Good evening, everyone. Welcome to our fourth of five webinars on updates in lung cancer management. We're thrilled to be here. We want to thank the American College of Chest Physicians and Chest for enabling us to put on this session. And we also want to thank our sponsors that include AstraZeneca, Genentech, Roche, and Merck, Sharp, and Dome companies. Without their help, we couldn't have accomplished and put on these seminars. Today's program will follow the learning objectives that we have listed here. I'll give you just a couple of seconds to look at the objectives and get you excited about what program you're going to be part of. It's really a privilege for me, Eric Edel of the Mayo Clinic, in conjunction with my co-sponsor, Dr. Mrogu from the University of Chicago, to bring this webinar to you with two internationally known medical and radiation oncologists. Dr. Flores is currently assistant professor at the Thoracic Oncology at Dana-Farber Cancer Institute as part of the Harvard Medical School. And Dr. Remmer is associate attending director of thoracic oncology in the Department of Radiation Oncology at Memorial Sloan Kettering. You can see the disclosures by each of our presenters. And now I would like to invite Dr. Flores to begin the webinar with her presentation. Dr. Flores. Hi, everyone. I'm delighted to be here. There's been a lot of data for the treatment of lung cancer since 2020. In 2020, we have seven different approvals. And in 2021, how we change lung cancer has changed. So I'm going to hope to make this as interactive and applicable to what you do every day as possible. I encourage you to ask questions as we go. You can put it in the Q&A section of this webinar. We're going to start with a question. Which of the following is true about the use of chemotherapy plus immunotherapy and the neoadjuvant, that means before surgery, setting for no small cell lung cancer? Neoadjuvant therapy delays surgery in patients with resectable lung cancer? The patients that receive neoadjuvant therapy have had longer surgical times and require more extensive surgeries? Or neoadjuvant therapy increase the rates of complete pathological response? All right. Ooh, you're going to learn about this question. All right, so lung cancer has significantly changed from what it used to be even 10 years ago. Before, it was squamous or no squamous. And then now we have become to the molecular pathology level and then a PD-1 expression. So lung cancer is no longer one disease, but many diseases. And that's what makes the treatment more complex. My mentor, Dr. Alex Adjei, told me that for a long time, it was carbotaxel. And that was always the right answer. That is not the case anymore. And what is important for our pulmonology colleagues is that a lot of these therapies are moving to the early stage. What this means is that we are now doing therapy in patients that before, they would only get surgery. And this is the current algorithm for the treatment of small cell lung cancer. Includes neoadjuvant therapy, adjuvant therapy, and for metastatic setting. The goal of this presentation is not for me to break down any molecular aspect, but how can our pulmonology colleagues be involved in this growing complex treatment paradigm that changes every six months for lung cancer? So honestly, when you see the algorithm, it's like, where do I go? All this drug has very different names. I went to pulmonology, so I don't have to learn these drugs. Well, for this webinar, we simplified this presentation quickly. And why is this important? Because we are requiring more and more tissue at the time of diagnosis. Before, for early stage, we were thinking that we were going to get tissue at the time of resection. But now it's changing. We need tissue before resection. And that is quite important, as many of you are essential members of the multidisciplinary team. And always, always, tissue will be the issue with lung cancer. Particularly now that 50% of patients have a target mutation. So for a stage 1b to 3a that are resectable non-squamous, we need EGFR testing at the time of diagnosis. For a stage 3 non-squamous that get definite chemoradiation, we still need EGFR, because we know these patients will not benefit as much from immunotherapy after chemoradiation. And Dr. Reimer is going to talk about the Pacific study but we need the testing so we don't put patients on drugs that don't work for them. And for advanced metastatic, all non-squamous need to get testing. And for particularly patients, non-smokers, young patients, will need that as well. So everything changed in the adjuvant treatment when we had the ADORA trial. And this is different. These are patients that require tissue genomic testing at the time of diagnosis. So the ADORA trial was presented in 2020 and changed how we treat patients with EGFR mutations that have resectable disease. So the ADORA trial is a phase 3 trial that included patients that have limited stage disease 1b to 3a. And we have to remember, all of this is based on the classification that is no longer up today. It's the 7th and now we're in the 8th. So these patients went to surgery. But most of them were recruited before surgery, meaning genomic testing happened at the time of diagnosis. Then they went to surgery. Some of them go chemotherapy after the surgery, not all of them. And then they were randomized to osimertinib, which is an EGFR therapy for three years versus placebo. The main endpoint was disease-free survival. And the study was terminated early because of the great response that was observed. And this is the benefit. So this is disease-free survival. We're showing the group that benefit the most, stage 2 and 3a. And the difference is between disease-free survival, 20.1 months versus 14.9 months. And I always joke about it because you can put a truck in between these two lines. But that is disease-free survival, right? And the data for overall survival is still pending. And how, like, I'm a pulmonologist, how this matters. It matters because we need tissue at diagnosis for genomic testing. And it matters because these patients are in osimertinib for three years. And osimertinib is known to cause pneumonitis. So I overworked with my pulmonologist when we see these very challenging situations in these patients with osimertinib. And it's a great one, it's a great tool to re-challenge these patients. So this is the overall population, including stage 1b. The benefit is less, so the hazardous ratio is still 0.20. This is the most updated data we have for ADORA. But we still don't have overall survival. We have 30% to 40% material data. So what happened with this drop? Well, we noticed that not everybody benefits the same. So stage 1b has the less benefit, and stage 3a has the greater benefits. And that is obvious in these Kaplan-Meier curves. You can see the more advanced stage, the greater the benefit for disease-free survival. So for 1b, I often have conversations with my patients because some of these patients may have been cured, and they don't need three years of osimertinib and all the side effects that comes with that. For 3a, definitely, because they have a 75% chance of having recurrence if they don't go in the EGFR therapy. For stage 2, they have a 40% to 50%. So that's right in the middle. But usually for 2b above, I recommend the therapy because the benefits are greater. Also, these patients are quite young. EGFR mutants are never smokers. So they don't have competing comorbidities that, you know, we affect the survival. Most of these patients will die of the disease. So you want to make sure that you give them the chance to get better. Potentially cure. There are some theories that we may be treating micrometastatic disease, but we still don't have overall survival to answer the hypothesis. Something that's very important about ADORA, this was presented at ESMO after ASCO, is that it significantly decreased the recurrence in the CNS from 1% to 10%. So 10% is the placebo group. Majority of these patients go chemotherapy in the adjuvant setting. And the challenges with CNS disease is it's very morbid, particularly for patients that have no other comorbidities. It significantly affects patients' quality of life. So in 2020, everything started changing after surgery for local lung cancer. These patients with EGFR mutation, which are 13% of patients with lung cancer, now are going in EGFR therapy for stage 1b or above, meaning tissue adignosis and complications for OC mertinib and a new population. Well, if things couldn't all get more confusing, we are back to where we started. So many neoadjuvant studies in lung cancer were negative, didn't show benefit. So we didn't do neoadjuvant therapy. But that changed with CHECKMATE A1-6, what incorporates chemotherapy and immunotherapy. So the new wild factor in this combination is immunotherapy. So CHECKMATE A1-6 is neoadjuvant nivolumab plus a platinum-based regimen for stage 1b to 3a. So these are patients that newly diagnosed. The tumors 1b are higher than 4 centimeters, and they have to have no sensitizing EGFR or ALK mutation. What is that important to me? Well, again, we are now doing NGS diagnosis for early stage because these patients with EGFR mutation and ALK alteration should not go in neoadjuvant therapy because immunotherapy doesn't work for them. So we don't want to delay therapy or delay surgery to give the neoadjuvant therapy when the drug doesn't work. So these patients were randomized to nivolumab plus chemo versus chemo alone. Then they went on surgery. Some patients have optimal chemotherapy after, most patients do not, plus minus radiation. And this is a new endpoint that we are learning from our breast cancer colleagues and its pathologic complete response. And the differences are clear. The people that received the chemoimmunotherapy had a pathologic complete response of 24% versus 2.2%. And you can see why the neoadjuvant studies in chemotherapy were not successful. There was a difference regarding the intention to treat versus the patients that got the resection, but the difference was still very large between the patients that got the combination therapy versus the chemotherapy alone. Again, patients with ALK and EGFR mutations should not get this. So a lot of concerns from my colleagues in surgery is like, neoadjuvant therapy can delay therapy. They can not allow patients to get surgery on time. So this data was later presented by a surgeon and showed that neoadjuvant immunotherapy plus chemotherapy do two things. One, it reduced the time of surgery, the median time for 184 minutes to 217, but also reduced the amount of surgeries, the amount of numbers that patients that needed total pneumonectomy, 17 versus 25. These are numbers, not percentages. A lobectomy increase of 77 for the combined arm versus 61. So what we saw is the combination not only makes surgery shorter, but also may allow for some patients to get less invasive surgery. For a pneumonectomy to a lobectomy, incomplete resections were more possible. But neoadjuvant immunotherapy should not be used to downstage patients. So neoadjuvant immunotherapy did not negatively affect the surgery outcomes. And that's one of the main concerns. What about side effects? If you give my patients all these fancy drugs, they're going to get sick and never get to surgery. Well, there was no significant difference between adverse events between the chemotherapy arm and the chemotherapy arm, the combination of experimental arm. There were more immune-related adverse events, but that all makes sense. If you get an evil, you get more immune-related adverse events. But overall, the adverse events did not significantly delay surgery for these patients. And this is just a summary. Major pathology response, pathology complete response, and experienced downstaging were the benefits of neoadjuvant chemoimmunotherapy in this patient population. And since then, it was approved in March 4th of 2022. Things change. A lot of patients, particularly patients that are high risk for recurrence, stage 3A, stage 2B, other risk factors in the histology of the tumor are getting neoadjuvant chemoimmunotherapy. So these patients can get complications from the nevo prior to the surgery that we need our pulmonologist friends to help us. And also, because we know immunotherapy stays in target for quite some time, they also can have side effects from the immunotherapy, including pneumonitis, after the surgery. And of course, we need tissue early on to do NGS so the wrong patients don't get the wrong therapy. And I can tell you, my tumor boards completely changed after this because now the conversation is not, I always see him in the clinic when he goes to surgery. That's usually what we used to say as medical oncologists. Now we're being incorporated early in the conversation for these patients. Now we're requesting NGS early. And liquid biopsy, going back to webinar number three, two or three, number three, I think, liquid biopsies are not very good for patients that have disease in the chest only because the patient is unlikely to be shredding tumor DNA. So tissue is an issue here. So let's make things a little bit more complicated. Neoadjuvant therapy is approved. Targeted therapy, adjuvant therapy is approved. Now we added immunotherapy in the adjuvant setting with IMPOWER0110. So IMPOWER0110 or IMPOWER10 as a desaluzimab, an immune checkpoint inhibitor, for a year for a patient after they get resected. So this trial is completely resected patients, 1B to 3A. You can see the recurring team here, 1B to 3A, tumors higher than four centimeters because the classification changed. So they got surgery. These patients did not get neoadjuvant therapy. Then they get adjuvant chemo for one to four cycles. And then they were randomized to follow up, because that's what we used to do, follow up and pray that the cancer doesn't come back, or a desaluzimab for a year, which is 16 cycles because it's every three weeks. The primary endpoint was disease-free survival, same outcome that the ADORA trial for EGFR. This trial is a little bit more immature than the ones that we have seen. So this is the data for a stage two to 3A, no small cell lung cancer. We have PD-L1 higher than 1%. So for these patients, don't we only need NGS? We also are needing PD-L1. We didn't need PD-L1 for early stage before, because what were you going to need the PD-L1 for? Didn't really affect much. But now we need it because a desaluzimab in the adjuvant setting, meaning after surgery, is only approved for patients with a PD-L1 higher than one. If it's less than one, they cannot get the drug. So these patients are getting a desaluzimab for a year. What that entitles, I have two patients already getting this drug. These patients, some of them are cured, but the immunotherapy adverse events are still there. And those are relevant, I think, for any internal medicine specialty, because we need an endocrinologist, a rheumatologist, a pulmonologist, all of them, to help us deal with these adverse events. Because now, some patients for a stage 1B to a stage 4 are going on immunotherapy. Many institutions are developing clinics specialized for immune-related adverse events. So what about overall survival data? Still very immature. So the three studies that we just discussed do not have overall survival data. So this is like approve, hurry up, and wait for overall survival data. For neoadjuvant and adjuvant trials, it takes quite longer to get these results. I won't make any conclusions of these overall survival data curves, because the data is still very immature. But we don't have data for any of the three trials. IM-POWER 110, more immune-related adverse events compared to placebo, because it's best supportive care, you get no drug. There were grade 3, grade 5 immune adverse events in the experimental arm. That means we have a few deaths, majority for pneumonitis. And grade 3 and 4, around 22%. So these patients are going on these drugs with more adverse events, no drug. And we're looking at systemic steroids, around 12% of them. And atelizumab was approved. So now we have three different regimens by three different trials that change how we treat lung cancer in less than two years. And just to add to this, there's also PERS-OKINO-091, which is very similar to IM-POWER 10. The difference here is the agent. So instead of being atelizumab, it's pembrolizumab. These results were also very promising. So immunotherapy in the adjuvant setting is probably here to stay. We don't know yet because we don't have overall survival data. But that increases the pool of patients that are going to be in immunotherapy to close to 90%. Because we have 60% of patients that are stage 4 that even if you have the target mutation, eventually they will get to immunotherapy when they develop a resistance to the mutation or to the target therapy. Then we have the patients with squamous cell and patients with small cell that also get immunotherapy and now we have a stage 1b to 3a that can get immunotherapy before surgery, three cycles or can get after surgery. And let's pull the sherry on top of the cake. There is a study done in China that is actually combining the neoadjuvant and the adjuvant. It is not approved in the United States and the FDA will not approve it until the study is done in a population that looks more like the U.S. But this study is including neoadjuvant chemoimmunotherapy, surgery, and then immunotherapy for a year. So you are gonna see all the immune-related adverse events during that interval of treatment. So additional updates outside of the immunotherapy window. We're gonna come back quickly to the targeted therapy and the Colbreak 100. This was presented last year and is currently approved. This is KRAS G12C. And why is this important for me as a pulmonologist? Well, patients with KRAS G12C tend to have higher prevalence of smoking history. There are still no squamous, almost all of them, but they have higher smoking history. So these are patients that we always collaborate with our pulmonologists because they tend to have COPD or many other lung issues undergoing KRAS G12C, which was found to be untargetable. But there's always a joke that the GI oncologists say, we cannot target KRAS. And then the thoracic oncologist said, hold my beer and then we develop KRAS therapy. I don't know if that really happened, but it's a good joke. So KRAS therapy, it is approved in lung cancer. This is around 12% of patients, making that 50% of patients we have target mutation. The agents can be hard to tolerate and a big pill burden. And let's make things more complicated. We have a drug that soon will be approved for HER2 mutant nose muscle in cancer. So there's around 1 to 2% of patients with lung cancer, and that will make the 50% of 52%. This comes from the DESTINY trial that was done by Dr. Jenea here at Dana-Farber. And it shows that patients with HER2 mutation can go and this is a drug conjugate that includes a monoclonal antibody, we a linker and a toposemidase inhibitor that has a payload. What this means to a pulmonologist? Well, around 11 to 13% of these patients develop ILD as a side effect. We expect that this compound is going to be approved in the second line setting probably in the next four to six months. So we are 11 to 13% of ILD, we are going to need definitely all of you. Because these patients with HER2 mutant nose muscle and lung cancer are usually never smokers, majority women. So the first line therapy is chemo immunotherapy. And then they go if it when this drug gets approved to HER2 directed therapy, we are 11 to 13% of ILD. And they actually had several deaths due to ILD in this study. And that's going to be a new ballpark for many else. We didn't see these toxicities with HER2 directed therapy in breast cancer. And it's just because the patient population is very different compared to lung cancer. But that just increased the amount of collaboration and importance of multidisciplinary teams. Alright, so what is the summary of all of this? Lung cancer treatment keeps changing. Now we have neoadjuvant chemoimmunotherapy that is approved. Patients get around two to three cycles prior to surgery. And patients need to be tested for NGS or next gene sequencing or biomarker or genomics. We have so many names, but the points they need to be tested prior to getting the therapy. So we need the tissue to get at least EJFR and now testing. Then they go on the neoadjuvant therapy, then they go on surgery. Then we have adjuvant immunotherapy, where you need a PDL1 to be higher than 1%. Here the need of tissue is less. And then we have the adjuvant EJFR therapy. Finally, there's one new drug that is expected to be approved for HER2 mutant osmocellular cancer that has a higher frequency ILD. And of course, the three years of osimertinib with pulmonary complications. I tried to summarize all these trials in 25 minutes, and it can feel quite overwhelming. But the point of all of this is that our patients are going to live longer and they're going to live better, but they're going to need to lose more because there's more and more patients. The overall survival in osmocellular cancer in the early 90s was six months. Now in patients with ALK mutant no small cell lung cancer, the median survival is eight to nine years. So you see how the amount of patients are increasing. It is a wonderful thing, but we need to be prepared for them. So takeaway points. Genomic testing is a critical part of the initial workup and should be completed before starting immunotherapy in the neoadjuvant setting. And also prior to any clinical trial enrollment in the neoadjuvant or adjuvant setting. Immunotherapy has become the standard of care for patients through the entire continuum for stage 1b to stage 4. There is new targeted therapies and there is new side effects we're learning. It's a rapid evolving treatment landscape where my collaborators, CHESS and other organizations are here to keep you updated. And finally, question two, which of the following targeted agents is approved and is the preferred agent for treating EGFR mutant no small cell cancer as the complete surgical resection? Osimertinib, Sotaricib, or Atisoluzumab. And you need to, I don't want to say the answer, you need to do the homework. Thank you so much. Very nice. Thank you, Dr. Flores, for a great review of the landmark studies that I do believe, as you said, it does affect what we do weekly in our multidisciplinary CHESS tumor board. As I'm reflecting on your talk, I have a couple of questions that as a pulmonologist, I'm thinking when I do a biopsy for lymph nodes, we always know that we get pretty reliable material for molecular testing and for PD-L1. But if we're looking at even more limited disease, stage 1a, b, but no lymph node involvement, that sometimes becomes a challenge to assure adequate material for comprehensive genetic testing. For PD-L1, I don't think people struggle that much anymore, given that only 100 cells are needed. But you mentioned the need for obtaining NGS at diagnosis, regardless of the stage. Can you please comment again, and just clarify for us how that impacts management, independent of OC for the EGFR mutated tumors? Because I think it's different than if we have a target for an early stage, given only one mutation, you know, maybe people can just do directed EGFR testing versus getting a large panel. Although we don't have targeted agents in the neoadjuvant settings. Can you clarify the need for a large panel NGS for very early stage? So I'm not a big proponent of NGS because we are allowed to include patients in other adjuvant trials that are going on for other target mutations. But if you have very limited tissue for 1b, 2a, EGFR should be done as a rapid EGFR, so you need less tissue. So if you know you couldn't get enough tissue, then EGFR alone is targeted for approved therapies. If you have more tissue, then of course, we're going to advocate for NGS and you're never going to find a medical oncologist who's going to tell you no, don't do the NGS, right? So if you have limited tissue, EGFR and OC should be prioritized outside of the panel, because those patients should not get neoadjuvant or adjuvant immunotherapy. And there is a question here in the Q&A that is very important, and it's that, are you concerned about the delay in getting the NGS prior to deciding about neoadjuvant? Yes, it's quite concerning, particularly in areas in which getting genetic testing is challenging, right? So that if you think the turnaround time is going to be too long, then just doing a spot EGFR and ALK should be the way to go. And then one more question is, I'm just learning about the code break 100. That was for stage four, I suspect. And that is non-small cell, non squamous or non-small cell all comers? The majority of the KRAS mutation by far happen in non-squamous, but it's a different patient population than other patients with target mutations, because these patients usually have a heavy smoking history compared to the EGFR ROS ones that usually never smoke. So you have more comorbidities with a drug that's already toxic. And maybe last question from my standpoint, I don't know, Eric, if you have any, or Andreas, in your institution, just to bring your institutional bias into discussion, do you perform NGS for squamous cell independent of the younger population, non-smoking, you know, that's in the guidelines, but outside of the guidelines, do you routinely do NGS for squamous? So we don't do NGS for the, as a clinical NGS. So we have our own protocol called 17,000, that's the name of the protocol, the number of the protocol, and we were able to do NGS in a research study. So we have that privilege that patients won't get charged because the problem about doing squamous NGS is that sometimes doesn't get approved by the insurance. But here I'm able to do that. And because my clinic consists of mostly younger women, I do NGS in the majority of my squamous. Because our 50, 48 year old, we very limited smoking history. But yes, we have the privilege to do NGS and squamous through our research protocol. But it's very challenging outside of this privilege to do it because of insurance coverage for those patients. Yeah. Excellent. Excellent job. Very nice presentation. Very thorough. I just want to make and you made this point a couple of times, but I want to reinforce it for our viewers that I think we've discussed this at our tumor board, particularly since the studies have come out this year. First of all, the overall survival we're waiting for. It's a work in progress, and we need to ensure that patients see both our medical oncologist and surgeons as we go down this pathway. And secondly, this is really for stage two and greater. As you said, stage one B is now stage two a at force greater than four centimeters. So we don't want our viewers to get confused that one B's very few of the team are going to be giving neoadjuvant with immunotherapy for a true one B in the eighth edition. So but exciting times. It's really wonderful that we're able to see this advancement on. I'm excited now to hear from Dr Remner regarding the changes in the advances advancements that he's seeing in radiation oncology. Thank you very much for having me. It's my privilege to present to you the updates on clinical trials in advanced lung can locally advanced lung cancer in radiation oncology. Here are my disclosures of note, I do have several investigator initiated trials, mostly related to this presentation for AstraZeneca and Merck. I'll be as objective as I can. Here's question number one, which of the following treatment paradigms is the current standard of care for unresectable inoperable stage three non small cell lung cancer? Is it concurrent radiation therapy and duralumab followed by duralumab? Is it concurrent chemotherapy, radiation therapy and duralumab followed by duralumab? Or is it concurrent chemotherapy and radiation therapy followed by duralumab? Please enter your responses now. Okay, it seems like the audience is very much on the same page. So maybe I don't need to give my talk. So when it comes to multimodality therapy, here is an overview over what what we can do. You heard from Dr. Flores about the resectable patients here on the on the left column, and the neoadjuvant therapy, definitive therapy and adjuvant therapy. And when it comes to deciding between resectable and unresectable, I always teach our fellows that you have to start with deciding on the definitive therapy and whether you take a patient down the surgical approach or the non surgical approach. And based on that, you can build the other components around the definitive therapy as building blocks. If it is surgery, you consider neoadjuvant or adjuvant therapy. If it's not surgery, then radiation therapy is the definitive therapy, and can be combined with concurrent chemotherapy, sequential chemotherapy, or with chemotherapy first or after radiation therapy. Now, this has gotten more complicated, as you've heard, by the role of immunotherapy, which is now being entered into all of these different components, and plays a role in the neoadjuvant setting or adjuvant setting, as you heard. And the same thing is happening and actually happened first in the unresectable patients, and we will go over the data for that in the definitive radiation therapy or chemo radiation therapy setting. And this is what my talk will focus on, on the unresectable patients that are being treated with definitive radiation therapy. It's been known for quite a while that radiation therapy is a great tool to increase tumor immunogenicity, in that it can increase the available tumor antigens to the antigen presenting cells, and it can upregulate MHC1 and alter the tumor microenvironment to really attract dendritic cells and tumor specific T cells or also tumor infiltrating lymphocytes. And it goes together with a whole change in the cytokine milieu in the tumor microenvironment. And it does that by really breaking down the cells and as the cells die, they set, release, you know, all their different components in a inflammatory environment that then really activates the immune system. Now tumors traditionally have had escape mechanisms that by releasing immunosuppressive signals, and that is really where the anti-PD or PD-1 or PD-L1 therapy came in, that really releases those breaks to make the immune system then recognize the cancer cells again or their antigens, and by doing so, then attacking even the live cancer cells. And the PACIFIC trial was really the key trial that put immunotherapy on the map for stage three lung cancer. And that was a trial on unresectable stage three non-small cell lung cancer who were treated with chemotherapy and radiation, and were then enrolled after completion of chemoradiation and randomized to the addition of duralumab, an anti-PD-L1 antibody versus placebo in a two-to-one randomization. And they had to start within 42 days after concurrent chemoradiation. The primary endpoints were PFS and OS, co-primary endpoints. And we now have five-year overall survival data that were just published in the JCO. And these are the updated overall survival curves. You see that the overall survival had a hazard ratio of 0.72 with the addition of duralumab, and it increased the five-year overall survival from 33% to 43%, a 10% increase. And that's been the largest increase that we've seen in the management of stage three unresectable lung cancer in the last 20, 30 years. And this was accompanied by an improvement in progression-free survival of about 14, 15% from 19 to 33% at five years. So about a third of our patients now are free of disease progression at five years with stage three locally advanced non-small cell lung cancer. Now, one of the questions was, now we have an effective drug, but does it improve survival by improving distant metastatic rates and preventing distant metastasis or by intrathoracic local recurrences? And the PACIFIC trial did not enroll patients prior to chemoradiation. So we don't have detailed chemotherapy and radiation data. And so we couldn't determine exactly local control in the sense of is the primary tumor or the lymph nodes that were initially involved what recurred. But what we do have is the intrathoracic versus the extrathoracic progression. And this is what was presented in 2019 at ASTRO. And you can see that duralumab improved the intrathoracic progression, which includes, let's say, you know, metastatic lung nodules, but also of course lymph nodes and the primary tumor, as well as extrathoracic progression, meaning distant metastasis. So it is effective on both. And that is likely what adds up to the progression-free survival and to the improvement in overall survival. And so we finally have a drug that can work on distant as well as intrathoracic disease control. Another aspect that was really interesting when diving deeper into the data was that about two thirds of the patients that did progress after the Pacific Protocol of chemoradiation and duralumab progressed only in one or two lesions. And that is particularly relevant as local therapies such as surgery or radiation therapy now play an increasing role in the treatment of what we call oligoprogression, meaning patients that when they progress only progress in one or two metastases. And so this is based on now three phase two randomized trials that showed a six month benefit just with the addition of local therapy in an oligometastatic setting. And it's remarkable how similar these trials were, even though there were three independent trials. And if this was a novel drug, it would get approved right away with this kind of benefit. Now, what are the open questions at this point? Building on these data, can we give immunotherapy concurrently with chemoradiation? And how do we balance that against toxicity? How do we treat patients that are not fit for concurrent chemotherapy and radiation and consolidative duralumab so that are not fit for this specific regimen? We also are looking into questions of what the optimal radiation dose and fractionation is, whether we can elicit an even more effective immune response. And on the industry side, there's a lot of interest in combining anti-PD-L1 and PD-L1 drugs with other immune modulators, co-stimulatory drugs. And then lastly, which are the optimal drugs and can we do dual checkpoint inhibition? Now, look, I'll present some of the trials that are ongoing. So Keynote 799 was the first trial trying to give concurrent anti-PD-L1 therapy using pembrolizumab with concurrent chemoradiation. And this was a two cohort trial, not randomized. Patients were given a carboplatin-paclitaxel backbone or a cisplatin-pemetrexib backbone in non-squamous patients only. The cohort A was a combined squamous and non-squamous cohort. And this was published by Dr. Jabbour in JAMA oncology and the results were quite promising with an overall response rate of around 70%. And you can see the curves here with, you know, that are really quite remarkable for, you know, a stage three patient population. And this was regardless of PD-L1 status. The toxicity overall was manageable, though slightly increased compared to what we saw with concurrent chemo radiation or the Pacific regimen with grade three pneumonitis, meaning requiring oxygen or hospitalization of somewhere around seven, 8%. In the Pacific trial, that was more around three, 4%. In the real world, the data are likely a few percent higher again. So this is important information, again, for you as a pulmonologist, just as we combine these drugs, as we pile on more and more drugs and combinations, the pneumonitis rates are going to inch higher. The Pacific II trial is looking at a similar question, but in a randomized fashion, two to one randomization of adding the Dorvalimab to the chemoradiation versus placebo and chemoradiation, but followed by placebo. So this is essentially moving up Dorvalimab by about eight weeks to start together with concurrent chemoradiation, but it compares it to the old chemoradiation only approach. And so this will probably read out later this year and will be interesting. However, it will be difficult to compare to Pacific I because Pacific I is now the standard and we will not know exactly should we now, let's say this works, give the Dorvalimab upfront or only after chemoradiation. And so we don't know exactly how they will compare to each other. However, an important advantage of this trial will be that patients are randomized from the beginning. So we will have detailed chemotherapy and radiation information, and we will be able to answer some of those questions that were not possible to be answered by Pacific I. Now this ECOG trial will answer exactly that question because it randomizes patients of essentially Pacific I versus Pacific II. So Pacific I is concurrent chemoradiation followed by Dorvalimab versus concurrent chemoradiation plus Dorvalimab followed by Dorvalimab. So this will be really the tiebreaker trial, if you will, to give us the final answer of how these two compare to each other in terms of toxicity, as well as efficacy. We look forward to these results. The CheckMate 73L trial is essentially a similar trial looking just at a different compound, Nivolumab. And it's given either concurrently with chemoradiation followed by a dual checkpoint inhibition, Ipinivo, or by Nivolumab alone, which is essentially Pacific II just with Nivolumab. And it compares this in a three-arm trial to the Pacific I regimen, concurrent chemoradiation followed by Dorvalimab. Of note, there was a small trial looking at Ipinivo combined with concurrent chemoradiation, and that was too toxic. So Ipinivo as a dual checkpoint inhibition combined with concurrent chemoradiation is too toxic. We'll see how it works in the consolidation setting. Now, this is all nice and good for the patients that are the fittest and the best and the strongest out of the non-surgical patients. But the reality is, depending on how aggressive your surgeons are, that many of the patients who are not fit for surgery may also not be fit for concurrent chemoradiation followed by Dorvalimab, or in the future, maybe for quadruple therapy of concurrent chemoradiation, Dorvalimab and X. So what do we do with these patients? They don't have an approved indication. And about at our institutions, about 50 to 60% of patients who are not fit for concurrent chemoradiation because they're too old, they have organ dysfunction, or the tumor is just too large and bulky. And so traditionally, we would treat them with sequential chemoradiation or just radiation by itself, which has a five-year survival of 5%. So that's really not, that's barely better than palliative therapy. And so we need to find solutions for that. Pacific VI is one of those attempts, and it's looking at these stage three patients that are frail. It's a phase two open-label trial, and it's looking at sequential chemo-RT followed by Dorvalimab. We have taken a different approach. This is our phase two study, and it's a single arm study. And we combine definitive thoracic radiation with Dorvalimab. The concurrent chemotherapy adds about 5% to overall survival over radiation alone. But as you've seen, the Dorvalimab especially early on added about 15 to 20% progression-free survival and 10 to 15% overall survival. So in this already frail population, we're essentially trying to replace chemotherapy with Dorvalimab concurrently. And this trial is two-thirds accrued, and we will have a planned interim analysis presentation at World Lung in August of 2022. So stay tuned. I can't say more than that because the data is embargoed. NRGLU004 is a trial from my colleague, Dr. Lynn at MD Anderson, where he tested a different type of radiation or different dose of radiation, 60 grain, 15 fractions, as opposed to the standard, which is 60 grain, 30 fractions over six weeks. So cutting the treatment duration in half to three weeks and giving a higher dose of radiation each time. And the initial endpoint was to first prove that that is safe to give a higher dose per fraction in combination with Dorvalimab without chemotherapy. And it turned out it is actually safe, but it was a small first initial trial to look into that in this patient population. So we'll likely see another trial building on this through the NRG cooperative group that will look into fractionation and combination of radiation and Dorvalimab. Now, there are a whole bunch of immunotherapy enhancing compounds, and this is only a small selection. This is by no means complete, that are ongoing, COAST, Skyscraper, Keeling, and Advantic, just a few of them. And these are all combinations of different antibodies like anti-TIGID or anti-CD73 that are trying to enhance the anti-PD-1 or anti-PD-L1 effects. The first one to read out is the COAST study, which was a phase two randomized study that was presented at ESMO 2021, and compared patients getting the Pacific regimen with Dorvalimab and Olectromab or Dorvalimab and Monalizumab. And the results were this. Another big jump in progression-free survival from 39% to the 70% range at around close to a year. Now, some people say that the Pacific arm in this trial underperformed, but nevertheless, this is a big improvement in a randomized phase two trial. The numbers are still a little bit on the small side. We'll see whether it holds up in a larger trial, but still, you can see how the immune therapy enhancing compounds really may very well push the curves higher, which is great for our patients. We are currently performing, my colleague, Dr. Shaberdian, a anti-IL-1 beta trial in combination with Pacific. IL-1 beta is important in tumor promotion and it creates that immunosuppressive microenvironment that I mentioned earlier. It can also, interestingly, suppress pneumonitis and pulmonary fibrosis. So it has the potential of making, you know, the chemoradiation and Dorvalimab more effective, but also decreasing toxicity, which would be a great combination. It's sort of the ideal combination, which rarely happens when we combine new drugs or add more drugs. But this is why we are very excited about this trial. And we're essentially adding Canakinomab to standard chemoradiation followed by Dorvalimab, the Pacific backbone. And yeah, this is an ongoing trial. It's about halfway accrued and we do not have formal results yet. Not to forget, even in the unresectable patient population, there are patients with EGFR and driver mutations. So this is the Laura study. And it's looking at, similar to the Adora study, adding Osimertinib on the back end after chemoradiation versus placebo. And this is specifically for patients with EGFR mutations. On the radiation oncology side, I would be held accountable as a radiation oncologist. I wouldn't be talking about what we are improving on the radiation side. There are novel technologies that allow us to target the tumor even more precisely, avoid the lungs even more than we can do right now. There are increasing MR linear accelerators that really allow soft tissue imaging to a degree that we haven't been able to do. In the thorax, it's a little bit challenging because of all the tissue density differences, but we are making progress. And especially for the mediastinum and the heart, the esophagus, it can be very beneficial to be able to see those even during the treatment and adapt the radiation as the tumor shrinks. It also has functional imaging capabilities, which might be very interesting in the future to detect early responses. And then there's proton therapy, which is a specific radiation technique that allows the radiation beam to stop and maximally spare organs that are distal to that stopping point. And there's an ongoing randomized trial, RTOG 1308, which compares protons versus photons. So that can be very beneficial in some patients when the anatomy and the geometry is right. Talking about new biomarkers, circulating tumor DNA is a hot topic. And it is not quite ready for prime time in the stage three settings, mostly because of detection issues. You heard from Dr. Flores how we all need more and more tissue because we're doing more and more genomic testing. And we do it earlier and earlier, but it is challenging, especially in the unresectable patients. And so CFDNA would be a great way to circumvent that issue. We just presented a post at ASCO a few weeks ago where with Notera, we were able to identify a tissue-informed patient-specific assay and develop that to detect 100% of stage three patients and even close to 60% of stage one and two patients, which really has not been described before. And we could see that it really separates between the patient that progress and recur and those who don't. And you can see how these curves separate, especially when you get longitudinal testing, multiple testing points. And yeah, so there's great hopes that this will allow us to circumvent some of the tissue challenges that we have in this frail patient population. So in conclusion, concurrent chemoradiation followed by consolidation development is the standard of care for unresectable and inoperable locally advanced non-small cell lung cancer. We are looking at different fractionation of radiation, combination of immunotherapy and radiation without chemotherapy or other immunotherapy enhancing combinations. Future developments certainly on the radiation side include novel technologies, such as the MR-LINAC and proton therapy and biomarkers such as ctDNA. And that brings me to the second and last question. What is the five-year overall survival with concurrent chemoradiation followed by consolidated duralumab, the Pacific regimen? Is it 33%, 43% or 53%? Please enter your responses now and I thank you for your attention. Happy to answer any questions. Thank you, Dr. Reimner. Again, I appreciate you updating us on what's in your radiation oncology trials. And again, as a pulmonologist who also does intensive care unit medicine, I unfortunately encounter patients that sometimes suffer toxicity both from radiation or radiation plus IO. And in the ICU setting, the severity is such that we always treat, right? We would hide those steroids. The challenge comes mainly in our clinics. And as Dr. Flores mentioned, the University of Chicago, we also have a dedicated clinic just on IO toxicity. But occasionally they need people like me to go and do a biopsy or a lavage. And I always wonder, does it matter if people have an IO-related toxicity or XRT-related toxicity since you end up placing everybody on steroids anyway? It's a very pragmatic question. As long as they don't behave infected, I feel like there is always this request for bronchoscopy, lavage, maybe even biopsy. And can you share what's in the guidelines in regards to that, if there are any, and maybe your institutional bias on how you address IO and XRT-related toxicity, especially when in combination, we know that the percentage is higher. And I think we've all seen that. Yeah. The short answer is no, we don't. And I agree with your pragmatic approach. Unfortunately, steroids are the only treatment that we really know of. And it works for both, at least in most people, before they get to the ICU setting. So the vast majority, when you initiate steroids early enough, when they develop grade two pneumonitis, will reverse quickly within a few days. And then it's just a matter of keeping them on the steroids long enough, especially for the radiation pneumonitis, until it settles down over time. I think it's my sense that radiation pneumonitis can hang around for a little longer, and maybe tapering slower is more important. Ultimately, it is really tapered to patient symptoms and trying to prevent a rebound of symptoms. In terms of determining whether it's from radiation or immunotherapy, I think the pattern radiographic can help. It doesn't necessarily change the management, but when it's very diffused bilateral, it's more likely immunotherapy. If it's sort of restricted to the radiation field, it's more likely radiation or a combination of the two. But there are examples also where, even before the immunotherapy era, you would see a diffused bronchiolytic picture from just radiation alone or chemo radiation. And so it's not a perfect measure. I don't use radiographic pictures really to determine who needs to be initiated on steroids. I think it's a clinical diagnosis. Almost every patient who gets radiation has a radiographic inflammatory picture to some degree, but most patients, 80%, 85% do not ever develop symptoms related to that. And that's okay. That's just as if you had surgery and you have a scar from surgery. You know that you had surgery. You know that you gave radiation. That's not something I would jump on, but it's based on clinical presentation. There's only, we just completed actually a randomized phase two trial at Memorial on the use of nintetanib in combination with steroids. Nintetanib has been approved for IPF and has been quite promising. And the manuscript is hopefully to be accepted sometime in the next week or so. It's under review. And that was promising. We presented the results and it showed promise in reducing pulmonary exacerbations in the following year compared to steroids alone. So that might be an avenue in the future. I don't think that, that was only in radiation patients. That was before the immunotherapy era when we performed that trial. How that applies to immunotherapy pneumonitis, I don't know. And my follow-up question then, and I don't know if Dr. Flores wants to chime in on this as well. Just a quick add-on. I think something that helps me with the immunotherapy pneumonitis versus radiation is the response to steroids tends to be a quick, faster for the immunotherapy-induced pneumonitis. They tend to feel better. Also, only a few patients that give steroids don't feel great. You know, like the tiger from the commercial and the cereal. But I think that, right, I feel great. I'm ready to go home as soon as you start that. Pregnancy's on one milligram per kilogram. But their response to steroids is faster. I have seen it with immune-related toxicity instead of radiation. And my question, maybe for the end here, unless Eric has other questions. In this combination, trials of immunotherapy and XRT, it looks like the outcomes are always the same as in oncology, right? Disease-free survival, overall survival, et cetera. Do people look at the quality of life at all? Is that measured and objectively documented? And I'm looking more for a patient-centered outcome in trials that have a high risk for toxicity. Can you comment on that? I can say for our own trials, definitely. I have PROs included in all of them. I have not seen a lot on the ongoing trials yet. I think they usually take a little longer to read out. And obviously, you want a little bit more follow-up. Also, the challenge is that they are not always the most sensitive instruments. So you need large trials to really see a difference. So while I think it is very important to include in all the trials, to really see a difference in a randomized trial, you need a big difference in effect to see that in a PRO. But I completely agree with you. I don't think they are sensitive enough to see like a three, four difference in rate three pneumonitis or so. You'll have to look at larger differences. In that same vein, is there any work looking at any sort of predictor, whether it's a biomarker or just the individuals that are getting radiation and immunotherapy now, where we can say this population has a higher risk so that we can keep an eye on them? Because some of these people, they'll get a grade one or two and we won't know about it. And all of a sudden they came in with a grade three or four. And by then, they're in big trouble. So is there any predictions that are used or any biomarkers or predictors that we can use? There is, to my knowledge, and Andreas, you can help me, there is no biomarker who would tell us who would develop the toxicity. I think also has to do with lung reserve and the patient's lung capacity prior to treatment, because those patients are a little bit more careful and I tend to watch them very closely because if they lose tiny little bit of lung capacity, the symptoms are catastrophic compared to a marathon runner that has to go through that. Yeah. From a radiation perspective, I mean, we have prediction models. That's what we use when we design the radiation fields. And the dose of radiation and the volume of lung receiving radiation definitely correlates with the risk, but it's not a perfect system. We also found that radiation dose to the heart correlates with survival and sometimes with pneumonitis in some studies for reasons that are pathophysiologically not clear. But so we pay attention to that when we design the radiation field. In terms of predictors, there are no biomarkers that I know of. Some people have looked at CT density of the lung tissue or at PET avidity of the normal lung tissue and sort of the inflammatory ground state. And some studies have found some correlation there. But ultimately, again, they're predictors, but they're not perfect. And we wouldn't put patients on steroids prophylactically because you don't know whether or not they will develop it even if they're at high risk. Yeah, and the medical oncologist is going to call you yelling at you. Why do you start this patient at more than 10 milligrams of pregnisone in immunotherapy? Exactly. So if we had an intervention that could prevent pneumonitis, which we don't have yet, or minimize that risk prophylactically, then maybe that would be more important to be able to predict that. Well, this discussion could go on for quite a bit of time. This is, as usual, the time flew by. I, again, want to thank CHEST for allowing us to put this webinar together, our sponsors for providing the resources, my co-chair, Dr. Murgu, and our esteemed panelists, Dr. Flores and Dr. Remner. Thank you very much for your expertise and your time. And I'd like to invite the audience to join us for our fifth webinar. It's been loaded up in the box. I'm not going to share the slide just for, well, actually, let me see if I can share the slide for completeness. It's the fifth in the series of five of our webinars, and we would encourage you to join us on June 28th for the fifth and final presentation. And with that, thank you again, panelists. Thank you again for the attendees for your attention. And I hope everyone has a pleasant evening.

lung cancer management

neoadjuvant therapy

adjuvant therapy

immunotherapy

radiation therapy

targeted therapies

ADORA trial

genomic testing

clinical trials

multidisciplinary collaboration