like to welcome you to this plenary session three. Together with Dr. Gao from China, we would like to moderate this session. My name is Pauline Wimberger. I am a director of the University Hospital in Dresden in Germany. I'm a gynecologist. We will hear excellent presentations today, and the colleagues will present us their thoughts and how to integrate the strategies from the presentations into clinical practice. I encourage you all to submit your questions throughout the sessions. And we will answer as many as we can within this session. So let's start. The first presentation will be from Dr. Ilse Betten from the University of Utrecht in the Netherlands. We are looking forward to hearing your presentation. It's your turn. Thank you. Good afternoon. I want to thank the IGCS for giving us the opportunity to present the results of our study on the impact of the learning curve of robot-assisted laparoscopy on the oncological outcomes of early-stage cervical cancer patients. I have no disclosures. The reason to conduct the study were the recent conflicting results on the safety of surgical, sorry, the reason to conduct the study were the recent conflicting results on the safety of robot-assisted laparoscopy in the treatment of early-stage cervical cancer. The learning curve could be a potential confounder and might offer a possible explanation for these conflicting results. Until now, studies on the learning curve of robot-assisted laparoscopy have mainly focused on short-term surgical outcomes like the duration of surgery and blood loss. Our objective was to focus on the impact of oncological outcomes, as this is considered the foremost relevant parameter when treating malignancies. So we investigated the learning curve with regard to cervical cancer recurrence and quantified its impact on survival. We included all early-stage cervical cancer patients consecutively treated with radical robot-assisted surgery as a primary treatment. All surgeries were performed by a single surgical team between 2007 and 2017. The primary outcomes of interest were surgical proficiency based on cervical cancer recurrence and the survival in the different learning phases of the learning curve. To assess surgical proficiency and be able to construct a learning curve, we used a risk-adjusted cumulative sum analysis. This analysis is able to detect small changes in surgical performance over time while adjusting for each patient's individual risk of surgical failure. And here we define surgical failure as cervical cancer recurrence. We calculated the individual risk with a risk model based on logistic regression analysis. And the survival rates were estimated with the use of Kaplan-Meier methods. In total, 165 patients were included, with a median follow-up of 57 months. The vast majority of our population was staged 1B1 according to the figure 2009 guidelines. On the right side of the slide, you see the learning curve we constructed with the use of the risk-adjusted cues and formulas. The x-axis indicates the number of procedures performed, and the y-axis indicates the cumulative sum of success and failure of the surgical team adjusted for the probabilities from the risk model. Both curves move upward for surgical failure and downward for surgical success. And both curves are limited by zero. The curves differ in that the upper red chart is designed to detect decrease in surgical performance, while the lower black chart is designed to detect increase in surgical performance. The magnitude of the movement of both curves is determined by the difference between the observed and the expected probability of recurrence. So for example, if a patient modeled as having a high risk of recurrence actually develops a recurrence, the curve ascends less than it would if a patient with a low risk of recurrence is diagnosed with a recurrence. As you can see, the upper red chart shows a peak at 61 procedures, with a consistent decrease thereafter as the chart moves toward zero, indicating satisfactory results with respect to the predicted recurrence rates. Hence, these first 61 procedures comprise the learning phase of this surgical team. The 104 procedures thereafter represent a more experienced phase, where the surgical performance is increased. As you can see, the lower black line moves further negatively, indicating an increase in surgical success. Based on this learning phases, we divided our cohort into two groups, group 1 representing the first 61 patients, and group 2 representing the 104 patients treated thereafter. The baseline characteristics between the two groups did not differ significantly, except for the follow-up duration, which was explained by the fact that the second group was treated more recently. The majority of both groups completed the three years of follow-up. And we further corrected for this difference in follow-up duration by using Kaplan-Meier methods to do the survival analysis, as you can see on this next slide. The five-year disease-free survival was 80% in group 1 and 91% in group 2, and there was significant difference. Also, the five-year disease-specific survival and five-year overall survival significantly increased in the patients treated after this learning phase. To conclude, we are the first to use this validated risk adjusted QSM analysis to construct a learning curve for robot-assisted cervical cancer surgery. In this monocentral study, we showed an initial learning phase of at least 61 procedures, with a significant increase in the survival rates of the patients treated thereafter. Of course, the key issue is to avoid putting patients at risk. And with our results, we want to raise awareness on the impact of the learning curve on the oncological outcomes. And nowadays, improvements in the learning curriculum have already taken place, such as mandatory simulation training and the use of dual robotic consoles, which allows for direct supervision by an expert. With our results, we want to encourage other centers to assess their own institutional learning curves and to include the learning curve in the design of future studies. I want to thank my colleagues and supervisors for their contribution to this project. And I want to thank you all for your attention. Dear Dr. Witten, thank you so much for this excellent presentation. And it's a very important clinical situation. We will discuss it together later on. So now I would like to invite Professor Mariani from the Mayo Clinic in the US. He will present data concerning in vitro cancer and the impact of involved synodes. Thank you so much for being here. It's your turn. Thank you. And I'm presenting this large study on the clinical significance of low-volume metastasis in sentinel node in endometrial cancer. And I take the opportunity to thank all my co-authors from multiple institutions from all over the world. I have nothing to disclose. Low-volume metastasis in the sentinel node in endometrial cancer are defined as 2 millimeter or less. They represent about half of metastasis in the sentinel nodes in endometrial cancer. But in spite of that, their clinical significance is still very uncertain in the literature. Patients with low-volume metastasis do reasonably well if treated with adjuvant therapy, but numbers are still limited and follow-up is short. Also, in an interesting study on ITC in endometrial cancer after lymphadenectomy, there is a suggestion that patients with ITC may be at risk for late recurrence. Given this uncertainty, we started our large, international, multi-institutional study with 26 centers from all over the world. We collected as many as 360 patients with low-volume metastasis in the sentinel nodes. This is an incredibly high number when compared to what's available in the literature. For the purpose of this study, we focus on those patients with reasonable follow-up, eliminating all women operated during the last 18 months. The data that we will present today include the population of 247 patients. As you can see, half of these patients have ITC, and approximately one quarter did not receive any adjuvant therapy or vaginal brachytherapy only. Here is a summary of the overall population stratified by type of metastasis and adjuvant treatment. Given the retrospective nature of the study, patients with high risk factors, like high grade and aggressive histology, were more likely to receive adjuvant therapy. And here you can see that with a median follow-up of almost 30 months, we have 77% recurrent free survival at four years. Considering the whole population, significant predictors of recurrence were grade 3 non-endometrioid histology, lymphovascular invasion, and uterine serosal involvement. As you can see, the presence of risk factor significantly increased the risk of recurrence many folds in comparison to patients without risk factors. For example, a patient with grade 3 tumor had a risk of recurrence almost nine times higher when compared to a patient with grade 1. In fact, for example, focusing on patients who received the adjuvant therapy, women with high grade tumor or non-endometrioid histology had a four year recurrence free survival of approximately 55% overall and about 68% considering only women with isolated tumor cells. This means that almost one every three patients with grade 3 or non-endometrioid tumor and isolated tumor cells still recur in spite of receiving adjuvant therapy. Now let's focus on the 49 patients with ITC who received either no adjuvant therapy or vaginal brachytherapy only. This is a very interesting group. With a median follow up of 22 months, we observe a recurrent free survival of 80% at four years. Due to the limited number of events and the still short follow up, we did not identify any significant predictor of recurrence in this subgroup. However, lymphovascular invasion and grade approached significance. But look at these survival curves in ITC patients who did not receive any adjuvant therapy. I find particularly interesting the stratification by grade. As you can see here, there are no recurrences until after 20 months in low grade patients, thus suggesting that we cannot draw any meaningful conclusions in this subgroup until we have more follow up. When we focus only on the 25 patients with ITC and grade 1 who did not receive any adjuvant therapy, we have only two recurrences. But still, 50% of patients have less than two years of follow up. Again, we need more numbers and more follow up. In conclusion, in patients with low volume metastasis, grade 3, non-endometrioid histology, lymphovascular invasion, and uterine serosal invasion were the strongest risk factors. Women with risk factor have a relatively poor prognosis, even when given adjuvant therapy. Low risk patients do relatively well, but need more follow up. The next steps for this study, we need a centralized pathology review. We need to increase the number and follow up, so please contact me if you are interested in participating to this important project. Thank you, and I'm particularly grateful to my statistician team, Michaela and Amy, and to all my research fellow, Khaled, George, Alisa, and the others, and all the co-authors from multiple institutions all over the world. Thank you. Thank you so much for this outstanding presentation. Dear colleague, as a short reminder, we would like to remind you, please send us some questions with the question and answer feature we have, and we will discuss, hopefully, all of them at the end of this session. So now, I would like to invite Dr. Flora Bakes from the Ohio State University in the US. She will give us a summarize and discussion concerning the two former outstanding presentations. Thank you. Thank you very much to IGCS and the organizers of this session for allowing me to present this distillation. Here are my disclosures. So the first abstract by Baten et al. discussed the impact of the learning curve for robotic-assisted hysterectomy. And they used this very complicated analysis, a risk-adjusted cumulative sum analysis to detect small changes in surgical performance over time, adjusted for the patient's individual risk of surgical failure or recurrence. And so, as you can see here on this graph on the right, they found a learning curve that consisted of 61 cases, followed by an experienced phase of 104 cases. From the time from the learning phase to the experience phase, the disease-free survival improved from 80% to 91%, and overall survival improved from 85% to 98%. And if we look at these curves, we see here on the left that the separation between the curves and the disease-free survival times are not so different from what we saw in the LAC trial. And is it possible that the lower curve in the LAC trial also has something to do with this learning curve? And could that be contributing to this difference between certain findings in the LAC trial as well? But there are some concerns. 165 cases were collected over 10 years. So, that means about 20 cases per year. So, does that mean that the surgeon becomes proficient after three years? And how does this compare to open radical hysterectomy? Did we see a similar learning curve, but did we just not capture it because we've been doing this for longer? Or could that be still the case for people who are just starting with open radical hysterectomy? And then the second question, how many surgeons should do robotic surgery or robotic radical hysterectomy? If we take the lens with the population over 7 million women that are in the age that potentially would develop cervical cancer have 670 cases per year. So, approximately 350 women with early stage cervical cancer that would be candidates for this procedure. Should we limit this then to one surgeon per center if we assume maybe six centers that are doing these procedures and limit this to only high volume centers? Are there other methods that we can shorten the learning curve with? Robotic simulators, review of surgical films, cadaver labs, or two surgeons per case. But there are some other factors that are remaining. There is a decreasing trend in cervical cancer incidents as you can see in the graph on the right. And can we still justify doing minimally invasive surgery after the results of the LAC trial and other NCDB studies have been presented? The second abstract was regarding low volume metastasis in sentinel lymph nodes. This is an international multi-institutional study. All patients had low volume metastasis, but there was no comparison group of patients without low volume metastasis. So, they identified that low volume metastasis, the type of low volume metastasis, was actually not significantly impacting the risk of recurrence, but the traditional uterine risk factors were, such as grade, histology, and lymphoblastic phase invasion. And if we look in this table on the right, and I call this lumping or splitting, should we be lumping or splitting these IDCs and micrometastasis together or not? When we look at IDCs in the table, you can see that with or without chemotherapy, there's not a significant difference in recurrence rates in this population. With micrometastasis, even with treatment, with chemotherapy and the radiation, 20% recurrence was seen. And of note also, adjuvant therapy for this entire population did not seem to have a significant impact on the risk of recurrence. So, if we dive a little bit deeper in this endometrioid population, without treatment, the recurrence rate was 13%, and the recurrence-free survival at two years, a short follow-up, was 81%. With treatment, this was 9%, and we do not have data on the recurrence-free survival for this population yet. And what was the location of recurrence? Was this vaginal, and were these very highly salvageable, or were these more distant recurrences that are much more difficult to salvage? And then there's this whole separate group of the non-endometrioid population who have poor outcomes regarding whether they receive treatment or not. And so, lymphovascular space invasion, it may be a factor, as the author suggested, but maybe we should just study this in endometrioid patients. And again, regarding the non-endometrioid population, these do poorly, regardless of treatment, and these are all treated populations. And as mentioned, the four-year recurrence-free survival was 54%, not much different from the serious population as seen in CORTEC-3. So, in conclusion, are these just prognostic biomarkers? For cervical cancer, we have our traditional biomarkers, such as the tumor factors, but should we be adding open versus minimally invasive experience, and now also, sorry, open versus minimally invasive surgery, and now also surgeon experience? For endometrial cancer, the best predictors for recurrence still remain histology-grade stage, and that's confirmed with this study also. The size of the sentinel lymph node metastasis may only apply to the endometrioid population, and adjuvant therapy does not seem to impact the outcomes in this population, but more follow-up certainly is needed. Should we focus our efforts more on molecular profiling, such as mismatch repair status that can be treated with immunotherapy, or to new that can be treated with trastuzumab and other molecular profiles to really determine which patients have the highest risk of recurrence and also be able to adapt our treatment for this? And with that, I thank you for your attention and for inviting me to do this distillation. Thank you so much for the excellent presentation. I would like to turn over to Dr. Gao. Thank you so much. Hello. Welcome, everyone, and thanks for the IGCS group giving me the opportunity to attend the meeting as a co-moderator with Dr. Willenberger. So, first, let me introduce myself. I'm a gynecological oncologist from Tongji Hospital, and I'm the co-moderator with Dr. Willenberger. Tongji Hospital, Huazhong University of Science and Technology from China. So, in this section, I will introduce the last part of the two speakers. So, first, let me introduce the third presenter, Dr. Robert Holloway, coming from Advent Health Cancer Institute, the United States. So, he will bring his topic, the Oncological Vaccine-Primed Immunochemotherapy in Platinum Resistant or Refractory Ovarian Cancer. Welcome. Yeah, you should be able to hear. Can you hear me? Yeah. Okay, let me get it up. Good morning. I assume you have sound and video now? Can you see my slides? Yes, yes. Okay. I wish to thank the IGCS on behalf of my research collaborators for the opportunity to present our novel phase 2 viral 15 trial oncolytic vaccinia albevec primed immunochemotherapy and heavily pretreated patients with platinum resistant refractory ovarian cancers. These are my disclosures. In 2003, Zhang and colleagues reported in the New England Journal of Medicine that approximately 50% of patients with ovarian cancers had tumor infiltrating lymphocytes or TILs at diagnosis and they enjoyed a survival advantage. 38% estimated five-year survival for TILs patients compared to 4.5% for non-TILs. In the manuscript shown here, Zhang and colleagues in 2007 performed elegant experiments in mice that revealed the chemotherapy enhancement of CD8 T cell immune response primed by vaccinia virus infection. Cisplatinum and cytoxin were shown particularly beneficial at augmenting the immune response through suppression of T regulator cells. Albevec is a modified oncolytic vaccinia virus with mutations and enhanced tumor targeting. Albevec infection triggers oncolysis, augmented neoantigen presentation, and immunologic cell death with enhanced tumor infiltrating lymphocytes. The image on the right shows rapid oncolysis and reduction of tumor cell aggregates and ascites by day five followed by replacement with lymphocytes and ascites by day 10. Albevec has been extensively studied in phase one trials with intravenous and intracavitary applications including a phase 1b intraperitoneal trial in ovarian cancer performed at AdventHealth Orlando and reported at ASCO in 2018. Viro15 is a multi-center open label phase 2 study of intraperitoneal oncolytic vaccinia virus, Albevec, followed by IV platinum doublet with or without bevacizumab in patients with platinum refractory or resistant ovarian cancers. The primary objectives were resist 1.1 response, CA 125 response, and progression-free survival. Secondary objectives were adverse events, duration of response, and overall survival. Translational data included analysis of TILs, gene expression and paired pre and post Albevec tumor samples, and tumor-specific T cell response in peripheral blood. 92% of cases had high-grade serous carcinoma. The median number of prior lines was four. Most patients had prior bevacizumab and PARP inhibitor treatment, and only one patient had PDL positive staining. Two-thirds of patients were performance data zero and some patients had up to nine prior lines of therapy including five prior platinum exposures. Half of patients were platinum refractory to the last therapy. Half were resistant. Safety results in this trial were consistent with the phase 1b trial. Most patients had mild flu-like symptoms lasting for hours to a few days, including fever chills and fatigue. Following the phase 1b trial experience, prophylactic hydrations were added daily during the intraperitoneal infusions to reduce symptoms. The trial's overall response in 27 patients was 54% with a 7.6 month median duration of response. The CLN25 response was 85% and the median progression-free survival was 11 months. There was no difference in outcomes for platinum-resistant and platinum refractory patients. 89% of patients achieved disease control as demonstrated in the spider plots on the left and the waterfall plots on the right. The CLN25 response was 85% and overall 96% of patients achieved a decrease of CLN25. Historically, it is well known that patients with recurrent ovarian cancer suffer a decrease in progression-free survival with each subsequent line of therapy. Von Hoffman colleagues described the effectiveness of subsequent lines of therapy using the PFS ratio with any ratio greater than 1.3 considered clinically meaningful. The Kaplan-Meier survival curves on the left show the median PFS pre-Alvivec was 4.5 months and it was 11 months post-Alvivec. The figure on your right shows that 74% of patients are to the left of the Von Hoff line indicating a clinically meaningful benefit following Alvivec-primed immunochemotherapy relative to prior lines of therapy. Alvivec's main mechanism of action is conversion of immunologically cold tumors to hot tumors with tumor-infiltrating lymphocytes. Here, paired samples from pre- and post-Alvivec biopsies are shown using multiplex IHC demonstrating the intertumoral infiltration of CD8 T cells approximately six weeks post-virotherapy and prior to the chemotherapy administration. Additionally, translational data reveals Alvivec-induced up-regulation of intratumoral STAT1 gene expression of interferon pathways resulting from influx of CD8 T cells. This promotes immunogenic cell death and affects glutathione transport, also known to be involved in platinum resistance. Elevated levels of tumor-specific T cells in the peripheral blood have been identified using the ELISPOT assay. We propose a prime and boost mechanism of Alvivec that drives the enhanced response of platinum doubletherapy and platinum-resistant ovarian cancer. Intraperitoneal virotherapy produces robust oncolysis and immune priming resulting in immunogenic cell death, changes in the tumor microenvironment, and long-term antitumor immune memory. Subsequent cytotoxic therapy boosts antitumor immunity through suppression of T-regulator cells and immunosuppressive monocytes, immunogenic cell death, further release of tumor antigens, and further boosting of T cell activity. In summary, the phase 2 viral 15 trial met its co-primary endpoints of overall response and PFS at a median follow-up of 36 months. There was no difference in response or PFS for platinum-resistant versus platinum-refractory patients. The RESIST1.1 response rate was 54% compared to 15% from the last prior therapy line. CA125 response is 85% compared to 21% of the last prior line. And the median PFS was 11 months compared to 4.5 months from the last line of therapy for these platinum-resistant, platinum-refractory patients. Alvivec has been shown to increase intratumoral CD8 TILs, generate systemic tumor-specific T-cells, and up-regulates intratumoral STAT1 gene expression of the interferon pathways. A registration phase 3 trial of Alvivec-primed endochemotherapy is currently being planned. I wish to thank the Advent Health Cancer Institute Orlando and the Gynecologic Oncology Associates Newport Beach research staff, the attending physicians fellows, and especially the patients and their families, and the Genelecs Corporation for their support of this research. And thank you for the opportunity to present. So thank you, Dr. Robert Holloway, for your very exciting work here. So as we all know, platinum-resistant or refractory ovarian cancer patient is particularly incurable in clinic. So finding the novel method to improve the outcome in this patient is critical, critically and urgently needed. So you now give us a very, very, I think a very exciting news, and I hope you will go to the phase 3 trials and will get the good one. Very good job. So thank you. So the next speaker I will introduce is the last speaker in this section is Whitelake Grebeel. She is a very famous professor from the Department of Gynecological Oncology, Medical University of South Carolina from the United States. She will bring her topics. So the next slide. Efficacy on individualized starting dose and the fixed starting dose of neuropathic pro-investigator assessment in newly diagnosed advanced ovarian cancer. Are you able to see my slides okay? Yes? No, no, no, not not yours. No. No, it's not work. Now it works. Perfect. Perfect. Okay. I think we got it. Does that look good? So it's a shared slide, full screen. Is it sharing the full slide? Yeah. Yeah, yeah, that's work. It's okay. Great. Well, I would like to thank the IGCS for giving us the opportunity to present on the efficacy of individualized starting dose and fixed starting dose of norepirib per investigator assessment in newly diagnosed advanced ovarian cancer patients. These are my disclosures. So norepirib is a PARP inhibitor approved for maintenance treatment of patients with recurrent ovarian cancer following a response to platinum-based chemotherapy based on results from the NOVA trial. All patients started the NOVA study with a fixed starting dose of 300 milligrams once daily based on phase one data. Due to the high rates of grade three and four thrombocytopenia seen in the study that required dose interruptions and adjustments, an individualized dosing regimen was introduced into the PRIMA study. The overall efficacy of this individualized or ISD regimen was discussed at ASCO by Dr. Mirza. As you recall, the primary endpoint of PFS in PRIMA was based on blinded independent central review. Investigator-assessed PFS was a pre-specified sensitivity analysis. Blinded independent central review and IA assessments were highly concordant with hazard ratios of 0.62 and 0.62 in the intention to treat population respectively. So in this presentation, I'll review the efficacy and safety outcomes of the individualized starting dose regimen based on the primary data cut and also an updated six-month efficacy analysis based on IA assessments. So most of you are familiar with the primary trial design of the PRIMA study. The primary endpoint of PFS was tested sequentially in the HR deficient followed by overall populations. The ISD was implemented in November of 2017 and the criteria is presented on this slide. Because this regimen was introduced late in the study at the time of the primary data cut in May 2019, follow-up time for patients who received the individualized starting dose was less than those who received the fixed starting dose. Therefore, I'll present the efficacy data based on the primary data cut of May 2019 and an additional six months. Safety and quality of life metrics will also be reviewed. So of the 733 patients enrolled in the study, 258 or 35% were enrolled after the amendment. Baseline disease characteristics were balanced between patients who received the individual starting dose or the fixed starting dose, except that more patients in the ISD subgroup had a partial response to first-line platinum-based chemotherapy, almost 40% compared to 26% of FSD patients. Dose exposure was similar for patients who received a fixed starting dose and individualized starting dose, ranging from 179 milligrams per day to 182 milligrams per day. Importantly, dose reductions and interruptions were decreased in patients receiving the individualized starting dose. The ISD subgroups were more likely to receive the individualized starting dose. So at ASCO, Dr. Mears presented the PFS data based on blind independent central review and the primary data cut, which is in teal. The test of interactions demonstrated no evidence of treatment difference between the starting dose regimens. The hazard ratios for the two subgroups were similar at 0.59 for the fixed starting dose and 0.69 for the individualized starting dose. The investigator-assessed PFS, shown in orange, was highly concordant with hazard ratio of 0.6 for FSD and 0.68 for ISD. With an additional six months of updated efficacy analysis, shown in purple, the median follow-up for patients who received ISD increased from 11.2 months to 17 months. Event maturity increased from 54% to 62%. With more time and maturity, the efficacy of the ISD regimen was sustained with hazard ratio of 0.68 and upper bounds of the 95% confidence interval less than one. Importantly, the implementation of the individualized starting dose reduced the rates of hematologic adverse events by up to 50%. The rate of high-grade thrombocytopenia was reduced from 48% to 21%, and similar trends were seen with anemia and neutropenia, as shown here. So, in evaluating if the quality of life was different with ISD versus FSD, no differences were seen in the mean FOSSI Health Utility Index scores between patients receiving norepirib and placebo in the FSD and ISD regimens. Similarly, no differences were seen in the Health Utility Index based on the EQ5D. So, in conclusion, the ISD regimen demonstrated comparable efficacy with improved tolerability based on a prospective analysis in the PRIMA study. The mean dose intensity was similar between the dosing subgroups. Fewer dose interruptions and reductions were observed in the ISD subgroup. Overall safety profile, including grade greater than equal to three hematologic toxicities, improved with the ISD regimen. Significant reduction was seen in the incidence of thrombocytopenia, anemia, and neutropenia. No differences were observed in the quality of life between norepirib and placebo in FSD and ISD regimens based on FOSSI and EQ5D PRO assessments. Recommended norepirib starting dose in first-line maintenance settings is 200 milligrams taken orally once daily with or without food for patients weighing less than 77 kilograms or with a platelet count less than 150,000. So, I'd like to thank the patients and their families for participating in this trial and thank you for your attention. So, thank you. So, thanks for your excellent work and important job. So, could you please stop the chat? Yes, okay. So, let me introduce the CIMR, Mark Halpert here, from Chitaerin National Cancer Institute to give us a presentation. So, just share the screen. Thank you. First of all, thank you, IGCS, for giving me an opportunity to distill these presentations. We have heard two excellent presentations so far and very relevant and I would say very promising as well. Next slide, please. So, these are my disclosures in terms of royalties. So, the first slide, or the first study is about an oncolytic vaccine trial, a phase two study of prime immunochemotherapy in heavily pre-treated ovarian cancer patients. So, this is a very, very important study. We know it's becoming a problem with survival increasing day by day. And I think I will just kind of just touch upon a very few points and then have a few discussion points at the end. But I think the rational or the biological basis is one of the many strategies to turn an immunologically cold tumor, which we know ovarian cancer is, into a hot tumor. And I think from Dr. Holloway's summary slide, it is evident that I think we haven't seen such promising results in a lot of interventions, which has happened so far in this scenario with 11 months progression-free survival with minimal side effects, 7.6 to 8 months of duration of response, whether it's a platinum-resistant or refractory, and a very good objective response rate overall, as well as CA125 response. What is noticeable, though, that, you know, there are a lot of patients, about 76% of patients who have failed PARP inhibitors, and 30% of them have upward BRCA mutations as well. So, this is clearly a problem and group for treatment. And then the next slide, please. So, some of the questions and ideas that I have is that, of course, we're talking about directing a local immune microenvironment by giving intraperitoneal oncolytic vaccine. We all know that some of these recurrences can be predominantly nodal. And, you know, this is also an area, perhaps, to just find out from the subsequent studies that whether it works as well in these sort of recurrence patterns as well. Whether it's a trendsetter or a practice-changing intervention, is it going to be only vaccinia, or are we going to see a plethora of other vaccines coming up with oncolytic viruses genetically modified? Or is it going to be a strategy where you see the functional immune status at the recurrent time point and then the immune targeting according to that? Just in terms of the PARP inhibitor failure, does it help previous PARP inhibitor failures in particular? Is it costly? What about expanding to other settings like first recurrence or even an upfront setting? And does it work in these different biological subtypes like clear cells, granulosa, other germ cells? And if this fails, is it immune targeting their subsequent recurrence? Is it more aggressive? Is the failure pattern different? Can this therapy be repeated? So these are some of the areas that I think we would need to be exploring in the subsequent studies. And I wish the team very good luck in the future studies. So the next study would be... Next slide, please. Again, a very important study of a dose reduction strategy, where the investigators are compared an individualized starting dose, which is based on body weight and platelet counts, versus a fixed starting dose of niraparib in newly diagnosed advanced ovarian cancer patients. And I think the importance of this study lies in the fact that it is possibly a very good example of a systematic way of doing a dose reduction strategy, which is personalized. And it will have, I suppose, in low middle income countries, a very big pharmacoeconomic implication. From the preclinical studies of any of these targeted agents, we possibly all know working in the lab that the maximal tolerated dose, which is often the dose which is prescribed, is different to the biological optimal dose. And whether you have similar dose reduction studies, well, the one which we know coming from India is intermittent PARP inhibitor study. So the philosophy is the same. I think we're asking the same question that is a lesser dosage regimen effective in a select subgroup of population. In this case, it's lesser body weight and platelet counts. I think it's been described in detail, the study design and outcome. Just to summarize, it shows promising results. It works. Lesser dose, interruption. And it shows lesser dose interruption, reduction of the dosage changes, reduction in the grade three, some of the adverse events without compromising the efficacy. So this is a summary. There's no difference in quality of life. This is interesting. I suppose the tools which we are using, I would imagine that a regime which has caused less interruption in scheduling would cause less anxiety and maybe in other ways, a better impression to the patients and the physicians as well. And I'm sure it would be also very pertinent to look into what would be the cost difference of going down a one-third dose reduction. The answer which I couldn't found or perhaps would be addressed later on, that of course, we're looking into an efficacy here of a reduced scheduling. And I suppose the numbers we're looking at is 170 in the, it's not IDS, I'm a surgeon, I'm sorry, is the ISD subgroup versus 88 in the placebo group. And is that good enough? Next slide, please. So some other questions I just wanted to point out, and it's maybe just a thought process, that the ISD group seem to have more prevalence of partial response compared to the complete response. And I was just wondering that whether there is a correlation between people who are nutritionally poor or have pathology causing low platelet count to be slow responders or it doesn't affect response anyway. And then the other question I was thinking that we know that there are patients who the body weight might have different body mass, bone mass, fat deposition. So what is the basis of going for a one-third dose reduction cut off like a 77 kilograms? Why not BMI? Has there been a pharmacogenomic or preclinical study done beforehand to decide on the extent of the dose reduction? Do we think on the basis of the study that actually a reduced dose, it might be more than a biological optimal dose actually, that it would work in everybody, even with patients more than 77 kilogram? And is there any trial planned? And then is it again going to be a trendsetter for other BARP inhibitors or other targeted agents? So I would thank my team and again for IGC as to giving me this opportunity to think about two great studies, which I think personally would be a trendsetter. Thank you. Thank you. Thank you, Simin. Lastly, you raised a lot of important questions and gave us a lot of further directions. You think a lot. So please let Wim Berger to give us some questions and answers. Yes, thank you very much for these excellent presentations. I would like to begin to start with two questions to Dr. Mariani. One question was, if you could please give us some information concerning the location of the recurrences. And the second question was the question whether you see any differences in patients who had only one involved sentinel node with low volume metastasis in comparison to the situation that more than one sentinel is involved. So thank you and thank you for your question. Regarding the location of recurrences, I didn't present this for the sake of time, but what I want to tell you is that they are all over. I look specifically at that if there was some patterns of recurrence, for example, grade one were more likely to be local in the nodes. This is not true. And so at least in this data that I have, I did not find any specific pattern of recurrence that can help say that perhaps some of them, they are salvageable. I didn't find that, but we look at that. We look at that point. Regarding the second point of the involvement of, if it's different, if you have just one lymph node, small metastasis versus multiple lymph nodes, two lymph nodes, three, four with small metastasis. I don't have the data for this particular registry. This is part of the next step that we are planning also to have a central pathology review. And so it makes sense to look at molecular data. It makes sense to look molecular in the primary and the characteristics of the node, the metastasis. We will be looking at that, but I don't have the data here. Thank you. Thank you so much. So another question to Dr. Baten, really excellent data concerning early cervical cancer. So we all know the data from the LAG trial. And so my question is, do you have seen in your population any differences concerning the use of uterus manipulator or also patients that had prior conization where there was a microscopic complete resection before performing radical hysterectomy? Thank you for that question. We did look at the parameters you said, but we didn't find any significant influences of that parameters, for example, conization. And with regard to the uterus manipulator, we did use the McCartney tube during the inclusion period, and we did not change that during that whole period. So we could not relate, we could not draw any conclusions for the use of a manipulator with regard to the learning curve. Thank you so much. Unfortunately, time is running. And so I would recommend if you have further questions to the presenters, please feel free to contact them via the eGCS link chat in the portal. So I would like to conclude this plenary session three. It was a really great honor for me together with Dr. Gao to be moderator of this excellent session. And thank you so much for all the discussions and the presenters for a really outstanding session.

plenary session

presentations

phase 2 study

oncolytic vaccine

ovarian cancer patients

intraperitoneal oncolytic vaccinia virus

objective response rate

tolerability

treatment outcomes