lymphadenectomy, because that is how we should be thinking about taking care of our patients. There is now a new COC guideline that is mandating three separate and two lymph node stations, one separately submitted, and one lymph node station. And so make sure that you're seeing that on all of your pathology reports. Centers are now being evaluated to make sure that they are in compliance. Pace of change is absolutely extraordinary in everything that we're doing. Less, maybe more, in some of the earlier stages of lung cancer. Patients are more complex than ever. We must work seamlessly in multidisciplinary teams, and I think above all else, we must make a guarantee of quality to our patients. Thank you so much for your time, and I'm happy to take questions at the end of the session. Okay, well, you're all honorary medical oncologists, so I could have gone stand-up paddleboarding instead of being here right now, but that's okay, I'm just teasing. So I'm Carolyn Presley. I'm a thoracic and geriatric oncologist. So I actually prescribe and give the medications that you've heard a lot about, but I'm gonna talk about the application of neoadjuvant therapy, so why neoadjuvant, and who should receive it. So just for those of you who don't live in this world all the time, neoadjuvant is before surgery, okay? So there's neoadjuvant, surgery, and then there's adjuvant. Adjuvant is after surgery, right? And then there's perioperative, which could be before or after. So just so we're all on the same playing field in terms of terms, I think these are really important to understand because this is a lot of data to digest at eight o'clock in the morning. So the rationale behind adjuvant immunotherapy versus neoadjuvant immunotherapy is different. And adjuvant, again, being after surgery. So the surgeon removes that lesion in that first box. So they take out the offending tumor, but there's micromatostatic disease that is left behind. This may be like four cancer cells, right? Then we give them immunotherapy, which is an antibody, right, through the vein. Takes about 60 minutes, 30 to 60 minutes. Hopefully they don't have an infusion reaction, which most people don't. But they need, it does have to go in peripherally. This is not a pill. It has to go through the vein. And what happens is then you activate the few different T cells to recognize and draw to the area those remaining cancer cells that are left sort of in the tumor bed area. So then those T cells, right, that's actually using your patient's own immune system to kill the remaining tumor tissue cells that are left over after the surgeon removes, hopefully, the bulk of the tumor. So what we think is happening, though, is that those T cells are just getting exposed to the neoantigens on the tumor cells that are left behind. So there are fewer and less diverse T cells searching for the tumor cells that have been left behind. So then if we actually give immunotherapy before the tumor is removed, think of all the different neoantigens that are in that tumor that's still sitting there, that all these different T cells can be activated. There's more of them, and there's more different types of T cells. So then when the surgeon removes the tumor tissue, you have many, many more in terms of quantity and then more diverse T cells to search out and kill any tumor cell that's left behind. And this is really the basis of why we think moving that treatment before the surgery is so critical now that we understand that a lot of lung cancer is really a disease that's hiding from our immune system. And we have to harness the immune system, our own innate immune system, to actually kill all the remaining tumor cells and then prevent progression and relapse. So this is incredibly anxiety-provoking for patients. They want that tumor out. And so it actually, I think, a big part of this whole panel and multi-D care, and as the pulmonologist or the provider, you might be a general internist seeing your patient. You might be a nurse practitioner. Trying to explain to patients why we think neoadjuvant treatment is so important is a critical role that that first touchpoint with the patient, you can start explaining why we think we need to do this first, that's an IV, versus just take out my cancer. I want it gone. I can't sleep. I'm so nervous. Take it out. So my colleagues did review Keynote 671, but this was just presented at ASCO in the spring. For those of you that don't know ASCO, but that's our huge, one of the world's largest conference for medical oncologists in particular, because this is where all of the newest drugs are presented. And my colleagues really reviewed this really well, so I'm not gonna spend too much time on this. But essentially, they were given a pembrolizumab or placebo plus chemotherapy before and after surgery. And this is, the difference between this study and Checkmate 816 is that then patients did receive pembrolizumab after surgery. And so that's a key difference, and we did see improved event-free and overall survival compared to those treated with resection and then adjuvant therapy, like we just kind of talked about. And so this is the overall survival and the intention to treat population. Our curves actually start to separate at about 24 months, which is pretty interesting. So we're not necessarily gonna see a major difference really until after 24 months. So this is small, so I'm gonna have to read this to you. But this is a key reason, so I'm just gonna put my geriatrician hat on. This is the median age of the patients included in this practice-changing clinical trial. And the median age was 64 in both groups. Does anybody know the average age of diagnosis of lung cancer? Anybody? Yell it out. 70. Yeah, 70. It used to be 70, now it's 71 in the United States, okay? So on average, these patients were way younger and healthier, these are the healthiest patients, and I'd love to hear Dr. Gillespie's opinion on how to select patients for surgical resection, right? Because you actually have to have a lot of people agreeing that these patients can actually go to surgery, right? And so I'm gonna beat them up with some neoadjuvant treatment, and then they've gotta go get this big surgery, right? So the data that we're using that is absolutely practice-changing is maybe not applicable to the patient that's sitting in front of you, which requires a huge amount of multidisciplinary teamwork and getting those PFTs, right? Erin is always gonna want PFTs. Always, always, always. So that's something that all of our pulmonary colleagues can do. And get tissue, obviously. But Checkmate 816, again, we talked about absolutely practice-changing. The nice thing about Checkmate 816, I would say at the patient perspective and the medical, it's three cycles, that's it. So they come in three times, they get their labs drawn, they get an IV, they get their chemo and their nevo, and then they're done. And you know, from a patient perspective, that's really appealing. And of course, I love Dr. Gillespie's, there is toxicity, and I'll talk about that in a little bit, but there definitely was improved event-free survival, overall survival, and past CR. And let me tell you, I don't think there's anything better to see that PATH report with a past CR. So these are the OS, the overall survival curves, New England Journal, 2022. Really amazing practice-changing. Those, you know, you could drive a bus through them, those survival curves. So really, again, love it. It's really, really, really amazing. So ADARA, also, this was, again, giving osomertinib after surgery for patients who had 1b to 3a non-small cell with an EGFR mutation. And this was presented at ASCO Plenary and published, and five-year overall survival tremendously improved, 88% versus 78% with placebo. And then these are those curves by stage. Again, seeing that, but in terms of 3a disease, the Kaplan-Meier curves are, there's a wider gap between them. The tricky part is, though, patients don't wanna take osomertinib for three years. It's really, and then they're like, well, then what happens after three years? Should I take it for five years? And there's a lot of toxicity associated with it, and patients can get pneumonitis from taking osomertinib. They can get rash, diarrhea, stomach upset. And so, you know, just when you think you're done with your treatment in terms of getting a big surgery, then now you're taking osomertinib. And so I'll be honest with you, when the PFS data came out, I was like, I don't care about PFS, because then what am I gonna give them when they recur? And so really, our institution waited until we saw the OS data, because I really think when we're focused on PFS, you really have to think about what patients, what you're putting patients through, when you can't actually tell them, this will actually improve your survival. And I think a lot of people are willing to do a lot to live as long as possible, but if it's just PFS and they're miserable, that's not worth it for a lot of patients. And so this data was really helpful in helping us to feel better about giving patients at least three years of adjuvant treatment. And again, this is a pill you take once a day. So neoedora is coming. Erin touched on it briefly. And this is now putting osomertinib, again, before surgery. So right now it's approved for after surgery. This is putting it before surgery. And so this trial is currently ongoing. The primary endpoint is major pathologic response. But so actually NEOS was a single arm phase two trial that was conducted at six centers in mainland China, and they've actually published their data already, looking at six weeks of neoadjuvant osomertinib followed by surgical resection. This was a small study. 40 patients were enrolled and treated. The overall response rate was 71%. I mean, this is amazing. 38 completed the six week osomertinib treatment, likely due to side effects. And then 32 patients underwent surgery and 30 underwent a successful R0 resection. And so there are a lot of other neoadjuvant trials and hopefully you understand the rationale for why we're so excited about this approach. But who should receive it? And again, I'm a geriatric oncologist, but I see only lung cancer, but we are an aging society. And by 2025, over 20% of all people in the US will be greater than 65 years of age. 60% of all new cancer diagnoses will be, everyone will be 65 and older. So we really have a skyrocketing aging population that will need treatment for lung cancer. And as you can see in our clinical trials, the average age wasn't even 65. It was younger than that. So the elephant in the room is really how will my cancer treatment affect me? And this elephant's saying, I'm right there in the room and no one even acknowledges me. Well, we're acknowledging the elephant, okay? And toxicity is a major issue. And I tell my patients, no cancer treatment is side effect free. And if anybody tells you that, they are lying to you. Every single cancer treatment has side effects. It may not be a physical side effect, but it could be financial toxicity. And at a minimum, there is time toxicity associated with receiving cancer treatment. And I think a lot of us actually have patients who come from several hours away to see us. And so we really have to keep this in the back of our mind. It might not just be a physical symptom in terms of side effects. There's a lot of other emotional, cognitive, financial and time toxicities that I think is becoming more and more common to measure. But in those big studies that we've been talking about, where's the quality of life data, right? Has that been published? Did they collect it? Yes. So in Insignia, which is actually in this stage four, so I'm waiting for it, right? I wanna see that to be highlighted at ASCO. So this is an article we actually wrote about immune related adverse events in geriatric syndromes to consider among older adults with cancer. And this is a nice review we published in JCO. Really thinking about when older adults are on immunotherapy, there's a lot of normal, like aging related issues that come up that could be worsened by the immunotherapy or actually could be a side effect from immunotherapy rather than an age related condition or vice versa. And so some free resources, the Cancer and Aging Research Group is a great free website. Anyone who's interested in cancer and aging can join. You don't have to be a doctor, you don't have to be a pulmonologist, you can be anybody. We also have a lot of patient advocates actually as part of our group. And then the FDA has actually put out a really nice guidance document on the inclusion of older adults in cancer clinical trials. This is also a really nice resource, low at all in the Journal of Oncology Practice about really what are the key takeaways the average clinician or provider should know about geriatric oncology. So in conclusion, and then we're hoping for a really robust discussion about how we're doing this in everyday practice is that neoadjuvant chemo and immunocombinations as well as TKIs are really, they're in the future. And actually it's not even the future, it's now. The future is now. And complete pathologic response and overall survival and improving. Watch, watch, watch for toxicity. And use available tools to help identify areas of concern and risk stratify patients. Great, thanks.

multidisciplinary care

lung cancer treatment

neoadjuvant therapy

key trials

effectiveness

toxicities

thorough staging

patient selection

molecular testing

improve outcomes