Good afternoon, good morning. I'm Nicolas Girard from Institut Curie in Paris and I welcome you to this ISLC ESMO 2022 NSCSE Highlight Webinar. Today we have two outstanding speakers, Lisa Hendricks from Mastro Clinic. Welcome Lisa. Thank you. And Jordi Raymond from Gustave Roussy in France, in Paris. Welcome Jordi. Thank you. Good afternoon. Good morning everyone. So today we will discuss the most recent data presented at the ESMO 2022 meeting that have an impact on our management of patients with non-small cell lung cancer. This webinar will be as interactive as possible and you are able to ask your questions, to post your comments on the chat and we will discuss after each section of the webinar these comments and questions. We will discuss the management of metastatic patients with targeted agents. We will discuss immune checkpoint inhibitor treatments and early stage non-small cell lung cancer. This webinar will now start and we will focus first on the management of patients with metastatic non-small cell lung cancer with targeted agents in the setting of oncogene addicted tumors with some major studies presented at the meeting. And the first study is the Apple trial, a trial focused on EGFR mutant non-small cell lung cancer patients, very expected results from this academic trial. Jordi. Thanks for the invitation. It's an honor to share this webinar with you, Nicolas, and also with Lisa Hendricks. And as you mentioned, this ESMO has been presented in this phase two randomized non-comparative academic trial that addressed the question, if it was feasible to perform longitudinal liquid biopsies with the aim to search the T7M mutation in a liquid biopsy in patients with advanced non-small cell lung cancer and EGFR mutant tumors, previously treated with a third generation EGFR TKI, and also aim it to explore if it was feasible to perform dynamic treatment approaches based on the results of this liquid biopsy. Based on this background, the Apple trial enrolled patients with advanced non-small cell lung cancer with common sensitizing EGFR mutations and were randomized to three arms of the trial, arm A of the trial. The patients have started the treatment with ozymertinib. It was just an exploratory arm of the trial because in 2016, ozymertinib was not the standard of care in first line setting for this population. Then there was the arm B, that it was the focus of the primary endpoint of the trial. And in case of molecular progression, the T7M mutation in a liquid biopsy, it was a central analysis by the COPAS test. Once we detect this molecular progression, the patients were switched directly to ozymertinib. And finally, the arm C of the trial, patients started with gefitinib, and at the time of resist progression, it was completely blinded the status of T7M mutation, patients were switched to ozymertinib. It's important to mention, however, that all the arms had the liquid biopsy once per month. The primary endpoint of the trial, it was just focused in arm B of the trial, was the progression-free survival at 18 months on patients on ozymertinib, taking into account that baseline was the time of the randomization in this trial. Next slide, please. I think that it's important that during this esmode has been presented the results of arm B and arm C. And as you can see here in this figure, approximately 70% of patients that initially started the treatment with gefitinib at the time of progression received ozymertinib, 70%. And specifically in patients with arm B, 17% of these patients switched from gefitinib to ozymertinib based on a molecular progression, the detection of this T7M mutation in a liquid biopsy. And the time elapsed between the initiation of this gefitinib and this molecular progression was approximately 260 days. The trial was a positive trial because the 18-month progression-free survival in arm B was 67.2, reaching the positivity of the trial because the lower bond of the confidence interval was above to 40%, 52%, meaning that it was a positive trial with a medium progression-free survival of 22 months. Based on this part of this primary point was positive, it was performed an exploratory analysis comparing arm B and arm C. And it's true that arm B reported a 40% higher 18-month progression-free survival compared with arm C, 67 compared with 53, but it had a hazard and no significant hazard ratio of 0.80. However, the trial was not sufficiently powerful for such comparison. And finally, the next slide, I think it's really important, the clearance of the circulating tumor DNA during treatment with gefitinib. We merged arm B and arm C and we could find that 65% of patients at baseline initially treated with gefitinib had a CT DNA positive at this baseline. And those patients who had a clearance of this circulating tumor DNA during treatment with gefitinib had a longer progression-free survival compared with those patients with a CT DNA baseline positive without this clearance. And this was even really relevant because it was an early marker of the efficacy of the treatment just performing this clearance within the four weeks after treatment initiation. So I think that Apple trial, it's a positive trial, it's feasible to perform liquid biopsies and decide the treatment based on the results of this liquid biopsy. Well, thank you, Jordi. This is very interesting data because we can see that in April, we can have this follow-up with the CT DNA. Obviously, there are many points to discuss. Maybe the most important point is what is the impact on the clinical practice of this data? Do you recommend CT DNA to be performed in all the patients now receiving any kind of EGFRT care? I think that the question is if we detect the mechanism of acquired resistance earlier and we treat these patients earlier, will it really impact in the outcome? It's true that it seems that there is a positive trend based on the Apple trial, but I think it's really important that the trial support that the liquid biopsy is an important tool for genomic profiling either at baseline and also at the time of the search mechanism of acquired resistance. And also, it's a very important, I think that will be very important as a dynamic marker for selecting the patients that perhaps are not responding to the initial treatment and perhaps to try to explore if we should escalate the treatment strategy. It's true that we don't have, for instance, results with an A, that is really important, but it's not a comparative trial. And perhaps if we had used a more sensitive test, not the COGAS test, but it's not really sensitive for searching the T-cell mutation, perhaps we could have more patients or a higher percentage of molecular progression and we could find a longer or higher impact in the outcome. But I think that despite of all of these limitations that I completely share as a clinician, I think that it states that liquid biopsy works for genomic profiling and for making dynamic treatment approaches during all the course of the disease. Thank you, Jordi. Please ask your question on the chat. If you have anyone or any comment, we will continue this discussion. Lisa, another trial in the setting of a collagen-addicted tumor is the CODBREK-200 phase 3 trial in the setting of KRAS-G12C mutations. I think this trial was long awaited, the results. We thought for, I think, quite some years that KRAS-G12C was undruggable, but multiple trials that failed to show improvements in outcome for these patients. And I think with the new smaller molecules, with new drug development techniques, we now have, yeah, at least drugs that work in these patients. And we had quite some promising phase 1 and phase 2 data for sotoracib, and now we have to phase 3. So in this trial, patients with metastatic or locally advanced non-small cell with a KRAS-G12C mutation and at least one prior line of therapy and at least treated with chemotherapy and immunotherapy and a good performance status and no active brain metastasis, so brain metastasis needed to be treated, were randomized either to sotoracib, 960 milligram once daily, or docetoxel. And the trial stratified for a number of prior lines of therapy, race, and the presence of brain metastasis. Primary endpoint was progression-free survival, blinded independent review. And during the trial, the protocol was amended for regulatory guidance to allow crossover from docetoxel to sotoracib and to also to reduce the patient number from 650 to 330. And you can see in the Kaplan-Meier curve below that it was a significant improvement in progression-free survival, 5.6 months for sotoracib versus 4.5 months for docetoxel, with a hazard ratio of 0.66. Response rates I didn't put into the slide, but were 28% for sotoracib, which is a little bit lower compared to the phase 1 and phase 2 data, which is what you generally see if you have phase 3 data. I think not really what we hoped. I think we would have liked to have a better progression-free survival, but it is statistically significant. Next slide. For the overall survival, I think you don't need to be a statistician to see that there was absolutely no difference. Median overall survival around 11 months for both arms. And if you look at the crossover rate, which will influence the overall survival for the docetoxel-treated patients, it was around one third of the patients who had a subsequent KRS-G12C inhibitor. So no overall survival benefit. Toxicity, it's not an easy drug, I think. There was quite some grey tree toxicity. And the most common treatments related at first events were diarrhea, nausea, loss of appetite, and liver test abnormalities. Didn't put it into the slide, but quality of life didn't decrease due to these toxicities. But I think it's something that you need to take into account when treating these patients. In general, we are used to the HFR and ALK TKI, I think, with a quite favorable toxicity profile. And this drug is, I think, a little bit more difficult regarding the toxicity. And also in daily clinical practice, you see quite some liver toxicity and diarrhea, especially if given directly after immunotherapy. So I think a positive trial, we have a new drug, but in the end, we really need to try to improve on these results with better drugs, combinations, whatever. Thank you, Lisa. This is a positive trial. It was obviously expected to see how Sotorazib versus the standard of care in second line, what was doing. We have a benefit in terms of PFS. If we look at one year, well, this is an impressive result, probably more than the median figures that we have in this study. Well, it's practice changing. I don't know if you have access to to Sotorazib, but I believe many countries have access through expanded access program or approval. Well, this is a new option for these patients, pretty frequent patients. How, Lisa, do you envision the integration of KRAS G12C inhibitors in the strategy? Do you believe that there is room for these inhibitors in the first line setting, combination with chemo and or kind of sequential approach or to replace chemo or IO? What is your perspective on this? I think it's a very good question. Based on these data, I would say monotherapy, Sotorazib first line, or even instead of platen-doublet chemotherapy for patients eligible for chemo, platen-doublet chemo or chemo-immuno, I wouldn't do it. For replacing, then I think you need a combination strategy. So far, I think Sotorazib combined with immunotherapy turned out to be quite toxic. So I think it's not the way to go. It would be quite interesting, I see, to combine it with platen-doublet chemo. Trials are in startup or are already ongoing. So I think that's maybe more the way to go than to combine it with immunotherapy. And in daily clinical practice, so in the Netherlands, we have access to an early access program. And especially the patients who just came off immunotherapy and immediately switched to Sotorazib, we run into quite some toxicity. And I think it's different from a clinical trial. Clinical trial patients enter a screening period. They need to wait a little bit. And now they are just referred. We do the request. And within a couple of days, the patient can start. So I think that's something different and really to take into account. I believe it's also important to generate some kind of real-world evidence data on these patients. Just one question on the CODE BREAK-200 trial. The accrual number decreased from 650 to 330. I believe it was based on an interim analysis showing the benefit. Do you have the response to this question? Yeah, I don't have to reason why the regulatory authorities requested to decrease the sample size, but it could be that it indeed was an interim analysis or even based on the phase 2 data, which were quite interesting, I think. Well, thank you, Lisa, for presenting this CODE BREAK study. Jordi, again, back to EGFR mutant non-translucent lung cancer. We have many trials ongoing in the first line, in the second line. Well, can you summarize these new avenues for the management of EGFR positive patients? Okay. I think that now we are trying to anticipate the potential mechanism of resistance. There is a MARIPOSA trial, for example, that is trying to combine the lasertinib, which is a third-generation EGFR TKI, plus amivantamab, a monoclonal antibody specific anti-EGFR and anti-MET to try to block the potential development of MET amplification. This trial is a phase 3, comparing this combination with lasertinib or ozomertinib. Also, ESMOD has been presented. We know that approximately 50% of patients initially treated with ozomertinib might develop, in first-line setting, might develop MET amplification as a mechanism of acquired resistance. It has been confirmed that the addition of anti-MET inhibitor in this setting, along with the continuum of ozomertinib beyond progesterone, might impact the outcome of these patients, with a response rate of approximately 40% and median progression-free survival of five months. However, if we just switch from ozomertinib to a MET inhibitor, the response is really limited, supporting that we mentioned at the time of bypass mechanism, we should continue with the ozomertinib and adding the drug that might block this bypass mechanism. Also, I think it's really important, interesting as an academic point of view, the clinical trials that are trying to evaluate the patients that deserve to be escalated in the first-line setting with ozomertinib, as I mentioned before, patients that start ozomertinib and there is not a decrease or there is not a clearance of the circulating tumor DNA, it could be suggesting that these patients are not responding and are trying to evaluate if these patients could obtain benefit of adding chemotherapy to ozomertinib with continue with ozomertinib. I think that this kind of dynamic strategies are really important. So I think the three major points is to anticipate the mechanism of acquired resistance, to try to block the bypass mechanism of acquired resistance and also dynamic approaches. And hopefully in these trials, we will have some CT DNA data to have a kind of follow-up of the biology of the disease. Well, thank you for discussing these two studies. At ESMO 2022, we also had many clinical trials looking at the use of immunotherapy in the first-line setting for non-oncogene addicted tumors. These are looking at long-term data from the landmark studies, but also looking at some new strategies through combination or through the modification of the administration scheme of IO. Maybe we can start with Poseidon, a phase three study with a combination of chemo plus anti-CTF4 plus anti-PD-L1. Jordi, can you discuss this data? As you mentioned, I think that immunotherapy has really changed the prognostic of patients with advanced non-small cell lung cancer. We knew the data of several strategies, but Poseidon trial is a randomized phase three clinical trial, which compared the classical Durvalumab plus chemotherapy compared with the chemotherapy. And also there was the dual immunotherapy, Durvalumab, Tramilumab plus chemotherapy compared with chemotherapy alone. We already know the results of this trial presented last year in the World Lung Cancer, where the combination of Durvalumab plus chemotherapy significantly improved the progression-free survival, but not the overall survival compared with chemotherapy. By contrast, the dual immunotherapy plus chemotherapy significantly improved both the progression-free survival and the overall survival compared with chemotherapy. During the ESMO has been presented the longer follow-up, the four years follow-up for this trial. And I think that it's really interesting that the four years overall survival for the dual immunotherapy plus chemotherapy was approximately 21% that they think it's clinically meaningful compared with just 8% for patients that were randomized to chemotherapy. And also there was a small benefit for patients initially randomized to Durvaluma plus chemotherapy. However, one of the major clinical questions that any of these trials, either Poseidon or check-maintenance LA trial has answered is what patients deserve to be treated with a dual immunotherapy compared with just one immunotherapy plus chemotherapy. And they have tried to explore some potential niches that patients that might obtain benefit of this, of adding this dual immunotherapy in the therapeutic strategy. According to the histology, it seems that this dual immunotherapy might benefit better patients with a non-squamous histology with a hazard ratio of 0.83 compared with a hazard ratio, sorry, 68 compared with 80. However, for patients with a squamous histology, it seems that they do not benefit for making a dual immunotherapy because the hazard ratio for overall survival was 0.83 and 0.18. Another potential niche of patients that might obtain benefit of this dual immunotherapy are patients with PD-L1 negative tumors because the hazard ratio with this dual immunotherapy for overall survival was 0.80 compared with the hazard ratio of 0.96 for patients who received Durvaluma plus chemotherapy, suggesting that perhaps PD-L1 negative tumors and non-squamous could be potential clinical characteristics that might select the patients for this dual immunotherapy. Next slide, please. But also there is the genomic profile. We know that lung cancer is an heterogeneous disease, and also they have explored the potential role of specific mutations according to the CAR-RAS, STK-11, and also the KIP-1. And as you can see here, again, the dual immunotherapy might be more beneficial, may obtain a higher benefit of this dual immunotherapy. The tumors of the patient with tumors harboring an STK-11 mutation compared with the Durvaluma plus chemotherapy. Next slide. Also, it seems that the tumors with the KIP-1 mutation obtain a higher benefit of this dual immunotherapy. However, keep in mind that in this group of these mutations, there is a very limited number of patients, so it should be very prudent, but it's relevant that approximately 20% of these patients are alive at four years. And finally, as you mentioned in the previous part of our meeting, the CAR-RAS, that it's 25% of patients. Next slide, please. In this CAR-RAS mutant tumors, again, the dual immunotherapy has an impact in the overall survival with a hazard ratio of 0.55 compared with a hazard ratio of 0.78 for patients treated with Durvaluma plus chemotherapy, and it's important that patients with the CAR-RAS mutant tumors treated with this dual immunotherapy, the four years overall survival is 33%. I think that this is interesting because it's a hypothesis generation suggesting that perhaps some specific patients with a specific clinical characteristics and also specific genomic alterations might obtain benefit of this dual immunotherapy, but it should be really assessed in a prospective clinical trial. Thank you, Jordi. Another study is the AMPOWER LUNG-1. Again, long-term data from a previously reported trial, but looking at an interesting strategy for second line. This is next slide. Next slide, yeah. We know that the high PD-L1 expression in more than equal or more than 50% is a strong predictive marker for the efficacy of immunotherapy as monotherapy compared with chemotherapy. AMPOWER LUNG trial is another trial that address the role of semiprimab and anti-PD-L1 in this setting of tumors with a high PD-L1 expression compared with chemotherapy. It's a trial that has already been presented and published, and it was a positive trial supporting semiprimab as a good strategy already approved by the health authorities as a first-line treatment strategy for patients harboring tumors with a high PD-L1 expression. During the asthma has been presented a longer follow-up, supporting again that semiprimab is better than chemotherapy with a median overall survival of 26 months compared with 13 months for patients initially treated with chemotherapy. And I think that this data is really relevant because 70% of the patients in the control arm at the time of progressive disease switched to semiprimab. And despite this high crossover, the overall survival is again in favor of this semiprimab. And I think that it's a strong evidence that semiprimab works because there is a 70% crossover. And I think this is a very important clinical point. Next slide. And also, however, when the patients progress on immunotherapy, it's not clear which is the best strategy. However, this trial allowed the patients who progress on semiprimab continue the semiprimab beyond progression and adding platinum-based chemotherapy. It's true that this strategy was based on physician criteria. And this is important because it might introduce some kind of bias. And it was just adding chemotherapy, continuing semiprimab. There was not any kind of randomization. There is a very limited number of patients included in this beyond progression and plus chemotherapy, 64 patients. And perhaps there are patients that had a better response, a longer time period with the first semiprimab induction. But again, among these 64 patients, the results suggest that the addition of chemotherapy, it's feasible, introducing a new response rate in one third of these patients, medium progression free survival of six months. The one year overall survival for these patients or half of these patients are alive at one year. And the median overall survival, it's 27 months. And despite the toxicity, it's a 36% grade three toxicity that is logical, relevant, and similar to other trials, exploring the combination of chemotherapy plus immunotherapy. It's true that this data is a proof of concept, but as I mentioned before, it was based on physician criteria. It was not randomized. And next slide. I think that if we want to compare or to answer if patients treated with immunotherapy and monotherapy at the time of the progression, what is the best strategy, switch to chemotherapy or continue the immunotherapy or adding the chemotherapy, it must be answered in a clinical trial. And this is a potential trial that will answer this question, the Insignia trial, that patient randomized to pembrolizumab at the time of progression on pembrolizumab, they will receive either carboplatin pemmetric set or pembrolizumab beyond progression and adding chemotherapy, taking into account that this Insignia trial enroll patients with a PD-L1 positive tumors, not patients only with a high PD-L1 expression. So I think that this trial will answer the best strategy at the time of immunotherapy progression in this setting. Well, thank you, Jordi. Back to chemo plus I.O., we have long-term data from the landmark Knot studies with chemo plus pembrolizumab in non-squamous and squamous cell carcinomas, Lisa. Yeah, I think a very short recap of the trial design because I think it's familiar for most listeners. So K9189 was for non-squamous patients without an EGFR alteration, and they are randomized either to pemmetric set, carboplatin or cisplatin and pembrolizumab or the same chemotherapy with placebo. Patients were stratified for PD-L1, platinum type and smoking history, and patients after the four cycles of chemotherapy, they could continue with pembrolizumab and pemmetric set or pemmetric set, and then upon progression, they could cross over to pembrolizumab. And just over half of the patients, if you take into account all second line immunotherapies, crossed over to immunotherapy in the chemotherapy arm. Co-primary endpoints were overall survival and progression-free survival. Next slide. And we all know the trials were positive, and now we have the five-year overall survival and progression-free survival data. So on the top, you see the overall survival data. Five-year overall survival almost doubled with the immunotherapy upfront. So 90% versus 11%. And in the table below, you see the five-year overall survival for the PD-L1 strata. And I think you can clearly see that, especially those with a high PD-L1 expression have the best five-year overall survival, over 20% for those with a PD-L1 of 50% or higher, and just around 10% for those that are PD-L1 negative. Progression-free survival below 10% for both arms, but still, I think the major improvement in progression-free survival with the addition of immunotherapy upfront. And especially the patients who completed the two years of treatment, so the 35 cycles, I think they do quite well. These patients are, in general, responding, or I think it's logical, with a median duration of response of almost 60 months. And the three-year overall survival rate after these two cycles, so in total, five-year, is 72%, and around 40%, so that's maybe a little bit less encouraging, are alive without progression or subsequent therapy. So I think this is also points, if you complete these two years, you need to follow the patients, because patients have a risk of a relapse, and you need to think about subsequent treatment in these patients. Next slide. Kine8-407, I think similar design, but then for squamous patients. Pembrolizumab, Carbolatin, and Paclitaxel, or not Paclitaxel, or the same with placebo instead of Pembrolizumab. And again, then maintenance Pembrolizumab monotherapy or placebo, and crossover for the upfront chemotherapy patients. And just over half, again, an effective crossover rate, and the same primary endpoints. Next slide. And I think, again, quite impressive five-year overall survival and five-year progression-free survival, and quite similar percentages compared to the non-squamous. I think this is not that you can say that it's really different. Again, high PD-L1, most benefit, and those with a low PD-L1, less benefit, but I think clear benefit still. So I think these two trials really say you should start with upfront chemoimmunotherapy and not with upfront chemotherapy. And again, I think quite similar data for the patients completing 35 cycles. A good three-year survival rate after the two years of chemoimmunotherapy. But again, over half of the patients did progress or had a subsequent therapy. So again, you should follow these patients. Thank you, Lisa. Very interesting data. Very interesting to look at the PD-L1 negative patients because they have a benefit from the addition of immunotherapy to chemotherapy, whatever is the histology. But at the end, the figures for PFS and OS are pretty low, actually, even in the combination arms. So thinking about what Jordi discussed on Poseidon or even what we have in 9LA for which we have probably more follow-up, well, this subset of patients, we probably can do better possibly with the combination with an anti-CTLA-4 agent, probably then leading to less importance for PD-L1 expression as a predictor of long-term outcome. Yeah, I agree. I think it's difficult to have cross-trial comparisons, but if you look, for example, at a Checkmate 227, it's nivolumab, ipilimumab. It's not registered or not approved by EMA. But if you look at the five-year overall survival for the PD-L1 negative patients, it's higher. It's just below 20%. So it's, I think, maybe a more interesting option. Checkmate 9LA, we don't have five-year overall survival data, but again, it seems that the PD-L1 negative patients do derive more benefit if you add anti-CTLA-4 to a certain regimen. So I think for daily clinical practice, then I think that's a good option. And maybe that's also a good step for the next trial. Yeah. Yeah, we have another one last trial to discuss, which is the French one, the DCIP trial, because you discuss all these patients receiving the two years duration of immunotherapy, which was planned in those studies, but maybe we can do less actually. And this was a question raised by DCIP. Yeah, I think it's a very relevant question. Two years of immunotherapy is financial toxicity. It's a burden for the patient. It's a burden for the hospital because all these patients go to the daycare and outpatient clinic, and a risk for patients because of a risk of toxicity. So if you can give less and have at least the same outcomes, that that would be ideal. And I think this is the question that the DCIP phase three wanted to answer. So pathology proven stage four, either squamous or non-squamous, good performance status, any PD-L1, no HFR-ALG, and these patients started with nivolumab, ipilimumab, so the Checkmate 227 regimen. And after six months, there was a staging and patients without progression were either randomized to continue the nivolumab, ipilimumab, or to go to observation. And if subsequent progression, then again had to re-challenge nivolumab, ipilimumab. Primary endpoint was progression-free survival. And I think, unfortunately, as already discussed, Checkmate 227, in the end, no EMA approval. So they aimed to have over 800 patients randomized to have, I think, a good non-inferiority trial. And in the end, the accrual stopped early. Next slide. And if you see in this figure, so lots of patients screened and treated, but in the end, I think only 71, so 27% randomized. So I think this is a hypothesis-generating trial. It has no statistical power to show that one regimen is superior to the other. But if you look at the PFS curves on the right, then in red, then you have the, well, stop-and-go strategy. So six months, and then observation and re-challenge. And this is absolutely not inferior, and it seems quite, well, better than continuing. I think that's not a conclusion you can make, but this is really worthwhile further investigating. I understood the French colleagues have already a next trial, I think with the Keynote 189 regimen, having the same principle to see whether you can give less. I think it's still a very relevant question. I don't know whether you can apply the same principle to chemo-immuno or double-immuno, but it's very worthwhile further investigating, but also to have more biomarker research to really see in which patients can you safely stop after six months. It's only radiological evaluation, ctDNA, other markers, artificial intelligence. I think this is really something we should do as academics to see whether we can give less to the patients and maintain good outcomes. And also possibly have a better personalization of immunotherapy in the first line, because we see it's highly heterogeneous based on molecular biology and the KIP-1 STK11 data, very interesting, but we need to know whether it's worth implementing this testing in the clinic. Well, many patients, they have NGS, and we have some kind of STK11, TP53 data, KIP-1 data, but is it worth integrating this as a decision maker? Well, I don't know yet. And these academic trials probably represent an opportunity to do that and have a better assessment on which patients and which strategy. Jordi, back to the Empower Lung 1 trial, with this second line based on continuation of semiprimab and addition of chemotherapy, this is a very pragmatic approach, actually, because in those patients with a PD-L1 high above 50%, well, there is this ongoing trial such as Insignia that you mentioned, but right now, it's always difficult to make a choice. We have to look at the burden of the disease and the general condition of the patient and so on. But at the end, I like the pragmatic strategy, starting with IO alone and then adding chemo if we have some early signs of disease progression. I think that is a hypothesis generating because probably in our daily clinical practice, in some circumstances, we can use this strategy, but probably we over-select the patients that we had this chemotherapy, probably the patients that have had a longer benefit of these initial immunotherapy patients, that there is perhaps some progression, but not a very huge burden of the disease with any kind of toxicity. So I think that this is an hypothesis generation. We don't know the patient's characteristics according to the disease characteristics where the progression was in the liver, was into the bones that are lower, more than three sites of progressive disease. All of these kinds of things are really important because perhaps the benefit is just linked obviously by the combination, but also by the selection. But I think that it's a really relevant question that will be answered in a clinical trial. But I think that we should, as you mentioned before, to define what are the patients that really obtained the benefit of this continuation beyond progression compared with just the chemotherapy, because that perhaps the benefit is just for the chemotherapy, not for continuing the immunotherapy, because this was not randomized to a semi-preliminary beyond progression plus chemotherapy versus this chemotherapy. That this is the clue to answer this clinical question. And I don't know if I can make some comment as you're talking about this with these academic clinical trials. I think that now we are in a crowded situation of a lot of mid-to-clinical trials with immunotherapy. And I think that this kind of academic clinical questions are really relevant. The treatment duration, also if we can change the schedule of the administration, why we should perform the immunotherapy every three weeks, why not one infusion every six weeks, why we really must double the dose when we double the interval, perhaps it's unnecessary. These kinds of things, I think it's really, I am a passionate of these kinds of questions because are important. More trials probably will not increase the benefit. I think that more or less we are in a plateau. As I said, when we make a cross-trial comparison, more or less all the trial has the similar three years overall survival, four years overall survival. So perhaps we should, as you said, modulate the patients that may obtain the better benefit with a better strategy and try to modify the potential strategy of the schedules of this immunotherapy. I agree with you. Sorry, go ahead. Maybe to add, I think it's really possible as academics to do these trials. So, for example, in the Netherlands, we now have a phase three trial ongoing with dose reduction of immunotherapy in first line. And I think it's quite difficult to get funding for it. But I think you need to have other ways of funding, for example, the insurance companies. And then I think you can also do these very relevant clinical trials, because in the end, we need to improve outcomes, but also have it financially possible for, I think, the health care system. Well, thank you. I fully agree. And but meanwhile, we have many ongoing trials with more and more combination. So this is very interesting to see that we are not ended with the understanding, the full understanding of the data that we already have with NTPD1, NTPDL1 and this NTCLA4 in the first line alone or combined with chemotherapy. But meanwhile, we have all these ongoing trials with anti-lag three and other checkpoints combined with NTPD1, NTPDL1 combined with chemo. And probably more than the median, I believe that the long term PFS, the long term OS are becoming relevant, more and more relevant to understand the true benefit of these new strategies. Do not hesitate to ask your question on the on the chat. And we will move to the last part of this webinar, focusing on early stage non-small cell lung cancer. And we have one first study, which is the ADORA phase three trial, the update of these data that were previously published. Jordi? Thank you. Yes, ADORA trial, it's a well-known clinical trial, a phase three clinical trial that explored the role of adjuvant osimertinib for three years compared with placebo in patients with completely resected stage 1B238, according to the 17M classification after adjuvant or not chemotherapy, according to the physician criteria. Approximately 60% of patients in the ADORA trial receive adjuvant chemotherapy, more common for patients with the stage two, stage three disease, approximately 75%. And just 20% of patients with a stage 1B receive this adjuvant chemotherapy. After this surgery, adjuvant chemotherapy, patients were randomized. And we know that it was a very positive clinical trial because already achieved the primary point that it was the disease free survival. And during this as much has been presented a longer follow up, additional two years of follow up, meaning that most of the patients could have the opportunity to complete the three years of treatment. And after this longer follow up, it reconfirms that is a positive trial and the disease free survival is in favor of osimertinib for patients with a stage two or stage three. It's a primary point with a hazard ratio of 0.23. And it's really similar to the hazard ratio when we include all the patients that were randomized, including a stage 1B with a hazard ratio of 0.27. It's true that in this trial, the PET scan was not mandatory and 50% of patients had a brain MRI and the other half of the patients has an exploratory to the brain based on CT scan. Next slide. We know that the benefit of this adjuvant osimertinib increase as higher is the stage of the disease is more relevant for a stage two and a stage three compared with the stage 1B. But one important point that you can see here in this figure is that the benefit of this adjuvant osimertinib start to decrease after that we complete the three years of treatment. It's like a winning effect. It starts to decrease, especially for patients with a stage two and a stage 3A. And it's less relevant for patients with a stage 1B, perhaps because we have not achieved the number of events. In the next slide, this disease-free survival benefit is because lower percentage of patients have a recurrence with osimertinib at this longer follow-up, 27% compared with 60% next slide with placebo. And as you can see here, the number of local or distant recurrence are twice times higher with a placebo compared with osimertinib. However, one of the most important figure of this updated presentation is this last figure, where you can see here that the risk of recurrence, either extracranial recurrence and intracranial recurrence in osimertinib arm, that it's in blue line. It's a start to increase when we stopped the treatment, suggesting that perhaps that we are not curing these patients. We are just delaying the course of the disease and also putting it to the question whether these patients should be treated with a longer time, more than three years. Also, I think it's important to discuss whether these huge disease-free survival benefit, it's really meaningful for patients and also for the patient, for the payers. And also I think it's really important if we think that we should enlarge the treatment due direction, what is the risk about the compliance? Because we know that as longer as the treatment might decrease the compliance. In fact, there is a phase two clinical trial that it's exploring this adjuvant osimertinib for five years. So I think that this updated results confirm the published data that there is a clinical meaningful improvement in the disease-free survival, especially with a very important brine protection that probably it's really meaningful for patients and also for payers. But perhaps put into the question that after three years, it start to decrease the benefit of this adjuvant osimertinib and we should change how to follow up these patients or to try to explore us in this phase two clinical trial to enlarge the treatment duration. Well, that's very interesting data. I believe it's very important to protect those patients from entering into the CNS disease. So it's clinically very relevant to have this adjuvant strategy. Very important also to mention, Jordi, that those patients had to receive adjuvant chemotherapy before starting osimertinib if chemotherapy was recommended based on staging and age and the usual features leading to prescribe it. Very interesting to me, this study, because here we have this combination of chemo followed by osimertinib, similar to what is done in the FLORA2 for the metastatic patients. So maybe this protection is obviously related to osimertinib. It's obviously something very important, but we have also chemo at the beginning. So maybe we are also protecting from the emergence of resistance mechanism because three years is very long. It's far longer than what we do in a metastatic setting. So very interesting to me, this conjunction between chemo and osimertinib in this adjuvant setting. We do not have seen any biological data, I mean, from this study. No, I think that the problem, based on this data that probably we are just delaying, it's really recommended that all the patients should receive adjuvant chemotherapy because it's the only strategy that report to improve the overall survival. And also it's true that the adjuvant chemotherapy in patients that were WALTAC reduced the risk of local and distant recurrence, but it was not clear that protect to the brain. So I think that probably the magnitude to reducing the risk of this brain progression, it's more related to the TKI. I wanted to say another thing, but now I lose it. But I think it's important to say that this patient should receive this adjuvant chemotherapy for sure. And one question on the chat is about this concept of delaying recurrence with osimertinib and whether it makes sense to consider OSI just at the time of recurrence, especially for the patients who could be cured by chemo alone. But we don't know yet, I believe. Who are those patients? I think that it was reported that perhaps in the future we will use the minimal residual disease. Also in ESMOD was presented a cohort of patients with EGF mutation completely resected. It was 24% of these patients that have a CT DNA positive after the surgery. It was really limited, just 24%, because 60% of the patients had a stage one disease. So it's less, it's more difficult to have a CT DNA positive after the surgery. But those patients that were CT DNA positive at baseline and there was a clearance after the surgery are patients that probably are completely cured because they have a three years disease-free survival of 80% without osimertinib, that it's exactly the same as this at our trial. However, those patients that do not have this clearance of the circulating tumor DNA after the surgery had this three years disease-free survival of approximately 25%. So perhaps patients with a minimal residual disease positive are the patients that might obtain the maximum benefit of this strategy. Perhaps in the future, the question in the chat, we will select the patients that might obtain benefit just with surgery plus chemotherapy, or that should add the TKI chemotherapy and after the surgery. Another Apple trial too. Yes, Apple too. Lisa, some data for those patients in the non-oncogene addicted tumors with immunotherapies, the KNOT-091 PEARLS study. Next slide. So I think the PEARLS, the KNOT-091 is the second randomized phase three trial with adjuvant immunotherapy. We also have the MPOWER-10 adjuvant atezolizumab compared with observation. And this trial, I think, is largely similar in design, but there are some important differences. So the same type of patients eligible, stage 1b to 3a, complete resection. And there had to be tissue for PD-L1 testing, which is, I think, in general, not that difficult after surgery. And each of our other patients were not excluded. PD-L1 testing was with a different assay, 22C3 compared with the sp142 and later on the sp263 for the MPOWER-10. And then patients were eligible for randomization, no evidence of disease, good performance status, and adjuvant chemotherapy was recommended, but not mandatory. And that's, this is in contrast to the MPOWER-10, where at least one cycle of platelet-duplet chemotherapy had to be given, but preferably four. Then patients were randomized either to pembrolizumab for one year or placebo, so different for MPOWER-10 than it was observation. Primary endpoints, DFS in the overall population and DFS in the PD-L1 high population. Again, different from MPOWER-10. MPOWER-10 was first DFS in the PD-L1 positive stage 2 to 3a patient population, then DFS in the stage 2 to 3a outcomers, and then DFS in the whole study population. And so far, the first two endpoints were positive for MPOWER-10. Here you see the DFS in the overall population for the Keynote 91, and it is a positive trial with a hazard ratio of 0.76 with a conference interval that doesn't cross the one, but it's not a huge difference, I think. Next slide. And I think if you then compare it to the MPOWER-10, then the results are, I think here, counterintuitive. So in the Kaplan-Meier on the left, you see the DFS for the high PD-L1 patients, and there was absolutely no difference in DFS. And I think it's something you wouldn't expect. MPOWER-10, the benefit was mainly driven by those with a high PD-L1. If you look at other trials, for example, the stage 3, in general, those with a high PD-L1 benefit most. And also, if you look at the metastatic setting, patients with a high PD-L1 benefit the most from immunotherapy. So I think this is surprising. The control arm seems to overperform. Maybe this is the explanation for the fact that there is no difference, but I think, yeah, there's really no difference. And I think, in contrast to the MPOWER-10, there seems to be a difference for the intermediate group, so the PD-L1 1 to 49, and even the PD-L1 negatives, although the hazard ratio crosses the one. And in the figure below, you see, indeed, the DFS for pembrolizumab, according to PD-L1, and the DFS for placebo, according to PD-L1. And here, it seems, indeed, that those with a high PD-L1 overperform. If you look at the EGFR-mutated patients, there was a very small subgroup in this trial, but they seem to derive benefit. But I think, again, counterintuitive, because in general, patients with an activating EGFR mutation don't derive benefit from monotherapy and immunotherapy. So I think it's interesting data. It's also difficult how to place this trial in the landscape we have. And I'm really curious about what the regulatory agencies will say for also for approval of this agent, because formally, the trial is positive for DFS in the overall population. But I think it's so conflicting with the data we have that, yeah, let's see what will happen. Yes, and we know that the authorities now request additional analysis based on non-preplanned subgroups of patients. So I don't know how they will interpret this data and what they can request. In Europe, we have important proof for the PD-L1 high, above 50%. Well, how they can integrate this study in this strategy, I don't know. It shows also that the adjuvant studies, it's difficult because there may be many prognostic factors that are not really integrated into the randomization. Those trials are randomizing patients after surgery. So there is some kind of heterogeneity before the study that we probably miss and which may explain these data. Lisa, what are the next steps in the perioperative landscape with I.O.? We have many trials with combining the neoadjuvant approach with the adjuvant. And how do you envision the future of perioperative I.O.? I think that the big question, if you only focus on adjuvant therapy, is how to select patients that really benefit because we know we also cure patients. And I think it's again, well, the toxicity for patients and financially, these patients should not receive immunotherapy. But so far, I think it's quite difficult to identify these patients. Another big question is neoadjuvant or adjuvant or a combination. And it will be quite difficult, I think, to design a good randomized clinical trial taking into account also all patient-related factors. But I think it's a very relevant question also how to identify patients who really should have neoadjuvant chemoimmuno or adjuvant. And I think, you know, checkmate 816, it was only three cycles of neoadjuvant chemotherapy and then surgery and then no immunotherapy. Most ongoing trials now also incorporate adjuvant immunotherapy. I think, again, you need patient selection who has enough with three cycles neoadjuvant chemo and then is finished. I think CT, DNA clearance or complete pathological response are very good predictors for long-term benefit. But I think it becomes challenging to see what should we do with the patients who don't have CT, DNA clearance, don't have a good pathological response. Should these patients continue the same type of treatment after surgery? Would it work because was it not enough to three cycles or should these patients receive something else? And I think that's also, I think, a space for biomarker research. And I think that the nice thing we have compared with the metastatic setting is that we have the resection specimen. So we have lots of tissue, also for translational research, and that's quite often lacking in a metastatic setting. Yes, I fully agree with you. And we have also for the stage three patients, as mentioned in the chat, the issue of resectability and marginally resectable tumors, resectable, non-resectable. And there is some kind of overlap here, which may explain some of the different outcomes that we see in the clinical trials. Jordi, one comment on these trials with IU? I fully agree with Les' explanation. I think perhaps today it's more clear that for a potential resectable stage three disease, new adjuvant chemoimmunotherapy, it's the standard of care. If it's feasible, it's approved in our countries. For a stage one, stage two, that usually we don't make any kind of new adjuvant strategy. Perhaps it's more difficult to put chemo-IO up front. And as Les has said, it's for me the most important question. It's what patients should be treated with each of these strategies. And this is really important, especially for those patients that are not a stage three disease. Hopefully more data to come. Well, thank you, Jordi. Thank you, Lisa, for sharing this discussion around ESMO. We have more meetings coming, ESMO-IO, ESMO-Asia by the end of this year. Hopefully more data, more subgroup analysis to better understand some of these results. Well, thank you, everyone, for attending this webinar. And the recording will be available on the ISLC website. Thank you.

liquid biopsies

Soto-RASIP

KRAS-G12C mutations

combination strategies

immune checkpoint inhibitors

semi-plumab

PD-L1 expression

adjuvant immunotherapy

osmiran-tinib

disease-free survival