Hello, welcome to the ELCC webinar focused on 2023 ESMO Highlights. My name is Pilar Garrido, I am a Medical Oncologist, Head of the Medical Oncology Department at Ramón y Cajal Hospital in Madrid, Associate Professor of Oncology at Alcalá University and also a member of the Educational Committee of the ELCC. For me, it is a real pleasure to be here and to act as moderator of this fantastic session because I have the pleasure to share the time with my dear friends and colleagues, Dr. Tomeu Massouti, Dr. Elena Linardou and Dr. Thelma Sequeira. We are going to review the ESMO Highlights and after the presentations have concluded, we will have time for debate. This activity has been planned and implemented in accordance with the accreditation of requirement and policy of the Accreditation Council for Continued Medical Education. The International Association for the Study of Lung Cancer is accredited to provide continual medical education for physicians. The International Association for the Study of Lung Cancer designated the life format for this educational activity for a maximum of one AMA-PRA category, one credit. A patient should claim credit commensurate with the extent of their participation in the activity. In this slide, we can see our financial disclosures. All faculty, planners and reviewers for the webinar today have disclosed their conflict of interest and this information is provided in this slide. This is the first one, the second one, the third one and the last one. Now, without further delay, it is my real pleasure to introduce my dear friend, Dr. Elena Linardou. She is a medical oncologist. She is Director of the 4th Oncology Department at Comprehensive Clinical Trial Center at Metropolitan Hospital in Athens, Greece and she is going to talk about new agents, new mechanism of action, CCTs for the presentation presented at the ESMO meeting today. So, Elena, please go ahead. Hello. Hello. It's Elena Linardou. As Dr. Garido already said, this year's ESMO was full of inspiration with many studies discussing and investigating new agents with novel mechanisms of action but also with new toxicities. So, we chose to describe some of these, to discuss some of these studies today as a sample of what has been presented in this area at ESMO 2023. So, here you can see a summary of the studies we're going to discuss. It will be the Tropion Lung-01 study, a study presented at the 3rd Presidential Session at ESMO and a study that investigated an antibody-trunk conjugate in a randomized setting in the second line of non-small cell lung cancer. Then we're going to see what the Mariposa studies showed. These were also presented at the Presidential III Session at ESMO. Mariposa and Mariposa-2 are two studies investigating a bispecific antibody combination with another targeted agent and also with chemotherapy, both in an attempt to address resistance in first and second line setting of FGFR-mutated non-small cell lung cancer patients. And last but not least, we will discuss the Delphi-301 study, a study in extensive states of non-small cell lung cancer that investigated a novel bispecific T-cell engager. Starting off with the antibody-trunk conjugates, I think you will all agree that this is a class of therapeutics that is very rapidly evolving. And you can see on this slide some of the targets and the antibody-trunk conjugates that have been already developed and are in advanced clinical studies in lung cancer. Here you can see on the right side of the slide, you can see in bold the targets for which we already have antibody-trunk conjugates in advanced clinical trials. And of course, there are several more targets that are being investigated with novel agents in earlier phase clinical trials. The study that was presented at ESMO was the Tropion Lung-01, a study that investigated the ATC DATO bottom-up derubstican compared to the standard of care in second line, which is docetaxel. Here you can see the design of the study, DATO-TXT was given in one arm versus docetaxel, 75 milligrams per meter square every three weeks, the standard of care. The primary endpoints were PFS and also overall survival. The study was positive with regards to PFS. You can see here the benefit that is in favor of the new agent, DATO-TXT. And although the numerical difference between the median PFS in months between DATO and docetaxel is not as impressive as one would expect, the study was positive. The ADC showed a statistically significant benefit in PFS over docetaxel. If one sees the overall response rates, you can see that there is a doubling of the response rate between the two agents, even though the duration of response among the novel agent and the standard of care is not that much different. In the remodeled survival, the data here are immature, so we still don't have the result on overall survival. What was very interesting in this study was that the maximum benefit seemed to be because of the patients with non-squamous histology. You can see here the benefit and the difference seen in PFS in the non-squamous population, and you can see in comparison that for the squamous patients, docetaxel was better, DATO-TXT was detrimental. There was no direct explanation, neither from the investigators nor the discussant in the session as to why this happened, so one can assume that probably the target or the payload of the ADC are not specifically beneficial for squamous histology. With regards to safety, I think it's important to know that the novel agent had a comparable, a favorable safety profile compared to the standard of care overall. Overall, the old grade of toxicity was better with DATO-TXT, however, one has to consider that specific toxic toxicities such as stomatitis, nausea, and vomiting, and of course, pneumonitis are specific for this novel agent, even though in this study, pneumonitis rates were very low. The other toxicities were more in the arm of DATO-TXT. So I think that in conclusion, we have the first ADC showing some benefits, statistically significant, even though small, over docetaxel in previously treated advanced non-small cell lung cancer patients, but only with non-squamous histology. We don't have overall survival data as yet, however, we have a favorable safety profile, but we always have to remember that these novel agents have certain toxicities that require careful monitoring and timely management. The investigators at the presentation concluded that DATO-TXT represents with this study, a new potential treatment option for previously treated non-squamous non-small cell lung cancer. I'm not really sure if the standard of care will change with this study, we need overall survival data, however, this is a positive study, the first ADC to beat docetaxel in second line. Moving on to the Mariposa studies, we had at the presidential session three, we had two studies with new agents and new combinations for patients with EGFR mutant advanced non-small cell lung cancer. We know that for these patients, Osimertinib, a third generation EGFR TKI, is the current standard of care in first line. However, the majority of patients will relapse and there have been identified several different mechanisms of resistance. The majority of cases, in the majority of cases, it seems that the secondary EGFR mutation or a metal iteration is the cause of the resistance, is the resistance mechanism. So it was logical for these studies to investigate agents that could address these mechanisms of resistance. Amivantamab is an EGFR met by specific antibody with immune cell directing activity and Lazertinib is a third generation EGFR TKI, which seems to have a very good CNS penetration. In these two studies, combinations of Amivantamab with Lazertinib or chemotherapy were investigated in an attempt to address resistance in first and second line. We'll see first the Mariposa study. This was a phase three global randomized trial. You can see three arms, first line patients not exposed to any prior therapy with EGFR mutations. One arm received Amivantamab plus Lazertinib. The second arm received the standard of care Osimertinib and the third arm monotherapy with Lazertinib. Primary endpoint here was PFS. The study was positive and you can see that there is a statistically significant and in my opinion, very clinically meaningful difference in median PFS with a hazard ratio of 0.70. The interesting also thing was that there was a difference in favor of the combination for the PFS with or without brain metastasis. You can see here that the combination of Amivantamab plus Lazertinib is better than Osimertinib in this outcome. With regard to responses, there were no significant differences. However, if one sees the median duration of response, again, you can see that this is in favor of the Amivantamab plus Lazertinib combination. The data on overall survival are here as well immature. However, there seems to be a trend in favor of the combined arm. And we come to safety. And I think here we have a significant challenge because we're discussing about first line patients where we already have a standard of care which has a very nice safety profile and it's oral. And now, on the other hand, we have a combination of agents, one of which is administered intravenously and also combined. They might be more efficacious, but they also have more toxicity. And the combination was indeed associated with higher rates of fall grades of adverse events related to either EGFR or MET inhibition. And one issue that is of concern and is a challenge for first line patients is the increased risk of venous thromboembolic events, which actually required an additional management intervention with prophylactic anticoagulation for four months. So all these issues and the specific toxicities of the combination have to be taken into consideration when we are going to change our standard of care. Moving on to the Mariposa 2. Here we have again a phase 3 randomized control trial. And now in second line, in patients with EGFR mutations that have progressed to nocimertinib, CNS metastatic disease was allowed. And the three arms of the study involved a combination of four drugs, doublet chemotherapy plus amivantamab and lasertinib versus chemotherapy. And you know that in this setting, in patients that progress on nocimertinib, chemotherapy doublet is the standard of care, is the standard option. And a third arm of a combination of amivantamab plus chemotherapy. Primary endpoint again was PFS. So we come to see the overall responses. And if you see on the left part of the slide, you can see that indeed the overall response rate was almost doubled with any of the combinations of AMI. Both AMI and chemo or AMI laser and chemo significantly improved the overall response rate. And they also significantly improved the PFS over chemotherapy alone. So a positive study for both the AMI combination arms. When we come to the intracranial PFS, again, we see that both combinations reduced the risk of intracranial progression or death by 45 and 42% respectively. So again, the intracranial PFS is in favor of either combination of AMI. I think what is important to note in this, but also in the previous graphs, is the fact that the addition of lasertinib in the combination with AMI and chemo doesn't seem to make a significant difference, even though we already know that lasertinib is a very good agent with a very high CNS penetration. It seems that the benefit of adding lasertinib is quite unclear for the overall response rate for PFS, but most of all for the intracranial PFS. And we come to safety. Again, we have to consider that we have a second line option, two second line options, options of combinations which are intravenous, but also have higher toxicities. So the combinations of AMI and lasertinib had higher rates of hematological adverse events and also venous thromboembolic events, but the AMI laser chemotherapy arm had very high rates of toxicity, 92% grade three or more treatment-related adverse events. Also, this combination had very high rates of interruption, very high rates of dose reductions and discontinuations. So, yes, we have new treatment options for patients with an unmet medical need, but we have combinations that have toxicity and especially the combination of the four drugs, AMI, lasertinib and chemotherapy, in my opinion, with very high rates of toxicity has to be very, very carefully considered, if at all, for certain patients that are very, very fit and we need a significant and fast response. Lasertinib, in my opinion, from this study is very unclear if it offers any intracranial benefit or any additional benefit if one counts the other toxicity as well. And last but not least, we move to the DELPHI 301 study. This study is again for patients with a high unmet medical need. We're talking about relapsed small cell lung cancer patients where we know that there are no approved options after the second line. Tarlatomop, the novel agent that was investigated in this study, is a bispecific T-cell engager that binds to both DLL3 on small cell lung cancer cells and CD3 on T-cells. DLL3 is a very attractive target. It's a target that has been investigated previously with other agents and is attractive because it's overexpressed on small cell lung cancer cells with minimal or no expression at all on normal cells. So the study DELPHI 301 is a study which is phase two and has involved patients with extensive stage small cell lung cancer that had received at least two lines of prior therapy, including a platinum doublet. The study investigated two different doses of Tarlatomop, 10 mg every two weeks or 100 mg every two weeks, with a primary endpoint overall response rate and safety. And if we see the results, consider, remember that we are talking about small cell lung cancer patients that have already received two lines of treatment. So an area where a 40% overall response rate with a very good duration of response and a disease control rate in seven out of 10 of patients, in my opinion, is very encouraging and is clinically meaningful for that group of patients with a high unmet medical need. The PFS, the median PFS was five months and the median overall survival was more than a year, 14.3 months. And also it's very important to consider that among the responders in the study, the duration of response in the majority, in 60% of the patients, was more than, was maintained for more than six months. Again, an effect that is very relevant and very clinically meaningful for this group of patients. And we come to safety. Again, novel agent, novel mechanism of action, but we have new toxicities, novel toxicities. Here we had the cytokine release syndrome, and we also have the immune effector cell associated neurotoxicity syndrome, new types of toxicities, which although they were largely confined to the first or the second dose of tarlatanab, and they were in the majority of the cases of lower grades, grade one or two. However, these toxicities are new. These toxicities are significant and potentially life-threatening. And these are toxicities that we have to be aware, both the medical teams that utilize tarlatanab, but also the patients to realize the first symptoms fast and early so that they can be treated and managed accordingly. So overall, I think from this sampling of cases with new agents, with novel mechanisms of action, and new toxicities, we try to present these new treatment options that we saw at ESMO 23 for patients with high unmet medical need. We saw antibody drug conjugates getting into the algorithms of non-small cell lung cancer, bispecific antibodies, and also T-cell engagers for small cell lung cancer. Most of the agents were investigated as monotherapies, but we also saw some very interesting combinations with the mariposa studies. However, before we change our standard of care, we have to consider all the challenges ahead, oral therapies versus intravenous administrations, high rates of new toxicities, challenging new toxicities that we have to closely monitor our patients and timely manage these toxicities. And of course, last but not least, we can't go away from what the paradigm is in non-small cell lung cancer, the quest for selection, for effective and careful selection of our patients, which cannot be managed in any other way but with the identification of new, effective biomarkers of response. Thank you very much. Thank you so much, Helena. An excellent presentation. And now, without further delay, it's my real pleasure to introduce the next speaker, who is Dr. Thelma Sequeira. She is a pulmonologist and associated professor. She works at the Institute of Portuguese Oncology in Lisbon, Portugal, and she's going to talk about new target agents and potential new standard of care. Thank you. Thank you all for coming to the ISLC webinar. We have really impressive new information that was shared at ESMO 2023. And today I'm going to talk to you about targeted agents. Do we, can we say that we have a new standard of care? We'll start off with Alina in the early stage and locally advanced non-small cell cancer with all positive patients. And then afterwards we'll see in the locally advanced or metastatic non-small cell and cancer, the Libretto 431 with red positive patients and the Papillon with EGFR exon 20 patients. So why is Alina necessary? What is the unmet need? Around 30 to 40% of patients with non-small cell and cancers are diagnosed with a resectable disease. And despite curative intent treatment, the risk of recurrence remains high. And particularly the ALK positive non-small cell and cancer patients tend to be younger patients are more common in non-smokers and unfortunately have higher risk of brain metastasis. And the truth is for resectable ALK patients, the current standard of care after surgery is still adjuvant based chemotherapy. So it seems natural to bring the experience of the metastatic treatment with the TKIs to the early stage in case of ALK positive patients. And that's exactly what the clinical trial Alina did. It evaluated the efficacy and safety of adjuvant electinib in patients with early stage ALK positive non-small cell and cancer. In concerning inclusion criteria, patients with stage 1b with tumors more than four centimeters up to stage 3a according to the seventh edition were included. Patients had naturally to be ALK positive, no prior systemic therapy and an ECOG PS of 0.1. A total of 257 patients were randomized in a one-to-one fashion to electin 600 milligrams twice a day during two years or until progression, toxicity or withdrawal. And the comparator arm was platen based chemotherapy for cycles. Patients were stratified according to stage and ethnicity. The primary endpoint was DFS investigator assessed. And concerning the key results, we have on the left side of the slide, stage two up to stage 3a with the median DFS that was not reached in the electinib arm comparing to 44 months in the chemotherapy arm with the hazard ratio of 0.24 and a P value that was significant. On the right hand of the slide, we have the intention to treat which aggregates stage 1b until 3a. And there's really not that significant difference comparing these two. Concerning CNS disease-free survival, we see this really nice graphic with electinib arm practically horizontal and the patients remain free of CNS disease in a vast majority of percentage. At 24 months, we're talking about 98% of the patients with a hazard ratio of 0.22. And we're talking here that this translate in a median follow-up of 27 months. So these patients recur less. It's true. We see that on the electinib arm on this graphic. And when they do recur, we can see it's more local regional recurrence comparing to the chemotherapy arm, where here we do have more distant recurrences. And as we can see on the right hand, the recurrences are mainly to the brain. So in the patients that did recur, what did these patients do afterwards? In the electinib arm, we can see that 47% of the patients that recurred on electinib received further TKIs, although interestingly, we can see that no patients received lorlatinib in further lines and 40% received chemotherapy. On the other hand, patients that recurred on chemotherapy, adjuvant chemotherapy, 76% received naturally a TKI. What about safety? Well, there's basically not anything new concerning electinib in the adjuvant setting. It's basically what we already have in the metastatic experience. So in conclusion, ELENA is the first and only positive phase 3 trial on ALK inhibitor in resective disease from stage 1b to 3a. The treatment with adjuvant electinib did result in a statistically significant and meaningful improvement in DFS. We did see an improvement in CNS disease-free survival. So this potentially represents an important new strategy for patients with resected ALK-positive non-small cell end cancer. So moving on to the next clinical trial, LIBRETO-431. Why was this necessary? What is the unmet need? We are testing RET-positive patients when present. They are a probable alteration for patients with non-small cell end cancer. However, the truth is that we're talking about a very rare disease. We're talking about an incidence of 1.7%. We do have an agent that is silpercatenib, which is a highly selective and potent RET kinase inhibitor. And the information that we have from phase 1 into LIBRETO-001, which led to global approvals by FDA, although conditional and like EMA also conditional, we're talking about in treatment-naive patients specifically a response rate of 84% with a median PFS of 22 months. And if we want to compare, we can only compare with platinum-based chemotherapy and pembrolizumab, which brings us to keynote 189 study. And here we have a reported rate of 48% of response rate with a median PFS with nine months. So at ESMO, Benjamin Best gave a really nice talk when he did the interpretation of this clinical trial. And the question that really we all have in our heads, is this really an unmet need? Did we really need a phase 3 clinical trial with such a rare disease and such impactful information on previously LIBRETO-001? The truth is, this did go ahead. So we do have this information. So this phase 3 LIBRETO-431 actually evaluated the efficacy and safety of first-line silpercatenib in patients with RET positive. So patients had locally advanced disease or metastatic with no prior systemic therapy, RET fusion positive that were identified either on NGS or PCR, and ECOG PS of 0 and 2, and symptomatic CNS were excluded. A total of 261 patients were randomized in 2-to-1 fashion, receiving silpercatenib 160 milligrams twice a day, with the comparator arm of chemotherapy with or without pembrolizumab. In this comparator arm, we knew that 81% of the patients received a combination of chemotherapy and pembrolizumab. So the patients on the comparator arm were able to cross over to silpercatenib in case of progression. And here, the data was presented with a median follow-up of 19 months. The primary endpoint was PFS according to central review. Here are the key results concerning our primary endpoints, and we see a median PFS of 24.8 months with silpercatenib against 11.2 months of chemotherapy with a hazard ratio of 0.465 and a p-value of less than 0.001. And these are in line with what we already expected with the previous phase 1 and 2 studies. And interestingly here, what we see with the PFS in the intention to treat with pembrolizumab population, comparing to the intention to treat population with all of them, is really there's not such a great difference to say not practically at all between giving pembrolizumab with chemotherapy or just chemotherapy with these patients. So really, it's more or less the same. Obviously, we have to talk about this with such impactful data. We have to remember that 62% of the patients on the control arm did cross over to silpercatenib, and despite this high percentage, we did have impactful data. Concerning objective response rate with the silpercatenib arm, we're talking about 83% and control 65%. Intracranial response was very nice also with 82% in the silpercatenib arm against 58% on the control arm. Concerning quality of life, it's clearly favorable to silpercatenib comparing to chemotherapy. And concerning safety in terms of grade 3 or more adverse events, 70% of patients receiving silpercatenib did experience against only 57% of the chemotherapy arm. However, in the silpercatenib arm, only 10% led to discontinuation. With dose adjustments and dose reductions, we are able to manage this drug. So this is actually a long-awaited new standard of care, and it was really a highly attended presidential, and it was a really nice place to assist and to see this live. Moving on to the next one, papillon. Why is this necessary? What is the unmet need? Concerning EGFR exon 20 insertion advanced non-small cell lung cancer, we know that historically the outcomes have been poor. We're talking about an 8% of 5-year overall survival, largely due to the insensitivity of this subpopulation to common EGFR TKIs and also to the failure of checkpoint inhibitors in this population. So we're talking about platen-based chemotherapy as a standard of care. We know that amivantamab received approval in this setting after progression of platen-based chemotherapy after Creseli's study, which Dr. Pilar Guerrillo earlier this year presented at the European Lung Cancer Congress, the update, with a total of 114 patients with objective response rate of 37%, a median PFS of 6.9 months, and a median OS of 23 months. So if we think about this median PFS of amivantamab after heavily treated patients in the Creseli study, and we know that chemotherapy is also around six months, it makes sense to put this combo in first line, and that's exactly what papillon did. It evaluated the efficacy and safety of first-line amivantamab in chemotherapy in this line setting in a phase 3 trial. So key inclusion criteria, locally advanced or metastatic non-small celling cancer, treatment naïve, exon 20 insertion, and ECOG PS of serum 1, and here also symptomatic CNS metastases were excluded. A total of 308 patients were randomized in a fashion of one-to-one with amiv and chemotherapy as with comparative to chemotherapy alone, and here also upon progression, patients were able to cross over to amivantamab. The primary endpoint was PFS. So presenting three key results here at ESMO, we saw that the combination of amivantamab and chemotherapy had a median PFS of 11 months against 6.7 of chemotherapy, which we already knew from past experience, with a hazard ratio of 0.39 with the p-value that was statistically significant, and here we have also objective response rates in the combo arm of 73% against 47% of chemotherapy, and patients at the median time to response is lower on the combo arm around 6.7 weeks against chemotherapy, where we're talking about around 11 weeks to response. What about duration of response? With the combo arm, we had a 9.7 months of duration of response against 4.4 in chemotherapy, and on the right hand of the slide, we can see the PFS2, which means if even giving the combo in first line and after patients progress, they still remain a little bit more progression-free survival and respond better giving this combo in first line comparatively to giving chemotherapy on first line. What about safety issues? The combo had grade three or more adverse events in 75% of the patients comparatively to the chemo arm with 54%, so it's cumulative, the toxicity. It led to discontinuation of the agents in the combo arm in 24% of the patients, although only specifically related to amiventumab, we're talking about 7% of the cases. So, in conclusion, patients with the exon 20 EGFR insertions with this first line combo of amiventumab chemotherapy did demonstrate nice PFS with this combo comparatively to chemotherapy. In terms of toxicity, it's something we know now it's cumulative and we'll have to know how to manage it. So, take-home messages. Patients with ALK positive in early stage, ELINA potentially establishes electinib as a new adjuvant treatment in this stage. Overall survival is needed, a little bit like the EGFR setting where historically we had a lot of clinical trials with disease-free survival was meaningful, but that did not translate in overall survival. I'd say that here it would be really important to have this overall survival robust to clearly demonstrate this as a new treatment in this setting. In patients with RAD positive, the Libretto 431 confirms selpercatinib as a first-line standard of care. And with the information from this trial, immunotherapy is really not that mandatory in these patients, which is something we've been discussing as a whole community in the mutated patients, if it really makes sense to associate chemotherapy and immunotherapy. Here we have a little bit more information. And to finalize the Exxon 20 EGFR mutated patients, the Papulum also establishes a potential new standard of care. Although we know that efficacy and toxicity here is addictive, it's additive to chemotherapy here and it's something we'll have to learn to conquer. Thank you. Thank you very much, Thelma. Dr. Sequeiro, really fantastic presentation. And last but not least, Dr. Tomeo Massuti, that is Associate Professor of Medicine and Head of Medical Oncology Department at University Hospital in Alicante, Spain, who is going to talk about new results in perioperative treatment with chemo and immunotherapy, a really hot topic in lung cancer. So please, Dr. Massuti, you can go ahead. Hello. Thank you, Pilar. First of all, let me thank to all attendees and to ILSLC to offer these opportunities to share and disseminate knowledge. I am going to review a small presentation related to early stage non-small cell cancer. And as you know, this field is a very dynamic scenario. We will focus on two less-breaking abstracts dealing with perioperative strategy, meaning preoperative systemic treatment, surgery and follow-up by postoperative treatment, mainly immunotherapy, as you know, because the chemotherapy has limitation according to CCP. Let me remember that the non-small cell lung cancer is mainly a systemic disease. Majority of recurrence, even in the earliest stage, are systemic distant metastases. And that is well known for all of you and also is well known. And let me remember that definitive surgery is a tool for offer to the patient chance for curative outcome. Coming with the pre- or postoperative dilemma, as you know, using chemotherapy, we only have two possibilities to apply to make chemotherapy treatment after surgery or before. The impact in outcome is very similar, but with the appearance of the immunotherapy, then we can move to the more prolonged treatment using systemic therapy upfront, followed by surgery, and after surgery continues with immunotherapy. That is, as you know, the neoadjuvant chemoimmunotherapy has achieved significant improvements in pathologic response, in terms of major pathologic response, and mainly in the pathologic complete response rate. And that means a change, I think, a very significant change in this scenario. As you know, also in the recent years, we have many trials dealing with this approach, mainly neoadjuvant chemoimmunotherapy, and the results until now were limited to the pathologic response and also even free survival. Here you can see the different trials, the CHECKMATE 816, the AGEAN, the NADIM-2, the K-Note, and the NeoTorch. In this, the results of these trials in terms of pathologic response and EFS are consistent, as you know, in the slide, which has a ratio around 0.5 and around 60% of EFS at two or three years. Let me move to the first abstract review. This is referred to the interim analysis two of the K-Note C7.1. That is, as you know, the design is a perio-temperative pembrolizumab versus placebo adding to chemotherapy cisplatin-based preoperative and following with pembrolizumab versus placebo during 12 months after surgery. These results are in some way mature because the median follow-up is up to three years. As you know, in the right part of the slide, you can see in this console diagram, but I would like, I ask you to focus in the post-operative treatment. The post-operative treatment was delivered, complete the post-operative treatment or pembrolizumab or placebo in less than 50% of patients. That is one of the things we need to remember. As you know, the stratification factor of the disease of this trial were disease stage 2 versus 3, PD-L1 less or more than 50%, and histology ischemus versus non-ischemus in geographic areas or geographic region. The randomization was one-to-one, and this trial has dual primary endpoints, EFS, but per-investigation review, and OS. And these are the first results on the OS. And move to the primary endpoint is overall survival. This strategy of perioperative pembrolizumab in early stage non-small cell lung cancer achieved hazard ratio for overall survival 0.72. That is significant, statistically significant, with the median overall survival not reached in the pembro arm and 52 month in the placebo arm. As you know, the curves start to separate after one year, and this separation is maintained along the time. This is the first trial that show us impact on survival of this perioperative approach. In addition to that, we can see the EFS results of the trial are aligned with the previous reported and with the hazard ratio of 0.559, with the median EFS 47 month in the pembro arm versus 18 month in the placebo arm. That is not only statistical, I think it's also clinically significant. If we move to the forest plot for the subgroup analysis, the forest plot you can see in the slide, we can see that the benefit of this approach using pembro pre and post is greater in smokers, current smokers, in the ischemos histology, and as you can expect in the higher PD-L1 expressions. There were no significant difference or no relevant difference in the subsequent systemic therapy that is important in order to evaluate the survival. In moving to the safety, the adverse events, there are no unexpected adverse events. Let me remember, let me emphasize that less than 10% of patients suffer immuno-related adverse events and less than 2% pneumonitis. So, this is the first trial I would evaluate. And now we move to the second one. The second one is the CHECKMATE-77T. It is a phase 3 trial comparing neoadjuvant nivolumab plus chemotherapy with neoadjuvant placebo plus chemotherapy, followed by surgery and adjuvant nivolumab for placebo for receptable stage 2 until 3b non-small cell lung cancer. Also, the randomization was one-to-one. The primary point in this trial is only EFS. The number of included patients were 461, and the secondary endpoints is pathological complete response, major pathological response, overall survival, safety. If we see the different prognostic factors, the potential prognostic factor in the different end, there are no significant difference, but the majority of patients came from Europe, have stage 3A or 3B. The majority, 90% were current or former smokers, and this is important to remember, around 40% were PD-L1 negative. That is useful to remember in order to make indirect comparison between trials. This is the consort diagram flow, showing this slide. The definitive surgery was performed in 77 and 78% of cases, and around 60% of patients start adjuvant therapy. And finally, 37% or 40% of patients complete the planned treatment, I mean the post-operative adjuvant immunotherapy. Moving to outcome, the primary endpoint, as you see, this is a positive trial with a hazard ratio for EFS of 0.58, with median EFS not reached in the nevo arm, and 80% in the chemotherapy placebo arm. That is in the same line as the other similar trials in this setting. These benefits are more pronounced in stage 3, in end-to-disease, in ischemic histology, like the previous trial commented, in the current or former smoker, in the higher, in this case, positive PD-L1 expression. This graphic, this is unplanned, but these pronostic factors were stratified, as you can remember. This graphic probably suggests a differential effect according to stage and PD-L1 expression of this strategy of chemoimmunotherapy, but it needs to be confirmed and probably specifically researched. Also, in an exploratory analysis, we can see in this slide the impact of adjuvant treatment in both settings, patients that were able to receive adjuvant therapy and patients, the subgroup of patients that were not able to receive adjuvant therapy. In both cases, the nevo arm, nevomass chemo arm, was superior to the chemo placebo arm, and in terms of magnitude, the hazard ratio was higher, the benefit through using the hazard ratio was higher in the subgroup, in the group of patients that received adjuvant therapy. You can see 0.55 and 0.45. One of the burning questions is really the pronostic value of PCR. I think there is an increasing volume of information that shows us that the PCR achieved after induction of chemoimmunotherapy is a major pronostic factor, and there is a question, an open question and a burning question, if this subset of patients need to receive or benefit from an adjuvant postoperative trial. In this way, in the ESMO also, there was presented the update of three years results of HM8A1 seeds by Mariana Provencio that is in the same line. This patient that in the patient that in this trial achieved complete pathological response, the overall survival at more than four years, the probability of survival is up, is upper than 80%. Finally, on the slide about the safety, the adverse events, it is necessary to remember that there was not unexpected new adverse events, but there was two treatment-related deaths due to pneumonitis after the neoadjuvant period. That is a word of caution in that. And finally, the burning question is really, what is the real impact of the follow-continue knee volume up after surgery? We cannot, we can use this graph coming from the checkmate A1 seeds and checkmate C77. As you may, as you can see, this is not a direct comparison, but as you remember in the checkmate A1 seed, the adjuvant treatment was not mandatory. So, these are the figures. And finally, the last slide is the take-home and the challenge to wrap up increasing role of neoadjuvant chemoimmunotherapy are becoming the standard of care for receptable non-small cell lung cancer from stage 2 to 3B even. The first results of overall survival outcome for perioperative pembrolizumab combined with chemotherapy were presented in the checkmate. And let me remember that in every case, in any case, attrition rate is around 20% in plant surgery and ranging from 15% to 20% in the adjuvant treatment compliance. What is the impact in the stage 2 or PD-L1 negative? It seems a lower impact, but probably is not that we have not sufficient data to exclude this patient. I think we can agree with the major pronostic value of pathological complete response and we need to address specifically the impact of postoperative immunotherapy, especially in this patient that achieved pathological complete response. As mentioned before by the other speakers, the detection of biomarkers, in this case for minimal residual disease, maybe ctDNA, might help to a better selection of patients continue with postoperative therapy. In patients that don't achieve pathological complete response, there is a clear room for improvement. Thank you for your attention. Thank you, Tomeu. So, we have five minutes for questions. I don't have any questions on the screen, so I will start by asking Elena a question about biomarkers. You mentioned three drugs. All of them were biomarkers theoretically focused. DATO was focused on TROP2, Tarlatamab in DL3, Amimantamab, Dual Target, EFR and MED. However, patients were included in this clinical trial, they were not selected based on biomarker status. What are your thoughts about, can you expand a little bit about the potential role of this biomarker when having a drug potentially focused on a target? Exactly, exactly. I think this is one of the main issues with these new agents. The problem is that not only the patients were not selected, but we have not seen as yet data on whether these were investigated. So, for the TROP2, we know that from previous studies that maybe there is some importance of the level of expression. However, in most of the studies, all the levels of expression of TROP2 responded similarly, there was no difference. So, all agents with the TROP2 targeting don't have selection in the study. And that's one of the problems with the TROP2 ADCs. With regards to the AME, we know that it's a bi-specific EGFR-MED. And the idea behind the Mariposa studies was to address those two resistance mechanisms, the new mutations on EGFR or the MED alterations. And they chose the best agent for that, a bi-specific for EGFR and MED. But they haven't checked or they haven't shown us if they check the presence of the target of the agent. So, I think especially if we're dealing with agents with such toxicity and we're bringing them to first line and we're aiming to change the standard of care, which is very well established, as I said, Ocimertinib is oral. Now we're looking with Mariposa to give an intravenous agent. I would definitely want to know which patient will benefit more. Absolutely. So, one of the sentences we always put in the last slide of any presentation is we need biomarkers. But even when we have, we don't design the clinical trial focused to answer the right question. Okay. I will ask now to Dr. Sequeiro a question related also to biomarker. For instance, when speaking about avimantamab in exon 20 insertion mutation in the second line setting, we know that EGFR exon 20 insertion are really a very heterogeneous population. There are many variants and apparently when using avimantamab alone, that can be a role for having different response depending on the variant. Do you think that when moving to the first line scenario and combining with chemotherapy, this is not going to be relevant? Any thought about the potential role of us? Because as Elena mentioned, we don't have any data, no? So at least the author didn't show any data. Yeah, thanks. Great question. Concerning EGFR exon 20, first of all, I think we should go a little bit back and we have to state the importance of NGS because this is a mutation that really needs next generation sequencing. PCR not always has the same sensitivity to pick up this mutation. And concerning the information that we have from previous studies, the location of the mutation could determine a different response. We don't have that kind of information. It wasn't presented. It wasn't shared with us. If this is going to impact on the first line with the combo combination, we're not sure. We don't have that kind of info. It would be nice to see, to see if we can select who would get further, better outcomes than maybe others to further select these patients. It might be something interesting. And also this can potentially be changing because I mean, it's true that we did see the interim analysis of PFS. The OS curves did cross together. So it was not statistically significant, although this is a secondary endpoint. However, we need to have a little bit more information to see what, where the information goes. But that's something I'd like to see if we can further select these patients and it will be interesting in the upcoming times. Thank you. And a question for Dr. Masouti, are you concerned about the 20% attrition rate for plant surgery? Because it's not only in this clinical trial, but it's in general, no? In the neojuvent setting. What are your thoughts about it? I fully agree with the concerns about the attrition, but there could be some explanation. One is the staging at the beginning of the trial. The other one may be progressive disease, but this is, seems not the major concern. That means this patient could not lose opportunities with this approach. I think we need to clarify to generate more information in this specific point, but I have no specific concern. Maybe the concerns could come from the more earlier stage. I mean the stage two. If we lose patient in the stage two, probably the concerns are arising and need to be addressed specifically. Maybe, probably the, even the differential impact on the stage need to be more, need to generate more information, but I don't think it's necessary in a specific trial. Maybe analyzing all the trials could offer some light in this aspect. Absolutely. There is a question in the screen about... Okay, yeah, you are right. This is a question I think for Dr. Siqueiro. What about ALK testing by PCR technique? So, this brings a little bit what we were saying previously. Well, it depends obviously globally what we're, what we have access to because we know it's quite different from country to country, from each continent. Ideally, when we're testing for mutations in the non-small cell and cancer, we ideally should go to a next generation sequencing. Not always that is available. So, it depends what we have in terms of reimbursement, in terms of government policies, hospital policies. It's quite different from country to country. If we do have the technology, if we do have the access, the NGS is more accurate. We have access to the variants. We have access to the much more information concerning the genetic standpoint. And also, even if we have co-mutations that could eventually pop up. So, this is something that is going to depend from from center to center. And it depends on local resources. Ideally, in an ideal world, it should go to next generation sequencing. Okay. I have many, many questions because I think this SMO meeting was really amazing for lung specialists. But I am sorry I have to say that we are running out of time. I will finish by thank you, firstly, the speaker. Excellent presentation. Thank you for the attendees, of course, to be there. And thank you the ELCC for giving me this opportunity to. And please remember that there are a lot of educational activities in the ELCC webpage. So, please visit the webpage. And thank you again for joining us today.

ELCC webinar

2023 ESMO highlights

non-small cell lung cancer

ADCs

bispecific antibody combinations

Tropium Lung-01 study

DATO-Texasamab

progression-free survival

adjuvant electinib

perioperative treatment