So, welcome to today's webinar. My name is Hidehito Horinouchi from National Cancer Center Hospital, Tokyo, Japan, and I will be moderating this webinar. And thank you for the IACC and the JLCS. This is a memorial first time joint webinar supported by both important organizations. Let's begin by running through the housekeeping notes. So, you will be able to find a video recording of the webinar on the website within the next week. Your camera and microphone will remain off for this webinar. Please enter any question until you have the Q&A discussion into the Q&A section at the bottom of the webinar. You may use the chat function for the other discussions, but mainly, I would like to request you to use the Q&A. And we will not be using the raise hand function for questions. We plan to have a keynote lecture and a panel discussion, and please enter your questions into the Q&A section at any point during the talks. So, I will hand over to Professor Mitsuzomi as a keynote moderator. Thank you, Professor Mitsuzomi. Thank you very much, Dr. Horinouchi, for my introduction. My name is Tetsuya Mitsuzomi from Kindai University, Osaka, Japan, and today, I'm very excited to have Dr. Enrique Ferp from Spain as a keynote speaker. As you may know, Dr. Enrique Ferp is the head of the Plastic Oncology Unit at Valdebaran Institute of Oncology, Valdebaran University, Barcelona. She's a lead author of the Infor 101 that was recently published, which will be the main topic of today's lecture, I assume. And also, you may remember, she's a lead author of the famous NATCH trial, which compared the preoperative chemo with the postoperative chemo. And also, she was the co-conference chair of the WCLC 2019 in Barcelona before the COVID-19 era. And also, she's the former board of directors of the ISOC. And Dr. Ferp, thank you very much for accepting our invitation. We are very looking forward to your lecture, so please start. Thank you, Dr. Mitsuzomi. It's a real honor for me to be here today, and I would like to thank ISOC and the Japan Lung Cancer Society. It's a real honor for me to participate in this session. So, I'm going to discuss emerging preoperative treatment using immune checkpoint inhibitors in patients with resectable non-small cell lung cancer. You can see here my disclosures. So, now we have three studies randomized that are positive using immunotherapy in patients with early-stage disease. I'm going to review the two trials using adjuvant immunotherapy, DIME-POWER-010, and also the Keynote-091, and also the randomized trial analyzing chemo plus immunotherapy in the new adjuvant setting, the checkmate H1-6. First, DIME-POWER-010. In this trial, 1,280 patients with completely resected stage 1b with tumor size of at least 4 centimeters, 2, and 3a, received at least one but not more than four cycles of cisplatin-based chemotherapy, and then 1,005 patients who still met eligibility criteria were randomized to receive one year of autosolution versus best supportive care. The certification factors included gender, stage, histology, and PD-L1 status, and the primary endpoints where the investigator assessed disease-free survival tested hierarchically. First, in patients with stage 2 and 3a and PD-L1-positive tumors, if positive in all randomized stage 2 and 3a population, and if positive in patients with stage 1b, 2, and 3a. A key secondary endpoint was the disease-free survival in PD-L1 50% or higher stage 2 and 3a population. When we analyze the patient characteristics of the patients randomized, the median age was 62. There are 65% of the patients male, 35% of the patients with ischemic cell carcinoma, and 40% of the patients with pathological stage 3a disease. PD-L1 status was negative in 40% of the patients. When we analyze the adverse events associated with adjuvant atelizumab, we have seen that there was a 0.8% grade 5 treatment-related adverse events, and in 18% of the patients, atelizumab was stopped due to adverse events associated with atelizumab. In this slide, you can see the disease-free survival analyzed in the three study populations. For those patients with stage 2 and 3a and PD-L1 positive tumors, atelizumab was associated with longer disease-free survival when compared to the control arm, with a hassle ratio of 0.66. At three years, there were 60% of the patients disease-free in the atelizumab arm, 48% in the control arm. In all randomized stage 2 and 3a population, atelizumab was associated with longer disease-free survival when compared to control, with a hassle ratio of 0.79. At three years, there were 56% of the patients disease-free in the atelizumab arm, 49% in the control arm. When we include the patients with stage 1b, 2, and 3a, the hassle ratio was 0.81. At this analysis, the statistical significance boundary was not closed, and the follow-up is ongoing. When we analyze the key subgroup analysis for disease-free survival in the Empower Zero time, we can see that the hassle ratio is similar in those patients with ischemic cell carcinoma and non-ischemic cell carcinoma. For those patients with pathological stage 2a, the hassle ratio is 0.68. For those patients with pathological stage 2b, hassle ratio is 0.88. For those patients with pathological stage 3a, the hassle ratio is 0.81. When we analyze all patients with stage 2 and 3a, we mentioned, and PD-L1 positive tumors, the hassle ratio is 0.66. For those patients with PD-L1 negative tumors, the hassle ratio is 0.97, and for those patients with PD-L1 50% or higher, the hassle ratio is 0.43. During the ELCC meeting, we presented the patterns of disease relapse for those patients with stage 2 and 3a and PD-L1 50% or higher. 44% of the patients in the control arm progress, 22% in the atesolizumab arm. The percentage of patients with local regionals-only progression was similar between the two treatment arms, around 15%. Distance-only metastasis was seen in 18% of the patients in the control arm, 5% of the patients in the atesolizumab arm. And CNS progression-only was seen in 6% of the patients in the control arm, 1% in the atesolizumab arm. The overall survival information was immature. For those patients with stage 2 and 3a and PD-L1 positive tumors, it was a trend in favor of atesolizumab. However, again, this overall survival information is not mature. And our conclusion was that IMPOWER-010 showed a disease-free survival benefit with atesolizumab versus best supportive care after adjuvant chemotherapy in patients with resected stage 2 and 3a, with pronounced benefit in the subgroup of patients with PD-L1 positive tumors, and the greatest magnitude of benefit for those patients with PD-L1 50% or higher. The Keynote-091 trial was presented by Dr. Pazares during the ESMO virtual plenary in March 2022. In this trial, LGBT criteria was similar. Patients with pathological stage 1b with tumor size of at least 4 centimeters, 2 or 3a, according to the 7-TNM classification. PD-L1 testing was performed centrally, and then the patients eligible for randomization were those patients without evidence of disease, adjuvant chemotherapy should be considered for patients with pathological stage 1b, and strongly recommended for stage 2 and 3a disease. And patients were randomized to receive pembrolizumab for one year or placebo. This is a placebo-controlled trial. Stratification factors included disease stage, PD-L1, receipt of adjuvant chemotherapy, yes or no, and geographic region. And the trial has two primary endpoints, the disease-free survival in the overall population and the disease-free survival in PD-L1 50% or higher population. Patient characteristics, similar of what we have seen in ANT-POWER, the median age was 65. 62% of the patients with non-eschemus histology. There are 30% of the patients with pathological stage 3a disease. In this trial, 14% of the patients were previously not being treated with adjuvant chemotherapy. And PD-L1 negative tumors were observed in 39% of the patients, and PD-L1 50% or higher in 30% of the patients. Adverse events associated with adjuvant pembrolizumab were similar of what we have observed with atezolizumab. There are 0.7% of the patients that pembrolizumab was associated to death. And in this study, there are 19% of the patients with pembrolizumab treatment discontinuation due to adverse events. These are the two primary endpoints. In the overall population, disease-free survival was longer with pembrolizumab when compared to placebo, with a hassle ratio of 0.76. The median disease-free survival was 53 months in the pembrolizumab arm, 42 months in the placebo control arm. In the population of PD-L1 50% or higher, there is no difference in disease-free survival between the two treatment arms. The median disease-free survival was not reached in any of the two arms, and the hassle ratio was 0.82. Subgroup analysis for disease-free survival in this trial show us that for pathological stage 1b, the hassle ratio was 0.76. For those patients with pathological stage 2, the hassle ratio is 0.7. For those patients with pathological stage 3a, the hassle ratio was 0.92. The hassle ratio in non-SKMOS was 0.67, 1.04 for SKMOS, and for those patients with, sorry, without adjuvant chemotherapy, the hassle ratio was 0.25, 0.73 for those patients receiving prior adjuvant chemotherapy. Overall survival was not matured in the study. The hassle ratio is 0.87, and the authors concluded during the presentation that data suggests pembrolizumab has the potential to be a new adjuvant treatment option for patients with a stage 1b with a tumor size at least 4 centimeters, 2 or 3a, according to the 70NM classification, following complete resection and adjuvant chemotherapy when recommended, regardless of PD-L1 expression. Here in this slide, you can see the disease-free survival in two studies, including all patient population, stage 1b, 2, and 3a. In keynote, the hassle ratio is 0.76, in aimPOWER is 0.81, including also patients with pathological stage 1b disease. And here, the disease-free survival in PD-L1, 50% or higher. As we mentioned in the keynote, there is analysis of patients with pathological 1b, 2, and 3a, and we mentioned the hassle ratio is not statistically significant. In aimPOWER, we have the information of PD-L1 high in pathological stage 2 and 3a disease, and in this case, the hassle ratio is 0.43. As you know, there are ongoing adjuvant immunotherapy trials, pending of the results, the ANVIL trial analyzing adjuvant nivolumab, VR31 analyzing adjuvant durvalumab, ALCHEMIST trial comparing chemotherapy versus chemotherapy four cycles followed by pembrolizumab versus chemotherapy plus pembrolizumab for four cycles followed by pembrolizumab. And then, I would like to mention a study from the Spanish Lung Cancer Group in the adjuvant setting, comparing four cycles of chemotherapy versus four cycles of chemotherapy in combination with immunotherapy, followed by immunotherapy. The first study is the CHECKMATE 816 in the neoadjuvant setting. Here, patients are included, eligibility criteria included, resectable stage 1b with tumor size of at least four centimeters, 2 and 3a, according to the 7th edition, but these are patients with clinical stage, not with pathological stage. Patients 358 were randomized to receive three cycles of chemotherapy followed by surgery, or three cycles of chemotherapy plus nivolumab followed by surgery. The stratification factors included the stage, PD-L1 and gender, and the primary endpoints were pathological complete response and event-free survival. 179 patients received chemo plus nivolumab, 179 chemotherapy alone. The median age was 65 years, 70% of the patients were male, and we have 63% of the patients included with the stage 3a disease. PD-L1 negative tumor was observed in 40% of the patients, and PD-L1 50% or higher in 23% of the patients. Overall, in the Nivo plus chemo arm, 83% of the patients had definitive surgery. In the chemo alone arm, 75% had definitive surgery after the neoadjuvant strategy, and when the authors analyzed the adverse events at surgery, there were no differences between chemotherapy and chemotherapy plus immunotherapy. We knew that pathological complete response was higher for those patients receiving chemo plus immunotherapy, 24% versus 2.2% in the chemotherapy alone arm, and when we analyzed the pathological complete response for those patients treated with Nivo plus chemotherapy, the percentage is similar in patients with stage 1b or 2 versus 3 in ischemus versus non-ischemus histology. According to the PD-L1 expression, the pathological complete response with chemo plus nivolumab was 16% for those patients with PD-L1 negative tumors. It was 44% for those patients with PD-L1 50% or higher. We mentioned the surgical outcomes. Overall, the percentage of lobectomies seemed slightly higher for those patients receiving chemo plus Nivo and the opposite, the percentage of pneumonectomies slightly higher for those patients receiving chemotherapy alone. In the recent publication and in the presentation in ACR, we have the data of event-free survival. Event-free survival was longer with chemo plus nivolumab when compared to chemotherapy, with a hassle ratio of 0.63. Median event-free survival was 32 months for those patients treated with chemo plus Nivo, 21 months for those patients treated with chemotherapy alone. When we analyzed patient subgroups, the benefit of chemo plus immuno in those patients with PD-L1 tumors was 0.85. For those patients in PD-L1 positive, it was 0.41. In those patients with PD-L1 50% or higher, 0.24. In the trial, those patients with pathological complete response had better survival outcomes, and also it was an interim analysis of overall survival. Again, not yet mature. The median overall survival was not reached in any of the two treatment arms. The two-year survival was 83% of the patients in the chemo plus Nivo arm, 71% in the chemotherapy alone arm, and the conclusion is that the checkmate 816 is the first phase-free study with a neoadjuvant immunotherapy-based combination for resectable normal small cell lung cancer to show improved event-free survival and pathological complete response, along with promising overall survival results. And these results support neoadjuvant Nivo in combination with chemotherapy as a new standard of care for patients with resectable normal small cell lung cancer. I would like to discuss the clinical trial endpoints. In the adjuvant trials, is disease-free survival, the definition is the same. However, there are some differences. IN9-POWER010, as we mentioned, is an open-label trial, and the primary endpoint, investigator-assessed disease-free survival, was tested hierarchically. First, in a stage 2 and 3A population and PD-L1-positive tumors, if positive in all randomized stage 2 and 3A population, and if positive in a stage 1B, 2, and 3A. In the Keynote-091, there is a placebo-controlled trial, and there are two primary endpoints, disease-free survival in the overall population, including patients with pathological stage 1B with tumor size greater than 4 centimeters, and disease-free survival in PD-L1, 50% or higher population. In Checkmate-816, pathological complete response is one of the endpoints. The definition, no residual viable tumor cells in the primary tumor and lymph nodes, and in this case, the pathological complete response was assessed by a pathology-centered review, and also event-free survival. And again, in the Checkmate, event-free survival was determined according to the blinded, independent, central review. We have discussed in the last years the role of measured pathological response. Definition is less than 10% of viable tumor tissue in the surgical specimens. Some studies, the termination of measured pathological response is challenging. I would like to recommend a paper from the ISLC published in JCO with multidisciplinary recommendations for pathological assessment for lung cancer of sectional specimens after neoadjuvant strategies. And we have a number of randomized trials ongoing with neoadjuvant strategies, and it's true that the measured pathological response is not one of the primary endpoints of these trials. 9POWER030 is analyzing chemo plus atelizumab in the preoperative setting versus chemotherapy. The primary endpoint is event-free survival. The Keynote 671 is analyzing chemo versus chemo plus pembrolizumab with the primary endpoints of event-free survival and overall survival. The Asian trial comparing chemo plus placebo or chemo plus durvalumab in the neoadjuvant setting with primary endpoints of pathological complete response and event-free survival, and also the Checkmate 770 analyzing chemo plus nivolumab. And again, the primary endpoint, event-free survival. Dr. Mitsudomi mentioned during the kind introduction the NADDS trial, and the reason to include here the NADDS trial is that probably we are discussing different patient population when we compare the adjuvant trials with the neoadjuvant trials. The NADDS trial published more than 10 years ago compared in patients with early stage with the clinical staging surgery up front versus surgery followed by adjuvant chemotherapy or neoadjuvant chemotherapy followed by surgery. In this trial, patients with stage 1b2 and T3N1 were included, again, the clinical stage, but we have seen at surgery that for those patients randomized to surgery up front, there were 20% of the patients with pathological end-to-disease that we were not able to diagnose in the clinical staging pre-surgery. Probably this has changed in the last 10 years, but the reality is that we detect a number of pathological end-to-disease at surgery not previously detected with clinical staging. So when we mentioned that in the neoadjuvant strategies, 10, 15% of the patients do not undergo surgery, probably they are not exactly the same patient population. In these trials, as we have seen in the Checkmate 816, there are 30% of the patients with the stage 3a included, and in the adjuvant immunotherapy trials, all patients have had surgery per definition, so the randomization is after surgery. All patients have completely resected tumors and probably we include those patients with pathological end-to-disease not identified pre-surgery. Compliance, we have seen in the next trial that the chemotherapy compliance was higher in the preoperative setting when compared to adjuvant setting when the patients were randomized up front with the clinical staging. In the neoadjuvant chemotherapy arm, 97% of the patients received preoperative chemotherapy. In the adjuvant setting, only 66% of the patients, and the main reason was a slow recovery from surgery. And then we have some information about immunotherapy compliance in the three trials. In the IMPOWER-010, we know that 1,269 patients received adjuvant chemotherapy. And finally, 1,005 patients were randomized to receive immunotherapy or control. In the Keynote-091, 1,955 patients were registered. And finally, 1,177 patients were randomized. And in the Checkmate-816, 773 patients were enrolled. And finally, 179 were allocated to neoadjuvant chemo plus nivolumab, 179 to neoadjuvant chemotherapy. But from these patients, 97% of them received the systemic therapy. We have some discussions about what we should do in patients with a stage 1B disease with immunotherapy. In the IMPOWER-010, there are 13% of the patients with pathological stage 1B. And according to the hierarchically designed analysis, including all patient population, the hassle ratio, as we mentioned, is 0.81. The statistical significance boundary where we include all the patients for disease-free survival was not closed, and the follow-up is ongoing. In the Keynote-091 trial, there are 14% of the patients with pathological stage 1B. And here, the hassle ratio for those patients with pathological stage 1B, 0.76, for patients with pathological stage 2, 0.70, and for patients with stage 3A, 0.92. In IMPOWER, in the Checkmate-816, we have the results together, a stage 1B and 2, and a stage 3A disease. And for those patients with stage 1B and 2 together, the hassle ratio for event-free survival is 0.87, for patients with stage 3A, is 0.54. The other discussion point is PD-L1 as a predictive marker in early stage. In IMPOWER-010, clearly, the results show that for those patients with PD-L1 high, 50% or higher, and stage 2 and 3A, the hassle ratio is 0.43. 53, 43, sorry. In the PILS-091 trial, there is no relationship between the benefit and the PD-L1 staining. And perhaps for those patients in Checkmate-816, we also see some kind of relation of better pathological complete response or better hassle ratio in event-free survival favoring chemo plus immuno for those patients, PD-L1 high. And when we analyze testing, probably testing now is a standard of care, but it's true that perhaps it's more easy to perform testing in those resected specimens when compared to those patients with only a sample at diagnosis. An important point of information for probably is the circulating tumor DNA. And this has been analyzed in DIME-POWER-010. There was analysis of circulating tumor DNA samples just before starting chemotherapy. And in general, what we have seen is that the presence of circulating tumor DNA is prognosis. However, the patients with circulating tumor DNA positive and also negative benefited from adjuvant adheslizum. There is a MERMAID trial ongoing analyzing the potential contribution of the circulating tumor DNA and the minimal residual disease determination. And in Checkmate-816, we know that for those patients with circulating tumor DNA clearance in the pathological complete response with chemo plus immuno was 46%, with chemotherapy was 13%. And I would like to mention this proposal. This is an important paper by Dr. Mitsudomi recently published and perhaps circulating tumor DNA may well have a role in the patients in the clinical practice. And it's true that, for example, those patients with circulating tumor DNA positive at diagnosis may well be in the future candidates for neoadjuvant strategies and perhaps to decide the treatment according to the presence or not of the circulating tumor DNA. So this is exciting times in early stage disease. Immunotherapy will change the standard of care, but you have a number of unanswered questions. We don't know if neoadjuvant is better than adjuvant immunotherapy, but probably as I mentioned, these are two different patient populations. We need to understand more the role of PD-L1 as biomarker. One important question in the adjuvant setting is better to give adjuvant chemotherapy followed by immunotherapy or the combination upfront of adjuvant chemotherapy plus immunotherapy. And also for those patients receiving neoadjuvant strategies, we need to define the adequate adjuvant therapy after neoadjuvant chemo plus immunotherapy and resection. And these are my final thoughts. Immunotherapy will be a standard of care for early stage non-small cell lung cancer. In my opinion, it's a far and out wide type. As I mentioned, adjuvant and neoadjuvant strategies probably will be different in different patient population. It's important to have more markers beyond PD-L1. Probably the circulating tumor DNA technology may help to individualize therapy and we need to focus on long-term survival needs. And thank you again. It's a real honor for me to participate in the meeting. Thank you. Thank you very much. It's a really comprehensive lecture about the perioperative therapy. So, so far we have the seven questions. So we are running out of time, but I'd like to go to the Q&A session. So the first two questions from Dr. Weihara, Dr. Sakata is very similar. So Dr. Weihara's question is, in patients with PD-L1, more than 50%, what factors can explain the different outcomes between the Pembrolol and Atezol study? And the second question is, why didn't the Keynote-091 trial show statistically significant results in the PD-L1 high expression? Did not show, right? Yeah. So yeah, this may be very difficult, but most of the people feel like that. So do you have any thoughts about why the Keynote-091 showed such results? Difficult question, as you know, we don't know the answer. It was unexpected. I think the results, the different results with PD-L1, in patients with PD-L1 high, were in some way unexpected. It's true that in 9.010, we have the results in patients with pathological stage two and three. Keynote include also patients with pathological stage 1B. As you know, one study is a placebo control, though the other one is open label. In one study, adjuvant chemotherapy was mandatory. So probably there are differences in the design. We don't have the answer for this important question. Okay, so let's move to the next one. Next one is from Dr. Suda. I think the recurrence patterns between Atezol and the placebo seem interesting. Is there any other data in IO-adjuvant or neoadjuvant studies regarding recurrence patterns? So including the CNS meds or the low-carbohydrate recurrence versus distant meds. So I think this is also a very interesting question. Do you have any thoughts on that? Yeah, I'm not aware of other data similar of what we have presented. It's true that when in 9.000, we compared the pattern of relapse in the whole population, including patients with PD-L1 1% or higher, there were no major differences in the pattern of relapse. And we have seen this difference in these patients with PD-L1 50% or higher. But yes, I'm not aware of any other experience similar of that. Okay. And the next two questions are also very similar. So Dr. Basho's question is, do you think preoperative or postoperative treatment will be the mainstream? So which of the preoperative or postoperative treatment will be the mainstream in actual practice in the future? So the next question is, it looks that preoperative immunotherapy has a better outcome compared to the postoperative. So he compared 816 versus 910 or 010. So do you know? But you mentioned that the population may be a bit different, but do you know, do you think, which do you think is the mainstream of the future preoperative therapy? Yes, it's true that we will have other randomized trial in the near future that we will have the results. But I think at least in my opinion, for those patients probably a stage one and two, we will, I think, recommend surgery and then adjuvant chemoplasm immunotherapy if needed. And I think for those patients with a stage three disease, now we are doing multidisciplinary treatment before surgery. So probably these are the patients that we will treat with chemoplasm immunotherapy and then surgery. But yeah, something that probably we'll have more information in the near months. So Dr. Horinouchi, we have four more questions, but can I extend a little bit more for the QA? Dr. Horinouchi. Yeah, up to you. Thank you. Okay, so the next one is regarding the reimbursement issue of the new adjuvant atezolizumab. What is your opinion about the PD-L1 requirement? Is there any difference between the FDA and the EMA? It's a very difficult answer, right? Yeah, so as far as I know, atezolizumab has been approved by FDA, no? For those patients with stage two and three and PD-L1 positive tumors, and we are still waiting for the approval by EMA. It's true that there are some countries in Europe, such as Switzerland, that they have now the approval for patients with PD-L1 50% or higher. I think for those patients with PD-L1 1 to 49%, probably there are a number of patients who also benefit from immunotherapy. I think this is, you know, from 1 to 49% is to a lot of different PD-L1s. Probably it's not the same as PD-L1 of 40% or 1%, no? So, yeah, we don't know for sure what would be the final decision by EMA, but I would be comfortable to use immunotherapy in patients with PD-L1 1% or higher. So for the EMA 010, can we use a 2-C3 antibody instead of the SB263? No? No, we have the results with SB263. Okay. And we have three more, but it looks like it's very long. So for the time sake, could you answer by typing? Yeah, perfect. To those questions. And it's a pity, but I have to close this Q&A session and I have to hand over the chair's role to Dr. Horinocci. Again, thank you very much, Dr. Perp. It's a very nice lecture. No, no, thank you. Thank you all. Thank you. And see you soon. Sure. Yeah. Thank you, Professor Philip. Yeah, yeah, it's a pity, but I would like to go into the Japanese session and I will change the language to the Japanese, solely for the international audiences, because this is a JLCS and ISLC joint webinar. Half of the portion will be in Japanese. So, I will switch to Japanese and start again. You can check some of the questions in the Q&A panel discussion after this. And after this, I will share some housekeeping slides. First of all, today's panelists, Dr. Mitsudomi, who is chairing the session, and Dr. Yatabe, who is a pediatrician at the Cancer Center, and Dr. Kenmon Shizugan, and Dr. Chitani, who is a professor and has recently moved to the University of Tokyo. Today, I would like to talk to the panelists and quickly show the slides of the disclosure under the rules of the Japanese Academy of Sciences. I will stop sharing the slides and move on to the session. As expected, we are running out of time today, so I have prepared some questions. I will pick up some of the questions from the Q&A panel. If you have some questions that you have not been able to answer, I'd like to answer them here. I've already covered them in the English session, but I'd like to go over them one by one. First of all, as I mentioned in the English session, I'd like to share them in the chat as well. Next, I'd like to talk about surgery. In the future, surgery will be used in Japan as well. However, some of the PDR-1 patients are limited to PDR-1 post-op, and some are not limited to PDR-1 post-op. There have been some very symmetrical results, so I'd like to ask you what you think about that. Today, I'd like to ask the panelists. First of all, Dr. Kenmotsu, what do you think about this? Thank you very much. I'm Kenmotsu from Shizuoka Cancer Center. Assuming that atherosclerosis is first approved, there is data that it is likely that there is a high rate of treatment in women, so I think there is a slight weakness at the moment, but I think it will become a standard value for women. It's very difficult to interpret the 0-9-1 that came out earlier, but if the indication changes, I think it will be possible to change the drug to be used based on the PDR-1 statement. At least, if the subgroup results and cannot be interpreted, the drug cannot be selected based on the results of the test at present, so in the case of PDR-1, it is currently available. I personally think that both PDR-1 and PDR-49 can be used, and PDR-1 is less than 1%, so it will be called PEMPRO. Thank you very much. Next, Dr. Tsutaya, what do you think? Thank you very much. First of all, from the results of INPOWER-010, I think I would like to use more than 50%, but the results of PDR-1 and PDR-49 are subtle, so I think it will be a discussion, but one is that there is a possibility that drugs that have not been used so far can be used, so I think there will be more options for patients. Also, more than 50% was a pretty good result, so even with PDR-1 to PDR-49, if it is close to 1% and close to 50%, the expectations we have may be slightly different, so I think the judgment will change a little depending on the number. Also, if it can be used anyway, I think it will be judged by each patient whether they want to use it or avoid it depending on the state of the N2 or the risk of relapse. Thank you very much. It's a picture like Dr. Gekamo. Dr. Yatabe also participated today, but even though the clone of the antibody is different, the result of the clinical trial so far showed that the atmosphere was different by more than 50%. Is there anything like that, Dr. Yatabe? In that sense, the decision is probably up to the government. In Japan, the cell block, for example, the one taken with the e-birth FNA, is probably not included in this trial. But in fact, I think it is quite diagnosed with e-birth FNA. Then, is it possible to use such an antibody? I think we need to discuss a little whether the test is suitable as a material. Thank you very much. It's exactly the same as the next point. Dr. Mitsunami, I forgot. Do you have any comments on this matter? Should it be more than 50%? Well, it is positive if it is more than 1%, but the fact that it is more than 50% positive is similar to the 4th P-NOTE 042 test. So, as Dr. Mitsunami said, I think it also includes the element of whether or not there is a benefit. Risk and benefit. In the case of PD-L1, if it is more than 1%, it is not possible to proceed in the same tone. If the percentage of PD-L1 is high, it is possible to proceed even if there is a slight risk, but if it is weak, it is better not to proceed. I think there is such a thing, such as persuading the patient's hope more strongly. I don't know about the yellow 91. I think there is such a thing because there is a chance. It is a trial and error. Thank you very much. Let's move on to the next topic. Next, since the 816 test was also included, for example, if it is after the surgery, it will be done during the surgery. However, when it comes to putting it into consideration before surgery, it is difficult to say at what point it is suitable to perform a bioma search that was done purely with 4 machines or how far it can be done. Dr. Hayatabe, I would like to ask you about this. First of all, in the same order as before, I would like to ask Dr. Kemo, for example, how far the facility is doing now, or if you have any opinions, Dr. Kemo, how is it? Speaking of the situation, we have not done a bioma search at all before surgery, so as long as there is no trial after surgery, EGFR and PD-L1 are not measured. I think it's a fairly conservative facility. However, in the future, if EGFR, TKI, and ICI are used after surgery, and if they are used before surgery, I think we will have to change the stance of the facility. However, as Dr. Hayatabe said, it is probably better to do it with a well-maintained body after surgery, so that you can do a more accurate biomarker test. In that sense, I personally think that following a primary surgery by chemotherapy is a very reasonable treatment strategy to evaluate biomarkers. Thank you. It's conservative, isn't it? How about you, Dr. Tsutani? Thank you. If it is not approved yet, I don't think it will be measured before surgery. However, in the future, if EGFR and TKI are used after surgery, we have to measure it before surgery. Otherwise, we won't know anything about PCR. That's right. Moreover, I think we will think about the treatment strategy while thinking about it before surgery. Also, if we don't know the status of the driver gene first, we may not know it later. So, I personally think that we need all the information we know before surgery. That's true. Dr. Hayatabe, how do you feel from the perspective of the person who is asked to do the test? If I am asked to do it, I will do it. One thing is that I don't think it's true if the test results are taken in the same way as the advanced test results are taken. Of course, the test results of the operable type are small and the approach is limited. For example, it's different from the situation where you can get it anywhere like a 4th generation, so I don't know if it can really be taken by the government. I would like you to consider whether you can get it in the same way as the 4th generation or not. One more thing. I think that there was a lot of discussion about PD-L1 in Japan, but as Dr. Philippe said, when I talk to people in Europe about EGFR, they are very concerned. Yesterday, EGFR status was not very relevant. Generally speaking, EGFR ARC is difficult to run because of the image check point inhibitor, so I think it is necessary to think about it. What do you think about this? There was a line in Dr. Philippe's last book, 816, whether it was PCR or not. If it was PCR, chemo and I.O. did not change, and if it was not PCR, neither was good. I think it is better to predict whether PCR will come out. In that sense, I think it is very important to make it appropriate for patient selection. Of course, it is important not to know EGFR, but I think it is important to predict the patient who will become PCR more accurately. Thank you. That is the next point. This is probably the last topic regarding the effectiveness of pre-treatment. I think Dr. Yatabe should comment on this. Dr. Mitsumori expressed his expectations about PCR and pre-treatment NPR. Well, we have made recommendations at ISLC, but how uniform can it be in Japan? How are the doctors working on this? First of all, at the Japanese Cancer Society's Cancer Committee, we are thinking about creating a unified protocol for evaluating the effectiveness of NPR with recommendations from ISLC. We will release it in the future. We are thinking about putting it in the 9th version of the NPR protocol. At the moment, we don't have a uniform protocol. It is only at ISLC. So, doctors who are interested in NPR are probably interested in it because it is a cancer society. However, it is completely different from breast cancer and colon cancer. Also, the term tumor bed is being used a lot. So, we can focus on breast cancer but I think it is difficult to go all the way to cancer. Thank you very much. Thank you for your report. Dr. Mitsutomi, Dr. Kenmochi, Dr. Chitani, do you have any questions? Dr. Chitani, Dr. Mitsutomi, go ahead. Mr. Tatani, please. Can I say something? Yes, please, Mr. Kenmoto. Up until now, we have been using radiological response. Compared to that, I feel that it is more effective to see it in a hospital. However, it is difficult to standardize. I think there is a hurdle that if the evaluation is different depending on the facility, it will be difficult in the first place. However, when the concept of MPR was unified and it could be seen from the same point of view in Japan and the world, I feel that MPR has a better effect on treatment than the resistor that we measured and evaluated at 30%. That's right. It is said that the internal meaning is measured and it is 30%. Mr. Ito, please. If you look closely at 100m816, there are few people who say that MPR is not PCR. So, the response is quite PCR. On the other hand, there are many people who say that MPR is not PCR. So, I think it is important to evaluate it as a surrogate marker as a trial, but I feel that it is not so important as a clinical practice. What do you think? It's a surprising comment. Even if it is strictly judged whether this is PCR or MPR in the clinical routine, the treatment is already done. So, I was wondering what it would be like. I think it is important to prove that if the decision is made early, it will be a surrogate that determines whether the clinical trial is effective or not. What do you think about the clinical practice and how to use it? I see. I think we should move on to the next point. The next thing I was thinking about is that when there are more options such as pre-treatment and post-treatment, what Dr. Mitsubishi pointed out is that if you evaluate it as a pre-treatment PCR, it will eventually be a post-treatment treatment. However, if it is an adjuvant, you don't have to worry about it in the primary surgery. I think it will be very different depending on whether pre-treatment or post-treatment will be the main treatment or whether surgery will be the main treatment. What do you think, Dr. Tsutani, including Dr. Mitsubishi's comment? Do you want to do all the pre-treatment from the surgeon around here? Thank you. Looking at the results of the three tests this time, the results of 816 have a big impact, so I personally think that it would be better to do pre-treatment if possible. For that reason, I think that pre-treatment, for example, accurate diagnosis of lymph nodes, etc. is very important. As Dr. Mitsubishi said earlier, whether or not it is a post-treatment PCR, if it is a PCR, you don't have to do anything post-treatment. However, I think that in the future there will be discussions about whether or not to do post-treatment PCR in a sandwich-like form, such as neo and adjuvant. In such a case, the effect of pre-treatment PCR may be quite important. Yes, it may be. How about you, Dr. Kemono? As Dr. Mitsubishi said, if it's not PCR, it's adjuvant, so I don't think it has anything to do with MPR. However, as Dr. Mitsubishi said, it only makes sense when interpreting the single arm test, and I don't think it makes much sense in clinical actual treatment. So, I think it is a good material to judge the effect of treatment in the early stage. Can I ask one more question? Yes, of course. I understand the feeling of adding adjuvant if it is not a PCR, but I feel that it may not change much even if it is added later to people who have not heard much about it in the first place. How about you, Dr. Kemono? Let's ask Dr. Kemono. As Dr. Mitsubishi said, we do maintenance because we think that it continues even in PR, so I think it is difficult to judge whether MPR is not effective or whether the ICI is insufficient. I think it's a bit of an exaggeration to say that it's not effective. I understand. Well, it means that the trial will prove it. That's right. So, when MPR seems to be good, it will be an end point to be able to make a decision whether to challenge the current standard treatment or not. However, as I said at the beginning, I think it is very important to proceed from the standard. Thank you. Finally, I have a question. Dr. Yatabe, isn't there a timing for the clinical effect judgment? For example, some people get PCR immediately after a little I.O., and some people get it gradually. I don't think we can change the timing for that. That's right. For example, in the case of superflare and progression, it is said that the demand is simultaneous. So, I think it would be nice to have a sub-analysis with a slightly different time point in the future trials in Tokyo. Actually, we would like to see it, too. For example, it's not an immune-checking inhibitor, but in the case of germ cell tumors, we sometimes see chemotherapy for people who were insufficient. So, we would like you to show us the results while considering those points and verify them. Thank you. It's 8 o'clock now, so I'd like to close the session in Japanese. Thank you to the panelists. Thank you. Thank you, everybody. I'd like to close this webinar. I would like to thank Professor Faber again, because she answered all the questions in text via the Q&A, and she is still joining even for the Japanese session. Thank you very much. I'd like to close this webinar. Thank you very much for attending. Thank you. Bye-bye.

webinar

preoperative treatment

immune checkpoint inhibitors

non-small cell lung cancer

disease-free survival

adjuvant immunotherapy

PD-L1 positive tumors

neoadjuvant chemotherapy

pathological complete response

circulating tumor DNA