Hello everybody, good morning, good afternoon or good evening based upon where you are based in the world. Welcome to the ISLC webinar based on the 2023 World Conference on Lung Cancer. We have titled it 2023 WCLC Highlights. My name is Dr. Nameet Singh. I am a professor of pulmonary medicine, a thoracic medical oncologist and the faculty in charge of the Lung Cancer Clinic at the Postgraduate Institute of Medical Education and Research at Chandigarh, India. And I'm honored and pleased to be moderating this webinar today. We have three excellent speakers who will be presenting two abstracts each, very important abstracts that were featured in the 2023 World Conference. And we will start this activity with some brief housekeeping items. This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education, the ACCME. The International Association for the Study of Lung Cancer, ISLC, is accredited by the ACCME to provide continuing medical education for physicians. The International Association for the Study of Lung Cancer designates the live format for this educational activity for a maximum of 1.0 AMA PRA Category 1 credits. Physicians should only claim credit commensurate with the extent of their participation in the activity. Now, all faculty planners and reviewers for the webinar today have disclosed their conflicts of interest, and this information will be visible to you in the next few slides. And so with that, I'm going to introduce the speakers one by one. So the first speaker is Dr. Christian Rolfo, MD, PhD. He is a professor of hematology and oncology at the Icahn School of Medicine and the Associate Director for Clinical Research at the Center for Thoracic Oncology at the Tisch Cancer Institute, Mount Sinai, New York. In addition, he is the president of the International Society of Liquid Biopsy. Dr. Rolfo is a globally renowned expert in liquid biopsies as well as drug development and molecular oncology. And so it's my pleasure to hand over the virtual stage to Dr. Christian Rolfo for two very important presentations. Thank you very much, Dr. Syed, and it's a pleasure to discuss today these two important studies that were presented at World Lung Cancer. The first one is the FLARA2 studies, and I'm following with the perioperative treatment in small cell lung cancer that was the AGM trial. So the FLARA2 studies is a phase two study that was presented with this. You see the design here, patients with non-small cell lung cancer, pathological confirmed non-small cell lung cancer with the two common mutations with performance status 01, a stable CNS metastasis where a low, and that's an important because we will see the results of this, and the patients were randomized one-to-one to receive Osimartinib plus combination of a double chemotherapy with parametric set carboplatinum, followed by maintenance, and in the control arm was Osimartinib at a normal standard dose, 80 milligrams QD. The total number of patients included was 557 patients, and the patients were evaluated by the RISIS one-to-one assessment, by independent review, and by investigators. The primary endpoint was progression-free survival, but investigator using the RISIS one-to-one, and also was a secondary analysis of overall survival, overall response rate, the duration of response, the DCR, and some assessment of quality of life and progression-free survival too in the secondary endpoints. So we will see these results, specifically the primary endpoint, and we see here for investigator primary endpoint, this is a very important data coming from this median progression-free survival month. You see that the difference there between 25.5 months compared with 16.7 months, and an important hazard ratio that is 0.62. Specifically the difference is a guarantee of 8.8 months, and the difference is stable at 12 months and 24 months in this setting. Surprisingly, in the independent review, you see also was an improvement. So generally we see this in the contrary way, because the investigators are a little bit more conservative, less conservative to take this kind of assessment, but you see here that was 29.4 months compared with 19.9 months with a guarantee of 9.5 months, and maintaining this 0.62 hazard ratio. So very positive results. And that was, if we compare, for example, with the FLARA trial, per investigator was similar, 18.9 months as well. The benefit was seen across all the subgroups, and specifically if we are taking in consideration the brain metastasis, you see here that patients with brain metastasis have an important activity, 24.9 months compared with 13.8 months in progression-free survival, and also in patients, was seen in patients without metastasis, obviously 27.6 versus 21 months. If we are looking for the mutation type, we see also that the patients with 858 have an important also benefit from 24.7 months compared with 13.9 months, and the hazard ratio is also very important, 0.63, very nice hazard ratio. Also obviously the benefit is known in exon 19, and that is in accordance what we see generally in difference between these two mutations. If you are looking for safety here, there are some obviously concern when we are adding chemotherapy, and if you look for the gray 3, any gray 3 in the arm for, in the control arm is lower, obviously, than the combination with chemotherapy, but if we are looking specifically for the gray 4 toxicity in the combination where most of these toxicities were hematological, so that is associated with chemotherapy. We know that, and it's not a surprise to have this kind of toxicity. So my take-home message for this study is that the FLORA-2 meets the primary endpoint. This is a very important trial because we have this opportunity to see progression-free survival that is improved compared with the Osimartinib alone when we are doing with chemotherapy. The benefit was observed specifically, as I say, in brain metastasis, and in patients covering the A5AR mutation. This is also improving a lot, but we have some of the concerns of the toxicities that is driven by the chemotherapy. So my open questions for this trial will be, overall survival still is immature to take some decisions where we will position this trial and this sequence, and maybe we need to use this data for patients that have specific commutations. That will be an important opportunity to understand. That is the part of the biomarker for escalating strategies that we need to improve, and in case of the platinum-based chemotherapy, the toxicity also, we need to try to see if it's possible to reduce that in some way, and also to, for example, see if the COMPEL studies or a diagnosis, if we can add Osimartinib at progression. So these are several questions, but in conclusion, I would say that was a very positive study. We need to find a way to do the sequencing to implement this trial. The second part of the presentation, I would like to talk about this AGM trial, and I took this slide from Dr. Cascone, that she presented in warland cancer as well, to see how we are in the landscape with patients with respectable non-small cell lung cancer, and that's how the ongoing phase three trials, we have the new adjuvant setting, the adjuvant setting, and the perioperative. Some of them we have, for example, in the KNODE-671, a recent press release that showed that there is a positive remark for overall survivor, positive result for overall survivor. We will wait for this data coming out to do an analysis of the data, but it's important to have these opportunities around the surgery for these patients. In the case of the AGM trial, it was a trial that was including stage 2a until 3b and 2 for the classification 8, and then patients who have lovectomy as liver resection or bilovectomy as planned surgery. Confirmed PD-L1 status and non-documented mutation of EGFR and ALK, so that was important because it was an amendment of the trial to include, so you will see that the intention to treat was modified from the total number 802 to 740. That was the total analysis excluding the patients with EGFR and ALK. So the trial was randomizing one-to-one patients who received durvalumab plus platinum-based chemotherapy for three cycles, sorry, for every three weeks for four cycles, then for surgery, and following with durvalumab for 12 cycles every four weeks. And the control arm was the placebo plus the chemotherapy and also the placebo at the control after the surgery. Primary endpoint, pathological complete response by the central lab, and the event-free survival using the independent review committee. And the secondary endpoints were also MRP by the central lab, disease-free survival by independent review committee, and overall survival. The data that we have here are very interesting. So we have first planet interim analysis, you see that this probable event-free survival was not reached in the arm of durvalumab, and in the placebo and control arm, it was 25.9 months with a hazard ratio that was very interesting, 0.68. If we look for the final analysis of the pathological complete response, the difference was 13%, 17.2% in the durvalumab arm compared with 4.3%. So very interesting data also in GAN and C4 pathological complete response. And this is the planet trial treatment and surgery summary for these 740 patients, 740 patients that were the intention to treat after EGFR and ACWR were removed. And you see here the patients were able to complete an 84.7%, the four cycles in the durvalumab arm compared with 87.2 in the chemotherapy control arm. And also the surgery was completed in 77.6 and 76.7% of the patients. So that means that when we are looking for the complete surgery, regardless the stage of the disease, in addition of the perioperative durvalumab in neoadjuvant chemotherapy did not impact in the feasibility of surgery. This is very important because sometimes we have these discussions with surgeons. The timelines relative to the surgery, they have here the median range for the last neoadjuvant treatment to the surgery was very similar, 34 days in patients with both arms. And also the median range for the surgery to the first adjuvant setting, the first adjuvant treatment was also very similar, 50 days versus 52 days. And the surgery delays were due to the logistics majority of the reasons that was the surgical delay and the surgical delay was performed or was seen in surgical or any delay was seen in 17.3% versus 22% in the placebo control. If you are looking for the data on the type of surgery and the surgery approach, we see that there are no negative effects on surgical approach for our type of surgery. And the chemotherapy and immunotherapy is associated with a higher resection zero, R0 resections rates, that is a very important also concept when we are discussing with surgeons. If you are looking in general in the neoadjuvant and perioperative phase three trials, surgical acceptability is very comparable, it's above 80 in the majority of the trials. And you see the NeoTorch, for example, the patients underwent the surgery in the 82% versus 73% in the AGM, as I say before, 80% in 0.6 in both of the arms and 0.7 in the placebo control. And also the checkmate, 116, you see there that the acceptability in the trial was above 80% in the experimental arm and also in the K-note 671. So we are waiting for the result of this last one, and we saw that it was positive, as I say. But in conclusion, I will say that this is an updated analysis that confirmed the result of the AGM with no negative effect of the neoadjuvant on the surgical outcomes. The neoadjuvant chemotherapy immunotherapy is overall safe, there is no major surgical delays of cancellation compared with the neoadjuvant chemotherapy. And also we have some questions here, perioperative approach to neoadjuvant chemotherapy when we compare neoadjuvant versus perioperative in the AGM and the checkmate 816, which one is the best approach? 20% of the patients did not went under surgery, so this is important that we consider what we need to do with these patients and also the optimal duration of the post-operative immunotherapy. Specifically, if we will offer this to the patients with complete pathological response, and the use of predictive biomarkers we saw in several other studies, ctDNA for minimal residual disease, PDR1 and TNB, could be also important when we are selecting this kind of trials. Specifically, we saw data, for example, in adjuvant with the in power zero thing with the PDR1 status. So we need to answer all these questions to get this in the clinical practice, but it's a very important data coming from these trials. Thank you very much. Thank you, Dr. Rolfo, for summarizing these two abstracts very well. We already have a few questions and I'll start with the first question in the chat, which says that how should patients with stage 4 EGFR positive and SCLC having an exon 21 L8 5-8R be optimally treated? And it says, especially in the light of recent real-life data on first-line osimertinib having median overall survival of approximately 18 months. And I think that brings us to the fundamental question whether all EGFR mutations are similar or not. We know that exon 19 deletions and L8 5-8R perhaps represent two different subtypes. And so what are your thoughts about that? No, I think it's very important to have this data in difference. We know that there are differences in these two mutations and we have evaluated that in treatments. We see also the commutations are playing an important role in the progression for survival, for example, and in other outcomes. So it's important to know this difference that we don't have this data at the moment. But I think we need to count in this. This is another possibility that we have at the moment with the toxicity. And knowing that the overall survival are not complete mature, I will wait for that data to select this in the patients. We are using actually chemotherapy and osimertinib in patients that are progressing without any mechanism of resistance. And that is a strategy that is there. But I think if we want to pass for this to the frontline, we need to know a little bit more about the overall survival. So remain a positive remark, but still waiting for more data. And I think this trial has to be interpreted in the context of two trials which were published three years back. One was the NAGA009 trial from the Japanese group and another was a trial from Data Memorial Hospital in Mumbai in which they combined Jeffitinib with Pemetrexid carboplatin. And expectedly, the outcomes were superior for the combination for progression-free survival. In fact, the NEJ009 reported its overall survival data also. And although it was numerically higher with the combination, it did not reach statistical significance. And the adverse events expectedly were higher in the combination as well. And so I think that's very correct that in order to select patients, if you have brain metastases, fit patients, younger patients, then the combination can be considered. But for perhaps elderly, frail patients, you may want to think twice before using this strategy. We all, everybody realizes the importance of looking, waiting for OS data. And as you rightly said, perhaps ctDNA monitoring may ultimately help us narrow down or choose more appropriately which patients to put with what therapy. And I'd like to take one more question and that is that how do you explain the benefit of chemotherapy plus Ocimartinib in brain metastasis because Ocimartinib alone has CNS penetration but not chemotherapy alone. And so it's a very interesting question. So I think we don't have the correct answer for that. Obviously, when we are analyzing the data we have there is a big bag, no? We are putting CNS all together. We need to see some characteristics. We don't know, for example if these patients were pre-treated with radiation because we only know that they are asymptomatic but were pre-treated, which kind of numbers of metastasis they have where a single metastasis where several metastasis in the brain. So it's important to know all these characteristics to understand a little bit better. For sure it will be some biological explanation why chemotherapy is improving in this because we know like the comment was there in the chat that chemotherapy alone is not able to penetrate the brain and get these responses. So maybe there is a kind of alterations. I don't know, I'm guessing it could be alterations for example, in the vasculature that we are doing or making more easy to penetrate and the synergies of the potential, for example, for Osimartin in the brain. So all these questions, I think we need to take with the biology behind. So CSF, for example, in these patients in the future thinking a little bit, we are doing already CSF for alterations and looking for these alterations in the brain. So it's a very interesting question but we don't have a real answer, unfortunately. So I'd also like to touch upon the perioperative immunotherapy field. This is something which is moving as fast as did the immunotherapy data for metastatic disease just a few years back. And I mean, we still don't have clear answers of what is the optimal dosing of the immunotherapy agents, optimal duration. And maybe we can get inputs from our other speakers, Dr. Lisa Hendricks and Dr. Clarissa Valdetto. What are your opinions about the AGN trial and how it puts the other trials into context, especially the keynote 675, 671, the Empower 010, which was a purely adjuvant trial. And so the Checkmate 816, which was a purely new adjuvant. And so we really still have to define what really is needed for most patients or how do we go about it, Dr. Lisa first and then Dr. Clarissa. Yeah, I think for me, the reassuring thing is that all trials more or less point in the same direction. Somehow new adjuvant perioperative immunotherapy can be beneficial for patients. And I think we really need to do as an academic society more to understand which patients should receive a certain type of treatment. And it also, I think in the end, practically depends on what is available in your country. For example, in the Netherlands, we can only give adjuvant immunotherapy in stage three PD-L1 high. So if you want to give this patient somehow immunotherapy in an early disease setting, and if you have something new adjuvant available, of course, then you go for new adjuvant because you will be restricted in the adjuvant setting. But I think we also need to look at biology, which patient really will benefit from only new adjuvant therapy. And probably these are the ones with a pathological complete response and those who don't probably need also some adjuvant strategy. But then we don't know whether it's really enough to add immunotherapy, monotherapy to patients who don't have a pathological complete response. I think it will be a challenge. And on top of that, I think the definition of resectable non-small cell is also a challenge because I think all the trials stated, well, the disease should be resectable. And we just also at WCLC, we had an EOTC initiative while discussing what is resectable non-small cell lung cancer, and I think it takes too much time to completely summarize it. The slides are on the WCLC website, but there was quite a lot of discussion about what is resectable. So I think we really need to standardize how we document which patients were in the trial before we're going to compare the clinical trials and also need to collect more data about the end status. Multi-station can be two, can be multiple. You really need more granularity. I think in general, I would favor based on biology, at least neoadjuvant therapy for the priming of the immune system. And then probably the majority of patients will need something adjuvant. But I think we need to find those and also those who don't need it. Thank you. I agree. I think neoadjuvant is an opportunity to understand better the biology of the disease. So we have for now, we need to recommend neoadjuvant immunotherapy and chemotherapy for most of the patients based on biology, of course. But it brings different discussions. All these trials, these me-too trials, kind of me-too trials, they bring a lot of new discussions like what to do after pathologically completed response, even bringing back radiotherapy for the discussion, because in last years, we kind of tried to take radiotherapy off our adjuvant approach. But now I think even this kind of discussion, we are able to bring it back to the table. And I hope all of these patients included in these trials, I hope they are collecting data enough so that we can make some conclusions regarding. So I think the real question now is adjuvant therapy after neoadjuvant therapy. That's the most important question we have for us now. And I can add on just the age of four. I think brain maths is like a really a challenge for us. And like, I only can think about biology too. Like there's no data coming from CDKN2A and B deletion. Maybe the chemotherapy approach has to do with this kind of alteration that we are seeing more and more in brain maths patients. Yeah, and coming back to the perioperative concerns, I think we need to work very close with the surgeons because sometimes like Dr. Hendrik says, the conversation that we have, we are pushing some decisions sometimes that we want that the patient is operated, but if the patient is not really operated, we need to don't offer sometimes some of the approach that we have right now. So we need to see when it's really respectable, the patient and the possibility to apply and reduce the tumor to be able to be resected, but not to be pushing some decisions to try to get treatments in patients that they don't have opportunity to be really resected. So these are the discussions that we need to have with our team. So it's very multidisciplinary. And Dr. Valdotto point a very important topic that is a radiation here, how we will integrate these in some of these patients. Thank you. So I think in the interest of time, we are going to move on to the next presentation and we are going to continue this discussion about immunotherapy in that as well. So now it's my pleasure to invite Dr. Clarissa Valdotto. Again, MD PhD, she's a medical oncologist and the president of the Brazilian group of thoracic oncology. And she's a member of the education committee of ISLC. And she's going to be again presenting two very important abstracts from the WCLC. All yours, Dr. Clarissa. Thank you. First, I'd like to thank the, and I'm honored to be here and thank ISLC for the kind invitation. So my first abstract, I believe is maybe one of the most important. It was present at the plenary session, but by Dr. Asamura. And it's the new lung TNM edition, the ninth one. They also presented chains for mesothelium and thymoma that are not shown today. And this first picture illustrates all the staging project effort over all these years. And I just would like to highlight for the new edition, the increasing participation of North American patients and also Latin American patient, although we are kind of shy yet, but there is increasing participation of other parts of the world. And this is very important. And also the number of data coming from electronica data capture. I think we have 25% of data captured from electronic records. So I think this is also a very important change over the years. So regarding T category, the main question, I'm sorry, it's going back here. The main question was regarding T3 with chest wall invasion. And there was insufficient evidence to recommend a modification. All the other subcategories were also maintained. So no change for T category this time. And the N category was maybe the most awaited results. A long time, we did not have changed in this scenario. And as we have been already doing our clinical practice, I believe they found a prognostic difference between single station N2 versus multiple station. So that now they recommended a change and split N2 into N2A and N2B category. I believe you all have been doing it in our clinical practice and daily clinical practice. And also the M category that has changed over in the last TNM stage edition, the eighth one, they tried to move on with this sub classification. And they show that regarding ME1C, there were a difference, a prognostic difference between if you have a multiple extraterrestrial metastasis based on the numbers of organs involved. So they proposed the change dividing ME1C into two categories. ME1C1, that would go for single organ system, multiple extraterrestrial, but a single organ system. And ME1C2, when we are talking about multiple organ systems. When you take out the group category, the groups, no major change except for the N2, where we have now the T1N2A categorized as stage 2B and not stage 3 anymore. And this, I think it's a very important modification, have to be aware of that. So this was the main changes in the TNM staging. And my next presentation, it's an oral presentation performed by Dr. Roy Herbis in our session. We know that TDL1 is an important consolidated IO biomarker. However, there are many challenges regarding its applicability, like different clones, intratumoral heterogeneity and interobserver variability. So in this abstract, AI was used to perform a comparison between digital and manual PD-L1TC as P263 scoring. So, and this is an exploratory evaluation of digital pathology as an unbiased automated method to identify patients with nosomal cell lung cancer benefiting from the tesolizumab. So they use data from Empower 110, that was a randomized, we all know, that was a randomized open-label phase 3 study looking at first-line tesolizumab compared to chemotherapy for PD-L1 positive patients. And mainly it was based on SP142 testing that is historically used in the tesolizumab trials, but it's an outlier because it looks at both the immune-infiltrating cells and also the tumor-infiltrating cells. In this trial, they tried to use a clone-agnostic artificial intelligence model to quantify PD-L1 expression on SP263 stained slides from this trial in Empower 110. And they tried to look at tumor cells because it's this clone used to look at tumor cells. So the results, there were 509 slides included. Overall, the correlation coefficient, the R coefficient, showed a strong association between digital and manual pathology. The R is 0.86, as you can see on the left in this slide. And compared with manual scoring, digital scoring identified 114 in 36 additional PD-L1 patients at 1%, and the 50% cutoff, respectively. So the concordance between manual and digital scoring was high at the 50% level cutoff. The overall percentage agreement was 90%, as you can see in the right, in the table on the right. And subiautomot at 1%. The overall concordance, percentage agreement, was 78%. But regarding overall survival, as it's shown in this slide, there was similar efficacy between manual and digital pathology. They also performed a continuous evaluation available for AI, and there was a progressively improved benefit for non-squamous carcinoma, but not for squamous. The benefit was maintained for all these famous patients. So they showed that there is not a good agreement in PD-L1 low score patients, but a good agreement, a strong agreement for PD-L1 high expressors. But regarding overall and progression-free survival, it was similar, the agreement between the two methods, manual and digital. And they move on to exploratory analysis, trying to look at TILs, PD-L1 cells in TILs. And they try to evaluate the meaning of that using AI. They move on to a further investigation using HIF in the tumor microenvironment patient is a greater density of PD-L1-positive lymphocytes in the cancer reptilian, and it could demonstrate an improved progression-free survival in the squamous carcinoma tisulizumab group. So they try to suggest that factors beyond PD-L1 tumor cell positive expression may drive response, especially for squamous cell carcinoma. So in conclusion, this exploratory analysis comparing manual to digital PD-L1 score in aspect two, six, three slides at this trial found 22% greater prevalence for PD-L1 positive when you have a low score, and 4% greater with a high score. It was very effective scoring these patients the digital way. And also they conduct exploratory analysis suggesting that especially for squamous carcinoma, maybe we have more than tumor cell PD-L1 to consider. So with that, I finish my presentation. Thank you, Dr. Clarissa. And so I'll start the discussion with the TNM staging, and this was something which everybody was awaiting for a long time, the ninth TNM edition. The proposed changes, and while we find that there are no changes for the T descriptors, they have split up N2, and they have also split up M1C. Now, this brings us to the fundamental question that I remember when we used to look at the sixth TNM, it used to be a very simple, you could just remember it on your fingertips, and you could remember the staging, and we move from sixth to seventh, and it became a little more complex, seventh to eighth, and now eighth to ninth. And if you look at, so these are the individual T and M, and if you look at the stage groupings, I doubt if anybody in current era will be able to remember them, and you always need to have a chart printed either in your clinic, or you have an app on your phone, or you have an image of the staging cards in order to accurately write the stage. And so my question is really, are we moving towards too much of splitting? Is it becoming too cumbersome for clinicians to use in real life setting, or is this the correct way forward? I mean, it's a provocative question, but I'd like to have your thoughts and maybe others as well. I think maybe we're gonna need AI to stage our patients in the future. Yeah, I agree. I totally agree, I fully agree with you. And I'm not sure if this kind of division will make sense in the future, because it's not so practical for the daily practice, and also because you're not moving to molecular staging. I believe we need it regarding lung cancer. I don't know if you're gonna put up with, even if we split and split and split again, if you're gonna put up with all the molecular features that could impact the prognosis, maybe more than size or N number, things like that. So that's my main criticism about this TNM effort. Maybe we have to move faster to the molecular biology integrated to the TNM staging. Precisely, I mean, TNM is just an anatomic staging, and we know that with the advances in the recent past, I mean, molecular profiling has a very important effect. And so I think perhaps in the future, we would need to have some side of model in which you incorporate the anatomic part, which is the TNM, and you factor in the molecular part, and maybe other prognostic factors, and then it gives you a more wholesome kind of system. What are your thoughts, Dr. Liza and Dr. Christian, on the TNM staging? I think it's a good question, and it will become very impractical in daily clinical practice. But if you think back on the previous discussion about perioperative immunotherapy, maybe these data can help us distill which patient needs which treatment, because now finally we have the N2 disease at least split up in single and multiple station, and probably even for these trials, it's just really counting the number of nodes that are potentially involved. But it's also, I think, for the oligometastatic state, well, at least we have the M1B, but that's a single metastasis in one extraterrestrial organ. I think we also have there the discussion how many metastases, but also for the M1A, it can be one contralateral lesion, and then you need to be aware that it can also be a second primary, or it can be multiple lesions, pleural fluid, pericardial fluid, et cetera. But I agree for future data collections, clinical trials, we really need to incorporate not only these details, but also the molecular data of each patient. Yeah, echoing what both of them say, it's important that we have this for the new adjuvant setting, but it's also important that we have, for example, and there are a lot of efforts trying to incorporate, for example, block T and B, that will be maybe the future, because the prognosis of a patient that is shedding ctDNA with early stage will be completely different than the patient that is not doing that. So I think we need to aim now for go to the precision, because in some way we are very keen to try to test in patients and see response monitoring with, for example, liquid biopsy. But we are not really taking in consideration where we are classifying patients and selecting treatment for that. So I think it's the moment that we start to organize, and I hope that we can see in the very short future TNM molecular classification to select our patients. And this also would help to try to make more routinely tested the patients, because once you incorporate in a classification... That's a very important question, a very important point to try to increase testing rates that unfortunately are very low. So we've got one question, and I'd like Dr. Clarissa to pick that up. Tumor infiltrating lymphocytes, they are different types, and so some are immunosuppressive, some may help. So is looking at the TILs in addition to PD-L1 really what the future is? And we know that you can actually segregate tumors into four different types based upon PD-L1 positivity or negativity and TIL positivity or negativity. So what are your thoughts on this? I don't know. I think PD-L1 is an imperfect biomarker. That's why we're always trying to find something to improve their accuracy in our trials. And I think this abstract looks like a way trying to move into different scenarios, trying to improve the work of the pathologists, because once you can rely on digital pathology, you can make things more uniformly over the world, especially regarding tumor infiltrating lymphocytes, where we have increasing difficulty for pathologists in order to give this kind of reports. And the other is trying to categorize better. I think this is kind of a hypothesis generation, this squamous versus non-squamous behavior of the tumor infiltrating lymphocytes. But I don't have a proper, I don't think I have a proper answer. I'm not sure if it's going to be the future, but I think it's kind of a way of trying to make PD-L1 more reliable. OK, thank you. So I think in the interest of time, I think we're going to have to move on. And now it's my pleasure to invite Dr. Lisa Hendricks, who is a pulmonologist, again, specializing in thoracic oncology. She works at the Maastricht University Medical Center in the Netherlands. She is the coordinator for lung cancer research at our institute, and her research focuses on brain metastasis, oligometastatic disease. She actually has been the first author in two recent ESMO guidelines on metastatic and SCLC, and is the EURTC chair for systemic therapy of metastatic and SCLC. So all yours, Dr. Lisa. Yeah, Dr. Singh, thank you for the kind introduction. And indeed, thank you also for inviting me for this webinar. And immunotherapy is also moving to the radiotherapy early space. So I will discuss the iSaber, but I think we all know that immunotherapy can also cause adverse events. And there was a very large retrospective series presented at World Lung focusing on these events. If you then look at the rationale for adding immunotherapy to radiotherapy, I think there is quite a lot of preclinical research showing that radiotherapy induces immunogenic cell death. It upregulates PD-L1. It triggers release of neoantigens. And it also triggers release of inflammatory signals recruiting immune cells to the TME. So I think there was really a preclinical rationale to combine these two. And now we also have a randomized study. So this is a phase two study allowing patients with node negative stage 1a to 2b, and multiple tumors were allowed, or isolated lung parenchyma recurrent non-small cell lung cancer. It had to be histologically confirmed. And you needed to have a diagnostic CT and a PET-CT of the body and also brain imaging once indicated. Invasive mediastinal staging according to guidelines once indicated. And of course, pulmonary function tests. Patients were stratified based on performance status, tumor size, histology, and the lung cancer history. So the stage, well, primary versus recurrence. And then they were randomized one-to-one to either SABR with these two fractionation regimens, or adding immunotherapy to the radiotherapy regimen. And I think in contrast to some phase three trials that are still ongoing, Nivolumab here was only given for 12 weeks, so four doses in total. Imaging follow-up was done with a CT of the chest every three months. Sorry, this is a typo for two years. PET-CT was done at month nine, and afterwards there was imaging every six months for three years, and annually thereafter. And I think also interesting because radiotherapy, we know that it can cause quite weird changes on your chest CT, which sometimes is quite difficult to distinguish from a tumor recurrence. The potential recurrences were reviewed by a blind and independent committee. Primary endpoints was the four-year event-free survival, and secondary endpoints were overall survival, toxicity, and predictive markers. If you then look at the results, so first the baseline characteristics, the majority of these patients had a good performance status, and I think of note also had a smoking history, and around two-thirds of the patients had newly diagnosed non-small cell. I think these were evenly distributed across the two arms. Two-thirds of the patients was staged with EBIS, approximately half of the patients had a brain MRI, and the majority of the patients had non-squamous histology. Unfortunately, PD-L1 status was unknown in one-third of the patients, but I think it's quite recommendable that there was enough tissue to test for PD-L1, even in early disease, and it was positive in only one-fifth of the patients. The GTV was a little bit lower in the saber arm than in the immuno-saber arm, so prognostically I think a little bit worse group in the eye-saber arm, but the median size of the tumor was the same for both arms. And the most common saber regimens were 50 gray and four fractions. And the median number of nivolumox cycles was four, so the majority, well, at least the median of the patients had four cycles. If you look at the right, then you see on the upper middle, the four-year event-free survival protocol. I think you see a clear benefit for adding immunotherapy to radiotherapy with a four-year event-free survival of 77% versus 53%, and also in the intention-to-treat analysis, you see a clear benefit. If you look at the subgroup analysis, and I didn't put the false plot in it, but small subgroups, so I think no definitive conclusions, but all hazard ratios were in favour of adding immunotherapy. If you look then into detail at the patterns of progression, it's not in the table, but infield recurrences were very, very rare or almost non-existent. Second primary lung cancers, and that's something to take into account, occurred in 3% to 8% of the patients, so it's lower in the immunotherapy arm, but I think that also stresses that we should do risk reduction management in these patients. And any recurrence that was, well, lower in the immunotherapy arm with 12% versus 36% in the saber-only arm. Toxicity, I think, well, you can be afraid still of more pneumonitis if you add immunotherapy after radiotherapy, but I think this was as expected for adding immunotherapy with some immune-related adverse events. Some more fatigue, but no high-grade pneumonitis in both arms and one grade 2 pneumonitis in the immunotherapy radiotherapy arm, so I think the treatment was quite safe. So I think my conclusion and take-home message from this Phase 2 trial is that it's promising, but we need confirmatory Phase 3 trials, and, for example, the Pacific IV is ongoing, but the duration of immunotherapy is different, and I think it's also interesting to enroll patients in these type of trials. If you then look more at the toxicity, well, I think everyone knows immunotherapy can cause toxicity, but we also have overlapping risk factors for cancer and heart disease, so tobacco use, hypertension, et cetera, are associated both with cancer and heart disease. And we also know that immunotherapy can cause cardiac events. Well, we think they are quite rare, but they can occur alongside all the other immune-related adverse events that are possible. And here, this is a retrospective single-center study. From 2016 to 2020, patients were included, but these were 1,800 patients, so a large series. Comorbidity index was quite high, and two-thirds of the patients only received one type of immunotherapy, and the others, well, it was stated multiple. I assume that's two, that is anti-PD-1 or anti-PD-L1 and anti-CTLA-4. Pre-existing heart disease, so the baseline characteristics, two-thirds had none, but I think there was no standard check for heart disease in these patients because I think that's not the regular care and daily clinical practice. But the majority of the patients with pre-existing heart disease had one heart disease, not specifically specified, but mainly tachyarrhythmias or ischemic. And if you look at other vascular comorbidities, around 25% had hypertension, less than 1 in 10 had diabetes, peripheral vascular disease, et cetera. And in the table on the right, you see the cardiovascular events during or after immunotherapy, and I think it's nice that they had a minimum follow-up of at least 18 months after starting of immunotherapy. Then you see again the events that occur are usually rhythm problems, so tachyarrhythmias, but also pericarditis from heart failure, myocardial infarction, et cetera. And if you look to the median time to events that was between, well, five and seven months on average, but I think of note myocarditis was in general within three months, and we've seen cases after one or two cycles only, and patients receiving multiple immunotherapies had a higher risk. They also did a multivariate analysis, corrected for age, hypertension, diabetes, and hyperlipidemia. Then you see again the diseases that I already discussed in the previous slide occurred more frequently in immunotherapy. So I think my take-home message here is that we need to be aware of cardiac problems in patients with non-small cell treated with immunotherapy. I think they can present quite asymptomatic. Dyspnea can have a lot of causes in patients with lung cancer, so I think it needs to be more in the back of our mind that we need to think of other differential diagnosis and not only the COPD or the pulmonary embolism or these type of things. And maybe in the future we should do more baseline screening for patients potentially at risk, because in general, as I showed you, the risk factors for toxicity are also the risk factors for heart diseases, so smoking, et cetera. We should screen these patients. Thank you. Thank you so much, Rupaliza. I think I've come to two important things here. So one is that when you combine immunotherapy and you have given radiation or you are going to give radiation along with it, I think the concern about pneumonitis is always there. And I mean, the pacific was designed, the initial pacific at least, was designed to give immune checkpoint inhibitor maintenance following concurrent chemo radiation. We now know that they're trying to do it simultaneously as well, and this trial also looked at doing it at the same time. So in real life, what we also know is that these are very fit patients who are chosen for trials. But in real life, you will have patients who may not be as fit and they may have been having comorbid conditions like COPD or coronary artery disease. And so really, how do you go about deciding when to use this combination strategy and when not to do it? I think for me, in the early disease setting, we still need a confirmatory phase three clinical trial. And I think some of these trials at least allow patients with a performance status of two cardiac comorbidities, restricted pulmonary function. But I'm a little bit afraid that in clinical trial practice, we don't enroll these patients. So even if it is allowed to enroll these patients, we don't approach these patients or the patients while they have lots of comorbidities, they have a poor performance status. And well, for them, the burden of a clinical trial is just too high. So for me, it would be more a call, well, enroll these patients in the clinical trial, but also have a clinical trial that's not too burdensome for a patient, that the patient wants to be enrolled. Try to obtain tissue, but that's also a challenge in these patients. If you have severe emphysema, the risk of pneumothorax, for example, is quite high if you try to take a biopsy. But I think before we have these data, a patient with severe comorbidities or poor performance status, I would not offer immunotherapy, autostereotactic radiotherapy and daily clinical care before I have the data that really benefits these patients, because on top of the risk of toxicity, the patients with a poor cardiac or pulmonary function are also at risk of dying of their comorbidities. So you really need to show benefit before you're going to do that in this patient population. The other abstract was looking on cardiovascular toxicity during immunotherapy. And we tend to routinely monitor endocrine functions at least. So do you believe that since a lot of these cardiovascular events may not go undetected, getting a baseline echo and getting it repeated periodically is what is something we should be following? I mean, what's your practice? And then I'll ask Dr. Christian and Dr. Clarissa about how they do it. Well, at least we do an electrocardiogram in all patients who are in a workup for lung cancer. So if there is something significant or we cannot explain complaints of dyspnea with pulmonary function tests or pulmonary comorbidities, we refer them to a cardiologist. But other than that, we don't do cardiac follow-up or screening. I know in the new asthma immunotoxic guideline, I think it's advised to at least do some troponin or other markers. But I haven't seen series or trials showing that you can detect more and that it's beneficial. And well, at least in the Netherlands, we always get the comment if it's also costly, you really need to show the benefit before you can incorporate it into your daily clinical practice. But maybe when now patients with lung cancer are surviving longer and maybe we even cure some of these patients, we also need to start paying attention to the comorbidities of these patients and risk factors, behavior like smoking, overweight, underweight, et cetera. I think what we also should do is try to counsel these patients really advise smoking cessation, help them exercise, et cetera, et cetera, that they not only survive their lung cancer, but that in general their health will be better and that they don't die of their comorbidities. Thank you. So what about you, Dr. Rolf? Obviously, when we have patients that they develop some cardiotoxicity that is something that we saw already in clinic with immunotherapy, there are guidelines like Dr. Henry was referring. So we have the guidelines from ASCO and ESMO that are very clear. We can also follow with troponin, echocardiograms. Even in some cases, we go for MRI of the heart as well. But in clinical practice, what we are doing in some patients who have some risk like hypertension, we prefer to do in some patients evaluation by cardiologists. In some of these patients, we started also with echocardiograms before in order to have some data, especially patients at risk. But it's not a common practice to do in all the patients assessment, cardiological assessment from the very beginning, like we are doing in other tumor types like breast cancer because we know that the toxicities of the drugs are very common. That may be something that we need to start to thinking about it. Obviously, there is the cost effective discussions, but I think it's important to have this kind of discussion with the cardiologists. It's good to have multidisciplinary team experts working with us and several centers now are also facing the idea to have multidisciplinary teams for toxicities specifically related with immunotherapy. I think that is very important when you have patients with toxicity that you send them immediately and you create a flow in your institutions to have this answer very, very quickly. The same here. It's not standardized as a follow-up, like we have for breast cancer and things like that. But especially when we are moving for an initial disease, I think we have to be very aware of this kind of toxicity. Thank you, everybody. I think we are past the hour. I'd like to thank all my esteemed speakers, Dr. Christian Rolfo, Dr. Lisa Hendricks, and Dr. Clarissa Baldotto for doing an excellent job with the abstracts. With that, I'd like to thank everybody who joined us. Thank you again and goodbye.

webinar

abstracts

2023 World Conference on Lung Cancer

TNM staging edition

N2 category

M1C category

immunotherapy

radiation therapy

non-small cell lung cancer