Hello, everyone. I think this is my first task as a president of the IGCS, and I really appreciate your participation here. So my name is Keiichi Fujiwara. I'm a G1 oncologist in Japan, and so serving as a president of the IGCS, so honored. So I hope that you have enjoyed three days, amazing meeting here in New York City. Well, thank you. So I'd like to first announce this social media contest winner. So I think the first, we are giving three social media delegates either complimentary IGCS membership in next year, or registration for the IGCS 2023 in Seoul. So the first person I'd like to announce is Dr. Anna Tatchiana Palacios-Torres. She did a great job. Is she here? No? So the second person is Jitu Bahaduria from India. Thank you so much for the contribution. And the third winner is a Dr. Nicarosia Mojica, also from Colombia. And IGCS would like to also thank the IGCS board members Dr. Andrew Tsunoda and Jo Ann, Mario Latteo, and Rene Pareja for their social media activities. They have done a great job, but they are not eligible for the winner, however. So I really recognize for those people who are communicating with the society, the IGCS and the real society. Thank you so much. So I think this is the exciting time for announcing this IGCS 2023 Annual Global Meeting. Please join the welcome of the Korean society. Incoming President Jae-won Kim, my friend. Thank you. Thank you, Mr. President. On behalf of the Korean Society of Gynecology and Oncology, we are very honored to have IGCS 2023 Annual Global Meeting in Seoul from November 5th to 7th. So we are excited to welcome you to our city, 600 years of history, at the same time modern and dynamic metropolitan. So we will make a meeting filled with strong science, networking, and the opportunity to explore Seoul. So please visit Seoul next year, all of you. Thank you. Thank you, Dr. Kim. So I know that the IGCS 2023 will be a fantastic meeting in an exciting city. And now I'd like to welcome the program chairs, Dr. Christina Fotolo, why don't you come up? From the UK, and also Dr. Seok-Jung Chang from Korea. So please come to the podium. And please talk about the meeting. All right, go. Thank you, Jo-Ara. Following the tradition of IGCS in-person meetings, IGCS 2023 will provide you with the opportunity to learn about the latest clinical advances, as well as international developments in research, practice, and treatment for the holiest care of women with gynecological cancer. So it will be a great opportunity to network with you all, to be inspired from each other. It's a great pleasure and honor, and I can only thank the IGCS for giving us this opportunity. Keep out, look out in the next few coming days and weeks, because there will be some critical key dates that will be sent to all of you and to many of you to help us and support us. So please, we would like to have you on board. So we will begin then with the abstract session. So we begin with the last session of our meeting, it's the plenary session and the abstracts that will be presented by some very expert speakers. We have seven presentations and we start with Dr Florian Jochum from France. Please use it, it's the last session of the meeting, use it as an opportunity to ask questions and to interact with us. Thank you. Thank you very much. I'm very happy to be able to present our work. So I'm Florian Jochum, I'm from Strasbourg University Hospital, but I'm now a PhD student at Institut Curie in Paris. So I'm going to present a work about the impact of comorbidities, post-operative complications and central volume on overall survival in a real-life cohort of 30,000s of rare cancer patients. I have nothing to disclose. So you have to know that in France, all the medical and administrative information relating to the reimbursement of French citizens for health care expenses are collected in a database which are named National Health Data System. It collates data of 95% of the population. We retrieved the data from all ovarian cancer patients in France between 2013 and 2019. You can see on the first plot the age distribution of the patient. In green is a patient with advanced stages and in yellow is a patient with early stages. We have a peak at 66 years and for the early stages, the patient has a median age of 60 and for the advanced stages, the median age was 67. In our cohort, the patient had advanced stages for about 80%. The first thing that we noticed in this cohort is that we actually have more than 30% of the patients who didn't get any surgery. For the patients who got surgery, 99% received an interval debulking surgery and 51% a primary debulking surgery. But still 30% didn't get any surgery. So who are these patients? These patients are patients with more comorbidities. So in this group, 37% of the patients had multi-comorbidities versus 28% in the surgery group. These patients also are the older age with 52% older than 70 years versus 29% in the surgery group. In total, 54% of the patients had at least one comorbidity. Almost a third of the patients suffered from multiple comorbidities. So two, three, or more than three comorbidities. And the coexistence of multiple comorbidities was most frequent in older patients. You can see that for the patient with no comorbidities, the median age was 63. And for the patient with more than three comorbidities, the median age was 72. The most frequent comorbidities were hypertension and obesity. Almost 25% of the patients had hypertension. And around 2,500 patients had obesity and almost the same number with diabetes. You can see here the negative impact on overall survival of multiple comorbidities. So the yellow one, the first plot, is for the advanced stages. You can see that the median survival was 54 months. And for the curve with the more red, it's survival for the patient with more than three comorbidities, and the median survival is 32 months. So there is really a clear impact for the advanced stages, but also for the early stages. We also analyzed the volume center in France for ovarian cancer, and we find very high heterogeneity. You can see the distribution of the number of patients operated by centers over the seven years. And the median number of patients operated on over seven years was 13 patients. So it's one or two patients per year. So there is a very high proportion of low-volume center and few high-volume centers with only 35 centers, which operated more than 100 patients over seven years, which means 15 patients per year. And you can see on this plot the in-persons of high-volume centers to improve survival. There is a median survival for advanced stages for the patient who were operated on the high-volume centers on more than 25 patients per year was 63 versus 53 for the patient who were operated on the center less than five patients per year. For the complication, we found that 16% of the patients presented a post-operative complication. The most common post-operative complication was digestive, 60%, and there was a peak of complication at D7. You can see here again the impact on overall survival of complication, and there is clearly an impact for the early stages, but also for the advanced stages. And finally, so this is a multivariate survival. And after adjustment, the number of comorbidities, the central volume, and post-operative complication was still significant. The EISER ratio for more than three comorbidities was 1.3. For high-volume, it's 0.8, and for at least one complication, it's 1.4. So the conclusions are that comorbidities are critical, and actually more than we think. Complication impacts survival, and again, actually more than we think. And in France, when we analyze the volume of the center, we see that we have very few high-volume centers, and there is actually an imperative need for organization of proper and constant care with centralization of care and designation of expert centers. Thank you very much. Thank you, Dr. Yeo-Hung. And we will now hear the dissertation by Dr. Okay. Thank you for your kind introduction. Today it's my pleasure to have an opportunity to discuss this topic. Before I start my presentation, I declare the no conflict of interest. This study is interesting in showing that the comorbidities and post-operative complications and center volume may be related with survival. Though we can consider the strength of this study, it's the investigation on the big data from French Ovarian Cancer Court registered at the National Health Data System. However, this study has limited its two aspects. The first, among all the patients, the rate of primary deburking surgery was only 31.4%, whereas the rate of chemotherapy alone was relatively high at 38.1%. Second, there is a lack of data about the success rate of optimal deburking surgery and the extent of surgery because it can be related with post-operative complication. Previous study that shows the preference to ineligible chemotherapy followed by the interval deburking surgery for advanced ovarian cancer were reported to range from the 10% to 30%. So the French Court study showed a similar preference to ineligible chemotherapy followed by interval deburking surgery at 30.3%. In the four random control trials for comparing the effect and safety between the primary deburking surgery and the ineligible chemotherapy, ineligible chemotherapy is likely to reduce the risk of surgical morbidity. The surgical morbidity in this study, 16.1%, seems to be acceptable and similar to that of ineligible chemotherapy group in the four random control trials. However, it's possible that the rate was measured relatively low. Such a low rate of primary deburking surgery and a higher rate of chemotherapy alone. The next point is that the French Court study shows that multiple comorbidities and post-operative complications were related to the impaired survivor. Furthermore, we can consider that the comorbidities increase post-operative complications such as loss, urinary tract infection, and wound infection. So this study also shows the digestive complication, 60.4%, as the current most common complication. The last point is that the prognosis was better in high-volume centers. In this point, we can consider that the rate of chemotherapy alone is expected to be lower. Post-operative deburking surgery is expected to be more frequent because wider the extent of surgical resection and the care of the post-operative complication is expected to be more adequate. In summary, the multiple comorbidity and relative post-operative complications were related to the impaired survivor in the brain cancer in this study. It's possible that comorbidities may increase post-operative complications, which can lead to the impaired survivor by undertreatment of ovarian cancer. And the high-volume centers are expected to act alone to improve the prognosis of ovarian cancer. The wider extent of surgical resection leading to optimal deburking surgery and more adequate management of comorbidities and post-operative complications are expected in high-volume centers. Thank you for your kind attention. That was an excellent distillation. Thank you very much. Gip, are there any questions from the audience for this very important real-life data? I have a comment to make. We did in the UK, and I think I presented it this morning in our meeting in the session I had with Nogo. We actually did the same in the UK, and we showed similar rates of no-operated patients, which is around 40%. So it's amazing to see, really, that if you use real-world data, and if you have as denominator all patients, around 35% to 40% of patients will never get operated. And that's not just in the UK. It's not just in France. It's really everywhere. It's just that very often people do analysis and studies with the denominator only surgical patients and not all patients. So we are missing, really, the point. If there are no more questions, thank you very much. You can go down. And it's my great pleasure to hear from Dr. David O'Malley, who gave a very passionate talk about PARP inhibitors this morning. I was very impressed. And Dr. Catherine Few for distillation. David. Thank you very much. And my passion for antibiotics-drugs conjugates is equal that to my passion for PARP. So I'd like to take this opportunity to thank the IGCS, the Program Committee, the members of the Scientific Review Committee for the opportunity to present this important final analysis of mirtuximab sorbentansine, which I'll refer to as MIRV, a folate receptor alpha-targeted antibody-drug conjugate, or ADC, in combination with bevacivimab, which I'll refer to as BEV, in women with recurrent ovarian cancer. These are my disclosures. MIRV is a first-in-class antibody-drug conjugate, demonstrating meaningful antitumor activity in patients with folate receptor alpha, expressing platinum-resistant ovarian cancer, regardless of the number of prior therapies or prior PARP use. Total analysis of three clinical trials showed MIRV monotherapy is a differentiated safety profile consistently primarily of low-grade reversible GI and ocular events. Here we present the efficacy and safety of MIRV in combination with BEV in patients with recurrent folate receptor alpha-expressing ovarian cancer. The study population included patients with folate receptor alpha-expressing epithelial ovarian cancer who were eligible for non-platinum therapy treated on 4 or 2. Sixty-six patients were treated in the dose escalation phase and an expansion cohort for platinum-resistant ovarian cancer, and 60 patients from a platinum-agnostic cohort. Using immunohistochemistry-based scoring on available archival tumor tissue was evaluated for folate receptor alpha expression. Patients were eligible for the study if greater than 25% of the cells had at least 2 plus standing intensity. 25% is defined as low to 49%, 50 to 74, medium, greater than 75, high. The primary endpoint is investigator-assessed confirmed overall objective response rate, and the secondary endpoints include duration response, progression-free survival, and safety. Patients treated with MIRV at 6 mg per kg using an adjusted ideal body weight were included. BEV was given at 15 mg per kg IV every 3 weeks until disease progression or intolerable side effects. A total of 126 patients were treated with MIRV and BEV. 50% were folate receptor alpha high, 40% were medium, and 10% were low. 46% of patients had 3 or more prior lines of therapy, and 52% had received prior BEV, and 75% had had the most recent platinum-free interval of less than 6 months or classically platinum-resistant. Here's the waterfall plot of all 126 patients showing that approximately 90% of patients had evidence of tumor reduction. Here's the objective response rate in the overall population and by folate alpha expression. The overall response rate was 44% with meaningful responses across all levels of folate expression, 52% in high, 39% in medium, and 31% in low. Looking closer at additional subsets of patients, there's a higher objective response rate in patients who are BEV-naive at 58% compared to BEV pretreated with an overall response rate of 32%. The objective response rate is similar in platinum-sensitive and platinum-resistant, 48% and 44%. There's a higher objective response rate in patients with fewer prior therapies, 61% for patients with one prior, 41% for two, and 34% in patients with three or more prior lines of therapy. We found the median duration of response was 11.8 months for the overall population. We demonstrated durable responses across all levels of folate expression. Let's look at additional patient subsets for duration response. Median duration of response is clinically meaningful across all subgroups ranging from 8 to 14 months. Similar to the objective response rate shown earlier, there's a slightly longer duration response in BEV-naive patients compared to BEV pretreated and improved in platinum-sensitive patients as compared to platinum-resistant. Interestingly, though very small numbers, show an increase in the duration response in heavier pretreated patients. Moving to progression-free survival, here are the Kaplan-Meier curves for the subsets evaluated. The curves follow the trends observed with the objective response rate and duration response in the subgroups. Treatment-related adverse events were mostly low-grade, manageable, and consistent based on the profile of each agent. The most common grade 3 or higher was hypertension at 16%. We saw a few patients with grade 3 diarrhea and fatigue. MIRV was discontinued in 37% of patients, but a median of approximately 13 cycles. There was 4 or 3% of patients that discontinued due to blurred vision. Remembering this goes across the entire experience of MIRV therapy and MIRV clinical trials. There was one death in a study that was deemed related to study treatment, and that was intestinal perforation, most likely related to BEV. In conclusion, the combination of MIRV plus BEV was highly active in a broad population recurrent folate receptor positive ovarian cancer patients. In the overall population, the response rate was 44%, 11.8 months median duration response and 8.2 months median progression-free survival. Consistent durable anti-tumor activity was observed across all levels of folate alpha expression regardless of prior BEV treatment, platinum-free interval, and prior lines of therapy. The safety profile of the combination of MIRV and BEV reflects the safety profile of each drug as a monotherapy. The most common treatment-related adverse events were hypertension, diarrhea, blurred vision, and fatigue. These data provide evidence to support MIRV and BEV as an efficacious combination of choice for patients with folate receptor-expressing ovarian cancer who are eligible for treatment with BEV. A randomized phase 3 trial called GLORIOSA or GOG3078, I do not believe it has an NGOT number assigned yet, is planned to evaluate the efficacy and safety of MIRV and BEV in maintenance for platinum-sensitive ovarian cancer patients with high folate receptor alpha expression. I would like to thank the patients, their families, and support across the world for this trial. Thank you. Thank you. It's a great presentation, Dr. Omari. The next presentation comes from Dr. Kathleen Alford. Thank you very much for this opportunity. I'd like to thank the IGCS Program Committee for this opportunity. I want to present this study on behalf of the co-investigators on tazolizumab and bevacizumab in recurrent endometrial cancer phase 2 multi-institutional trial. These are my disclosures. Clinical data across several solid tumors, including endometrial cancer, suggests synergy between immune checkpoint inhibition and anti-angiogenic agents. The combination of tazolizumab and bevacizumab has recently shown improved overall and progression-free survival in hepatocellular carcinoma and non-small cell lung cancer. This study sought to evaluate the efficacy and safety of a tazolizumab and bevacizumab in endometrial cancer. Here's our study schema. It's a phase 2 multi-center, single-arm trial. It enrolled patients with recurrent endometrial cancer, relapsed refractory to curative therapy. Patients could be included if they had one to two prior lines for endometrial cancer, measurable disease at the time of recurrence, and prior carboplatin and palchotextile were acceptable. No tissue or tissue biopsy was required given the exploratory endpoints, which I will highlight. We also collected pretreatment blood before the treatment for the exploratory endpoint. Treatment included bevacizumab and tazolizumab every 21-day cycle, and treatment until progression or adverse events. We also collected post-treatment blood collection, first at two cycles post-treatment, as well as continually following after that. Exploratory endpoint included objective response rate, secondary endpoint, PFS, OS, and safety, as well as objective response rate by immune-related response criteria. Exploratory endpoint includes immune subpopulations by CyTOF and multi-parametric fluorescent imaging by Codex. And for today's talk, I'll only focus on the CyTOF as exploratory endpoint. In terms of demographics and clinical characteristics, of significance were that 80% of the tumors had mismatched repair proficiency, and the stage of diagnosis was even between stage 1 and 2, and 3 to 4. In terms of histology diagnosis, the majority were endometrioid, followed by carcino-sarcomas, serous, and clear cell. In terms of tumor grade of diagnosis, the majority were grade 2 and 3. In terms of the overall clinical activity, we found 30% objective response rate for all patients. In terms of the mismatched repair proficient tumors, there was 33% objective response rate. The median duration of response was 15 months, with a range of 2.9 to 34 months. In terms of median progression-free survival, 7.87 months, with a range of 5.5 to 11.7 months. In terms of highlighting the significant duration of response, we identified that patients with partial response or complete response had a significant duration of response you can see highlighted there. And this is a waterfall plot that really highlights the greatest percent reduction in tumor size by mismatched repair status, and you can see that in blue, for the tumors with mismatched repair proficient, we did have a significant number of patients with complete response. We look at the overall adverse events, and we looked at whether it was grade 3 due to tazolizumab versus bevacizumab, and we found that 7% were grade 3 due to tazolizumab and 22% due to bev, with no grade 4 adverse events. In terms of dose interruption, 79% had dose interruption, 4% had dose reduction, and 16% discontinued due to toxicity. When we look at what were the adverse events themselves, we found the majority were fatigue, diarrhea, and hypertension. When we looked at the grade 3 events, we found that the majority, you can see on the right-hand column, was hypertension, and included the usual fatigue and diarrhea that we know and can manage with other regimens. We next asked, could we possibly identify which patients could respond or progress on this treatment? And to utilize this and identify this, we utilized CyTOF, which is cytometry time of flight. It's a multi-parametric, single-cell proteomic technology platform. It was additionally invented by Scott Tanner and applied by Gary Nolan. And Sean Bindel and Gary Nolanzab was the first to publish this in 2012 using peripheral blood mononuclear cells. And the technology is to utilize antibodies conjugated to rare metal ions, so therefore you can investigate, at the single-cell level, multiple types of antibodies and signals at the same time. And so we applied this technology to blood from patients pre and post two cycles of tazolizumab and bevacizumab. And so when we identified a sub-cohort of eight patients and really looked and correlated their response in terms of partial, progressive, stable, or complete response, and on the figure on your left, you can see those are including each of these patients in those four categories. And we did identify the non-classical monocytes and the ICOS-expressing T-regulatory cells did actually increase in the progressive disease in terms of that patient. And interestingly, the ICOS-expressing T-regulatory cells have been found to be more immunosuppressive than the ICOS-negative T-regulatory cells. And in another study in melanoma patients, it was identified that those who received IL-2 therapy that progressed on that therapy did have an increase in expansion of those ICOS-expressing T-regulatory cells, thus highlighting that possibility that we could correlate, you know, patients that could progress on this treatment earlier on. So in summary, endometrial cancer is rising mortality. Drug development is needed to match this urgency. There are recurrent endometrial cancer active regimens, such as pembrolizumab and levatinib-pembrolizumab. However, development of alternative immunotherapy, anti-angina combination, with a strong signal efficacy and tolerability is needed. And there is an ongoing alliance study with Brian Somovitz as the PI that does actually continue to look at this combination of bevacizumab and tazolizumab in biomarker-negative, and this is the ENDOMAP trial. And the primary endpoint, again, is similar to what we looked at in terms of objective response rate. And finally, I'll end that CyTOF analysis as an exploratory endpoint could perhaps identify patients who may not benefit early, and this can be incorporated in a future analysis and should be highly considered. So I'd like to acknowledge Katie Moore, who's a senior PI, as well as the other study co-authors, including Matt Powell, who's a translational co-PI, and the PIs at the other sites, including back at UAB and Calumet Court at Washington University. Thank you to Genentech and Roche for drug supply and funding this trial, and special thanks to the patients and families who participated. Thank you. Thank you, Dr. Moore. That's a great presentation, and now we will hear the dissertation from Dr. Angelica Rodriguez. I would like to thank the organizing committee for the opportunity to discuss these two outstanding trials. In common, the use of anti-angiogenics combined to novel therapies in advanced gynecologic cancer. These are my conflicts of interest. Since the publication of Dr. Folkman's pivotal trial related to anti-angiogenics, several groups have explored deeply the use of anti-angiogenics in several clinical contexts, including gynecologic cancer. In endometrial cancer, response rate to single agent anti-VEGF is limited to 10 to 15% response rate only. But there is a strong rationale to combine anti-angiogenics to immunotherapy. Not only a rationale, now we have strong clinical data, as you all know. It was recently presented at ASMOD this year, the updated data of the keynote 7 to 75 of lymphadenib combined to pembrolizumab in advanced endometrial cancer. And the combination of immunotherapy and anti-angiogenics increase response rate, progression-free survival, and overall survival. And this is the rationale for Dr. Catherine Fu's trial, exploring the use of atizolizumab and bevacizumab in advanced recurrent endometrial cancer, a phase 2 trial. This is indirect comparison, so it's limited. But as you can see on this table, overall response rate between Fu's data and the keynote data is quite similar. Also the duration of response and also the medium progression-free survival. And the good side of this coin is that toxicity seems to be less in the combination of BEV and atizolizumab compared to lymphadenib and pembrolizumab. For example, combination grade 3 or more due to the immunotherapy was 7% with atizolizumab compared to 13% with pembrolizumab. And furthermore, with anti-angiogenics grade 3 or more, 22% in the atizolizumab group compared to 66% in the lymphadenib group, three times higher with lymphadenib. But the number of patients who discontinued treatment due to toxicity was similar. The discontinuation of the combination was similar between the two studies, around 16%. But this story will not finish here. Many groups are studying the combination of anti-angiogenics and immunotherapy, just like centilimab and enlotinib, just like the combination of cabozantinib and nivolumab with promising clinical activity. And not only that, the endomap is trying to bring more granularity to this data, selecting patients according to the biomarker. So I will finish this first abstract with these conclusions. Anti-angiogenics combined to immunotherapy are effective in advanced endometrial cancer. And atizolizumab demonstrated clinically meaningful activity in this disease. Lymphpembrol is standard, but toxicity is challenging. Better tolerated regimens are necessary in this palliative clinical context. Randomized non-inferiority trials are welcome to a final decision. Changing gears to ovarian cancer, Dr. O'Malley presented data from the ADC MRF combined to BEV in advanced relapsed ovarian cancer. Differently from endometrial cancer in ovarian cancer, bevacizumab has proven activity in frontline relapsed platinum-sensitive and in the difficult-to-treat platinum-resistant patients. And since the presentation of the Aurelia trial almost a decade ago, there has been no significant advances for those patients. But there is a new holy grail on the horizon, ADCs. And Dr. O'Malley presented the data of MRF combined to bevacizumab. And on the title of the presentation, the group was focusing on the efficacy in patients with and without prior bevacizumab. And as you can see, yes, the combination of BEV and MRF is efficacious in patients previously exposed to BEV, 32% of response rate. But there is a tendency for a reduction in response rate from 58% to 32%. But we need to be careful in this analysis because there is also a tendency of decreasing the response rate when patients are submitted to more lines of treatment of cytotoxic treatment. So this reduction may be due to heavier-treated patients. Reduction is also needed to analyze the data based on classic cytotoxic concepts. It was very interesting to see that despite lower response rates, heavier-treated patients presented longer duration of responses. This number is small, but it needs our attention. I would like to suggest to you to see the data from Destiny Breast 01. This is a trial in advanced breast cancer patients receiving trastuzumab derixtecan. And even heavily pre-treated patients derived high benefit from an ADC comparable to patients in the initial setting. And before going to the direct comparison to the RILA trial, which is standard, I would like to emphasize that this data is not restricted to platinum-resistant patients. Approximately 25% of the patients were platinum-sensitive. So I will focus the discussion here based on the platinum-resistant cohort, approximately 75% of the patients. And there was an increase, if again we do this indirect comparison, there was an increase of 50% in response rate from 30% to 44% comparing MIRV and BEV compared to the RILA trial. Is this BEV necessary for these patients or should we go for MIRV alone? It seems to be necessary to add BEV if you compare the data with the SORAYA trial. The SORAYA used MIRV in platinum-resistant patients and the response rate was around 32 and compared to 44% in the patients with the combination of BEV and MIRV. And a lot is coming. Now there is the MIRASOL trial, which is testing in platinum-resistant patients MIRV compared to chemo. But I need to remind you that Forward 1 was negative with a similar question, just a difference in the criteria, the biomarker inclusion criteria. And also there is the GLORIOSA testing, MIRV combined to BEV in platinum-sensitive patients. Probably it will change completely the way, the algorithm of treatment that we use now. If GLORIOSA is positive, probably this combination presented today will move to earlier lines. So you probably use BEV combined to MIRV in earlier phases. But if it's negative and MIRASOL is positive, there will be conflicting data with Forward. And so the combination shown here with the trial Forward 2 will be welcome again. So probably we will be using DAVA-Cisumab or in earlier or in later phases. So my conclusions, MIRV-etuximab and BEV demonstrated clinically meaningful activity in platinum-resistant ovarian cancer. Is BEV synergic to MIRV-etuximab? Not clear, but better response rates than in psoriasis trial in a similar population. We should be cautious of classical oncology analysis of biomarkers and clinical activity when studying ADCs and MIRV seems to be just the beginning of the ADC journey in ovarian cancer. Thank you so much. That was great. Thank you very much, Dr. Marley. Phuong and Rodriguez was brilliant. Any questions? Yes. Oh, God. They're running. Who is running first? Brian. Brian is the president. No, those were great. Thanks for those presentations and thanks for everyone for staying so late. Usually there's like three people here at the last session. For Dr. Phu, two questions. One, what are your thoughts about in the DMMR patients? Do you think they really need BEV-etuximab? Does it do it, you know, because we don't really know. Do you think they need it? I don't know. Do they need the added toxicity of that? And then the second question in relation to BEV-etuzumab, where that's a pure VEGF, do you think that the dirty TKI component of Linvatinib is what makes the difference, not necessarily the VEGF component? Great presentation. Thank you so much. I agree. I think that, you know, that question about whether or not BEV is needed, in this trial, it's difficult to actually to conclude that. So I think that would be future studies that would, you know, but I think biologically that would be a question. In terms of the TKI versus BEV alone, you know, I think that's been a question. You know, how much do the other inhibition of the receptor tyrosine kinases or tyrosine kinases, like, make a difference and make an impact? So I think, again, that question is definitely biologically sound, but whether or not we can answer it, perhaps, like, in a clinical trial setting would be, perhaps, ideal. Will. Thank you. I have one question for each of you. For Dave, I have one that has 14 subparts. I hope you don't mind. Yeah, 14. Yeah. All right. No. So. So. Hopefully, they're all about statistics. Yeah, they are. No, I had a question. Dr. Fuchs, the, why do you think that the response rate in the DMMR population is so low that, you know, you showed there's only, there are only six patients or whatever, seven patients. There's one responder. Why is that? Because I would have anticipated that in that population it should have been driving the response rate when I was doing the math. Why do you think that was the case here? Yeah, no, we were wondering the same and whether or not the transitional component was hopefully going to help us understand the immune cell population, what actually might be really driving the response, not just the mismatch repair deficiency part, but actually the immune cells are actually active. So that's something that we're going to ongo, ongoing analysis to figure out. But I agree, that's really important to understand and see in this trial. That maybe we need a different marker. Thank you. And then Dave, or Dr. Malley, for the, you know, the two, two interesting observations. One is that this was, this was used in, in full receptor different populations. So you have low, medium, and high with good responses across the board. So one is, you know, do you think Bev actually essentially erases that element that were necessary for that particular biomarker for Rituximab? And the second is, can you comment on the fact that out of, there was only one out of 129 patients who had a bowel perforation and, but there were half of the patients or so that were outside of the Bev label, including those that had prior Bev. So why did, why was it so different than what we saw in the Conistra study? Thank you. Well, I think we've gotten smarter and we're smarter with the patients that we put on Bev. So if they have bowel involvement, if they've had symptoms of small bowel obstruction, I think in a real clinical practice on that, that was part of the enrollment, which is not to have patients have recent SBO, TPN, that we as clinicians have gotten better at predicting who's going to have a bowel perforation. So the 1% rate, you know, the paper that Debbie Richardson and I did when she was a fellow was 7% in our hands at that point from our institution for bowel perforation when combined with chemotherapy. And now in this prospective trial, it's less than 1%. So I think we've gotten better at, we're smarter on who to get. With regards to the, you know, kind of level playing field, I do believe though, and there is some rationale here that beyond high folate receptor with the Bev, you are able to get better responses. And Anjali did a beautiful job in the distillation. I was, and when we look at similar response rates to Soraya, where all the patients were pre-treated with Bev, there's only one to three priors and they're all high folate receptor alpha. But interesting, the duration, Rob Soraya trial, Rob and Ursula's, was about seven months median duration response and ours is about 12 within a range of about eight to 14. So that three to four months of improvement in the median progression of free survival is when we see when we add Bev to chemotherapies, we're also seeing at the ADCs. So even though more patients that were not high folate receptor alpha, even more heavily pre-treated, we still saw a numerically slightly higher response rate. But the DOR, about 50% longer. That's brilliant. What are you, there is a question from the audience. Yes. Kevin Holcomb from New York. My question is for Dr. O'Malley. I want to make sure I read the slide correctly. Is it the case that the patients with the lowest receptor expression had the highest percentage of complete responses and the longest duration of response? And if that's the case, how does that inform future trial development? Well, we're very small numbers. So you had four of the 10 respond. Three of those four were CRs. And so when you have the CRs, the duration obviously is much longer. I think it speaks to the heterogeneity of our tumors. I think it speaks to where we, as we move forward, ADCs and what we're seeing in the HER2-nu ADCs across breast, that, you know, one plus is good enough. We are going to continue to learn more. The development plan limit to high folate receptor alpha after forward one obviously was a development plan. Moving forward, I think we need to expand it to those beyond just folate receptor alpha, and I'm saying that as PI Gloriosa, which we are limiting to high folate receptor alphas. But moving forward, we'll see more trials include less expression, and we'll hopefully be able to answer that question. Excellent. Thank you very much. That was a great discussion. Thank you. So we now go to a completely different topic, a bit more surgical, and it's my great pleasure to introduce Dr. Diana Wong, who is going to talk about how the practice has changed after the FDA announcement for the marcelators for the treatment of Lyme and sarcomas. Diana. Thank you, everyone. I'd like to thank the program committee and President Coleman for giving us the opportunity to present our research on the trends of metastatic leomyosarcoma following the U.S. FDA warning on laparoscopic power marcelators. My name is Diana Wong. I'm presenting on behalf of Dr. Eakin as well as our research group. I have no financial disclosures. Leomyosarcoma accounts for 1 to 2% of all uterine malignancies. Nearly 50% of leomyosarcomas are diagnosed during surgeries for presumed benign fibroids. The risk of power marcelation is associated with the risk of undetected dissemination with an estimate between 1 in 360 and 1 in over 7,000 cases. Marcelation of leomyosarcoma is also associated with an upstaging in 20 to 40% of all cases and a more than threefold increased risk of recurrence and death. In 2014, the FDA posted a warning on power marcelators. Since that time, there has been a 19% decrease in minimally invasive surgeries for myomectomies as well as a 6% decrease for hysterectomies. There has been an ongoing debate regarding the use of marcelation. By converting to open abdominal hysterectomies, there's an increased risk of morbidity and mortality with this open surgery. Furthermore, risk-based models show that there are more quality-adjusted life years with laparoscopic surgeries. Given these limitations and this background, we propose to evaluate the pattern and incidence of advanced-stage leomyosarcoma before and after the FDA warning. We also wanted to evaluate the survival outcomes of patients with leomyosarcoma over time. We performed a population analysis using two major databases, first using the United States cancer statistics from 2001 and 2018 looking at incidence data, and the second database we used was a national cancer database from 2004 to 2016 looking at five-year survival outcomes. We calculated statistics using the average annual percent change as well as looking at Kathleen Meyer survival estimates. For demographics within the U.S. cancer statistics within this 18-year time period, our study included almost up to 850,000 patients with uterine cancer. And specifically for leomyosarcoma, we had over 16,000 cases. When we look at the average annual percent change, which is the percent increase or decrease associated with this cancer per year, we see that for all uterine cancers there has been an increase of 0.7 percent per year across this 18-year time period. And for leomyosarcoma specifically, there's been an increase of about 0.5 percent per year. We then performed a deep dive looking at race and ethnicity within the subset of leomyosarcomas. Interestingly, we had about 25, almost a quarter of all these cases were in the black women population. And this population had a significant increase of almost 2 percent increase per year within this time period compared to whites, which actually had a decrease of about 0.5 percent per year. We then looked at the U.S. cancer statistics database, and we showed that prior to the FDA warning in 2014, the incidence of distant leomyosarcoma increased at about 4 percent per year. Interestingly, after the FDA warning in 2014, the incidence of distant leomyosarcoma decreased at a rate of 4.7 percent per year, which almost is the opposite trend of what we had seen earlier. We then wanted to look at whether there was a proportional increase of local or regional leomyosarcoma, where the gray line on top shows the local and the blue line on the bottom shows the regional. And we did not see a change in the incidence of either local or regional disease. Next, we looked at the five-year survival using the national cancer database, which we divided into three time periods, the first being 2004 to 2007, 2008 to 2012, and then 2013 to 2016, the latter of which is around the time of the FDA warning. We did not see a difference in survival outcomes across these three different time periods, looking at nearly 10,000 patients. The results of our study need to be interpreted with caution. First, we don't have central pathology review. And second, we don't have information on who actually received morcellation and follow-up outcomes of these patients with respect to survival. It was difficult to prove causation with our analysis. Nevertheless, this study uses two of the largest databases and allows us to look at incidence trends as well as survival trends across an 18-year study period. In conclusion, since the FDA warning on the use of the power morcellator in 2014, we note a decrease of 4.7% of distant leomyosarcoma per year. However, we did not see a corresponding increase in local or regional disease, and there was no improvement in survival over this time period, possibly due to the short follow-up period. The correlation of these findings to the FDA warning of power morcellators warrants further investigation. I'd like to acknowledge all of our collaborators, particularly Dr. Chengyi Lau, Dr. John Chan, as well as Dr. Ritu Solani. Thank you. That's excellent. And now we will hear the distillation of Dr. Jubilee Brown. Dr. Brown. Thank you. Great. Thank you so much for the opportunity to be here, and congratulations to Dr. Iggen and Dr. Huang for their excellent presentation. So I'm fortunate to distill this information. These are my disclosures that are relevant. So 2014 was an interesting year. So following 16 years of power morcellation and 136 articles on power morcellation, unfortunately in 2013 a Boston-based anesthesiologist underwent power morcellation, and unfortunately leomyosarcoma was detected in the final pathology. So the Wall Street Journal wrote about this and cited worse outcomes due to dissemination of undetected cancer in patients with suspected fibroids. In 2014, Senator Elizabeth Warren queried the FDA, and the FDA discouraged the procedures and many hospitals banned morcellation, effectively removing power morcellation from the arsenal of treatment. J&J pulled their morcellators, and following that, in November of 2014, the FDA issued their safety communication. The scientific inquiry actually came next, which one would argue would be late, and that scientific inquiry was very scant on data. As we all tried to pull this information together, there were only a total of 20 patients in the literature, 10 of whom were upstaged. These were all case reports. And then PARC told us that with power morcellation, the odds ratio of death from power morsellation due to unrecognized Lyme or sarcoma was three. You can see the graph from Dr. Rain Bennett on the right, which shows a worse disease-free survival in patients who underwent power morsellation compared with other types or no morsellation. And those data were recapitulated by that AHRQ. The corollary to this concern, though, as Dr. Huang outlined, was that worse outcomes were anticipated due to the concern that all of the MIS cases would be converted into open procedures. And Dr. Sitoff and others suspected and showed that more hysterectomy-related deaths would be encountered and more quality-adjusted life years were added by continuing on with minimally invasive surgery. But you know, these concerns for worse outcomes from banning morsellation, they didn't happen. Why? Because we had better equipment, people rallied, there were better techniques, better surgery, and better risk stratification. So the worsening in outcome that we thought was gonna happen, it didn't. So the goals of this abstract are actually quite excellent. Trying to reconstruct causation from historical data. The questions are, can that be done? Perhaps most importantly, are the methods valid? And also, what are the outcomes? So I would say that the methods here are very robust. They're absolutely the best that you're going to get. So these authors looked at the U.S. cancer statistics. These are the official federal cancer statistics in the United States, including the CDC's National Program of Cancer Registries from 46 states and territories. And include the NCI's SEER program, which represent 22 diverse U.S. geographic areas. The mortality data is pulled from the CDC's National Center for Health Statistics. And really, these represent the newly diagnosed cancer cases and deaths for the whole U.S. population. That National Cancer Database, it's the best data that we have. It's from over 1,500 Commission on Cancer accredited facilities. And their software analysis that they did, or the regression analysis that they did, utilized joint point trend analysis. And this is really the standard of care to analyze rates. So what about the outcomes that we're seeing? Local, regional, distant metastases, and survival? Well, interestingly, the only thing that is worse in their evaluation is distant metastases, 4.67% decrease per year. That is statistically significant. And this is, actually, it's a big number of patients. It's a large number of true patient numbers, despite Lyme or sarcoma being a rare tumor. So this does appear to be a real change over time. And this correlates with changes in morcellation utilization over time. But no effect on regional or local metastases. Well, why not? And does this correspond to a decrease in survival? No. So why not? These are really the unanswered questions. Maybe it's because Lyme or sarcoma is just a very aggressive tumor. Maybe it's because tumor biology trumps everything else. Maybe it's because this is such a bad tumor that that improvement in distant metastases that we see just doesn't correlate with survival because it's such a bad actor. Maybe we haven't seen the full effect because of time, and it'll be interesting to see what happens in outcomes over the next five to 10 years. So should we go back to power morcellation? Absolutely not. But I think what this does highlight is the need for better systemic therapy and overall therapy for Lyme or sarcoma. So congratulations, Dr. Dr. Eakin and Dr. Huang, and thank you for your attention. That was brilliant, and also it put really things into perspective. Thank you very much, Dr. Brown. Any questions? Yes, please. Thanks for the interesting talk. Were you able to correct for changes in hysterectomy rates in the United States over that time? Yes, we corrected for hysterectomies in pregnancy. Okay, and did hysterectomy rates go down proportionally across all groups? It did. All the data presented were corrected, so we didn't present any uncorrected data. I mean, it's not like if we don't do morcellation, we really have to just open them all up. We can always do it, laparoscopic dissection, just do a mini-laparotomy to remove the fibroid or just do it vaginally. We really have to find the ways around it. It's not that we have to condemn patients to huge laparotomies, and we just need to think, and like we did with the LAC study, to just improve our technical skills, really. Excellent, thank you very much. Thank you. Thank you, Dr. Wong and Dr. Brown. It's a great work, and now we will hear from Dr. Rilian Gien. Great, thank you very much. Thanks to the program committee for allowing me to present this work today. I'm presenting this on behalf of the co-investigators at Energy Oncology. These are my disclosures. So recurrent ovarian clear cell carcinomas are an area of unmet need. These tumors are chemoresistant with response rates less than 10%, and they really have limited options in the recurrent setting. PD-1 in ambition has been studied in epithelial ovarian cancers that include all histologic types, and the overall response rates has been quoted to be about 15%. But among those phase two studies that included all histologies, there seem to be really dramatic and durable objective responses with immune checkpoint inhibitors, specifically in clear cell cancers. And as illustrated here, for example, there would be patients with clear cell histology with recurrent disease and peritoneal carcinomatosis, but have a complete response to nivolumab, as an example. Also, in addition, NRG GY003, which was a study evaluating recurrent epithelial ovarian cancers, giving patients either nivolumab plus ipilimumab versus nivolumab alone. When they did a subset analysis, they found that the clear cell histology group had a five-fold increased odds of response to the immunotherapy. Now, this represented only 12% of the cohort, but this was hypothesis-generating and thought-provoking. Mismatch repair deficiency has been evaluated in ovarian cancers in a number of studies with small numbers in heterogeneity, but overall, the early studies looked at the frequency of MMR deficiency in clear cell ovarian cancer and found the rate to be approximately 12 to 15%. So, based on epithelial ovarian cancer response rates to single monotherapy for immune checkpoint inhibitors, the rate's about 15%, and there seems to be this signal in clear cell carcinomas. The thought was, well, how can we improve that response rate with combination therapy? IDO1 is an enzyme that catalyzes the amino acid tryptophan to kynurenine, and that increase inhibits the antitumor cell-mediated immune response. So, if you could inhibit IDO1, you decrease kynurenine and therefore down-regulate the T regulatory cells and thereby increase antitumor immune response. In early studies of pembrolizumab and the combination of that and epicatastat, which is an IDO1 inhibitor, there were overall response rates of 53% with overall disease control rate of 75%, and this was a profound effect in melanoma. In fact, this led to a phase three study in melanoma with this combination. And also, early studies in renal cell carcinoma demonstrated a 47% response rate. So, this was the rationale for this study. NRGGY-016 was a single-arm phase two study of recurrent or persistent clear cell carcinoma of the ovary. Patients were given pembrolizumab, 200 milligrams IV every three weeks, along with epicatastat, which is the IDO1 inhibitor, 100 milligrams orally twice a day, and these were given until either progression or toxicity. The primary endpoint was overall response rate with secondary endpoints of toxicity, progression-free survival, and overall survival. This was a flexible two-stage design, and the study was powered to detect a 25% increase in response from an estimated 15% baseline. The planned first stage accrual was for 10 to 14 patients, and if there was a minimum number of responses to open to the second stage, the total number would be 25 patients. And these are the results. The first stage opened in September of 2018, and closed six months later in April of 2019 because of the rapid accrual of patients in the first stage of 14 patients. The accrual rate was 2.3 patients per month, and as you can see, exceeded the projected accrual rates for this study, which is for a rare tumor. Among these 14 patients, the median age was 65. About 20% had prior radiation therapy. The vast majority had at least two lines of prior chemotherapy. 20% had prior bevacizumab, and among those that we knew the MMR status, none were MMR deficient. The objective response rate in the 14 patients showed three partial responses. Overall, this was a 21% response rate with a median duration of response of 6.9 months. There were four patients with stable disease, giving a disease control rate of 50%. Secondary endpoints, the median PFS was 4.8 months, and overall survival, 18.9 months. For adverse events, the most common adverse events were grade one to two, which consisted of nausea and vomiting, fatigue, and metabolism and nutrition disorders, which were electrolyte abnormalities or appetite. The most common grade three AEs were bowel obstruction or electrolyte abnormalities. There were three grade five serious adverse events. One was a bowel perforation, and one death unlikely related to treatment, but definitely related to disease. And one death was attributable probably related to treatment and definitely related to disease. In July 2019, the study met criteria to open to the second stage. However, at that time, the phase three melanoma trial with the same combination of drugs came out and was reported to be negative. There was a lot of discussion at that point whether the epicatestat dose was at an adequate level. There was subsequent preclinical data that suggested that perhaps the dose should be 600 milligrams twice a day rather than 100 milligrams twice a day. During that time as well, there were other studies and other solid tumors with this drug combination that closed. Therefore, this study closed prematurely in February of 2021 due to insufficient drug supply. So in conclusion, Pembrolizumab and epicatestat as a combination gave an objective response rate of 21% in the small cohort of recurrent clear cell carcinomas of the ovary. Therefore, based on these numbers, the effect is inconclusive. Also, we are not sure what the additional attribution of the IDL1 inhibitor was above and beyond the Pembrolizumab. What we do know, however, is that there was a rapid accrual of patients in this first stage that exceeded expectations and really demonstrates the enthusiasm amongst patients and clinicians for trials with recurrent clear cell cancer. And there is definite need for future trials in this rare tumor. I'd like to thank my co-investigators for this trial, including Dr. Rob Coleman, who's the co-PI. I'd like to thank the NRG oncology leadership, as well as, of course, to all patients and families enrolled in the study. Thank you. APPLAUSE That's great. Thank you very much, Dr. Guillen. And then we proceed now to Dr. Shusmita Gorthandas, who will present her abstract, followed then by distillation. Thank you. Thank you to the committee for selecting our work on molecular stratification of ovarian clear cell carcinoma. I have no disclosures. Ovarian clear cell carcinoma represents 5 to 10% of ovarian cancers in the United States. And there are geographic and racial differences in incidence. In Japan, Taiwan and Korea, clear cell represents 10 to 25% of ovarian cancers. In the US, incidence of ovarian clear cell in the Asian and Pacific Islander population is about twice that of other racial groups. However, the genetics related to these differences in incidence are not well understood. Additionally, ovarian clear cell is associated with endometriosis. Self-reported endometriosis significantly increases risk of ovarian clear cell with an odds ratio of 3.05. And similar genetic alterations can be found in ovarian clear cell carcinoma and adjacent atypical endometriosis. Ovarian clear cell has worse oncologic outcomes for advanced stage than other epithelial ovarian cancers. Due to its rarity, clinical trials are not powered to make conclusions for ovarian clear cell, despite known differences in response to treatment. Recommendations for surveillance and treatment are nonspecific and typically follow those of high-grade serous ovarian cancer. There is a need for ovarian clear cell targeted therapies and it is essential to understand the molecular landscape of clear cell carcinoma. In this study, we sought to characterize the mutational landscape of ovarian clear cell, define if genetic alterations are associated with clinical pathologic variables and outcomes, and investigate if endometrial cancer-based molecular subtyping can be applied to ovarian clear cell and if subtypes are associated with outcomes. Patients with ovarian clear cell carcinoma who underwent clinical panel-based tumor normal sequencing from April of 2015 to January of 2021 were identified. Pathogenic somatic alterations, clinical pathologic variables, and survival outcomes were obtained. Ovarian clear cell carcinomas were classified into endometrial cancer molecular subtypes per the MSK database protocol and these subtypes were based on the four TCGA endometrial cancer subtypes, pol E, MSI high, copy number high, and copy number low. Following central pathology review, 119 ovarian clear cell carcinomas were identified. Median age at diagnosis was 53. Forty-one percent were less than 50 years old and 59 percent greater than 50 years old. Stage of diagnosis was equally distributed with 54 percent being early stage and 46 percent late stage. Sixty-one percent of patients self-identified as white, 17 percent Asian, and 6 percent black. The majority had endometriosis noted on pathology. Molecular subtyping in endometrial cancer has now been established. Subtyping of over 1,800 endometrial cancers at our institution found 40 percent were copy number high, 31 percent copy number low, 23 percent MSI high, and 5 percent pol E. When looking at endometrial clear cell histology only, subtype distribution in 56 cases was 55 percent copy number high, 37 percent copy number low, 7 percent MSI high, and 2 percent pol E. In comparison, when applying the same subtyping classifications to ovarian clear cell carcinoma, we observed that all four subtypes were present, but the distribution was different. With 83 percent copy number low, 12 percent copy number high, and 4 percent MSI high, 1 percent pol E. The subtype distribution in ovarian clear cell versus all endometrial cancers is significantly different. While endometrial clear cell is more like ovarian clear cell distribution, it is still significantly different. Ovarian clear cell carcinomas were enriched for copy number low subtype. Analysis of associations found that endometriosis was significantly more prevalent in ovarian clear cell carcinomas of copy number low molecular subtype. 73 percent had endometriosis on pathology. This heat map depicts all somatic gene alterations in our cohort. All altered genes are listed on the left in order of frequency of alteration. Each column represents one patient. Gray boxes represent wild-type genes. Colored boxes correspond to genetic alterations per the legend on the right. Here we show the top of the heat map with the most frequently altered genes. The four most frequently altered genes were ARID1A, PIK3CA, TERT promoter, and PPP2R1A. Beyond incidence, we compared genetic alterations in patients based on demographic groups. Here we compared patients who are greater or less than 50 years old at diagnosis of ovarian clear cell carcinoma. Zooming in on the most frequently altered genes, patients diagnosed at less than 50 years old were more likely to harbor PIK3CA alterations. Here we present survival analysis, which was performed by Kaplan-Meier method. When looking at outcomes, as expected, patients diagnosed with stage 3 and 4 disease had a shorter progression-free survival and overall survival than stage 1 and 2. For progression-free survival, it was 11 versus 33 months, and overall survival 52 versus 113 months. Other demographics that were associated with progression-free survival were race and molecular subtype. Patients who self-identified as Asian had a median progression-free survival of 11 months compared to 23 months in the white population. In the molecular subtypes, MSI high or poly had the longest median progression-free survival at 27 months, followed by copy number low at 22 months, and copy number high at the shortest progression-free survival at 8 months. In overall survival, the copy number low ovarian clear cell carcinoma had better overall survival, though not statistically different from the other groups. PPP2R1A alterations were significantly associated with worse overall survival, with a median overall survival of 32 months in the altered group versus 68 months in the unaltered group. Lastly, to account for bias, univariate sensitivity analysis, including only patients that had initial treatment at our institution, was performed. These found the same survival associations that we presented here. In conclusion, ovarian clear cell carcinomas are heterogeneous with varied clinical outcomes and molecular profiles. The most frequent somatic genetic alterations were ARID1A, PIK3CA, TERT promoter, and PPP2R1A. When classified by molecular subtype, the majority of ovarian clear cell carcinomas were copy number low, and molecular subtype distribution was significantly different from that of endometrial cancer and of endometrial clear cell carcinoma. In this retrospective series of ovarian clear cell carcinomas, stage at diagnosis, race, molecular subtype, and PPP2R1A alterations were predictive of outcomes. These results weren't validation and independent and prospective series to determine if molecular subtyping can be utilized for treatment and prognosis. This was a multidisciplinary effort, and I just want to thank everyone who helped us to put it together. Thank you. That was excellent. Thank you very much. Now we look forward to the distillation by Dr. Skanda. Thank you. I see the slides up here. I don't know if you guys can see them yet. Oh, back. Thank you. I appreciate you guys trudging through a long day. This is the third day of an amazing meeting. I'd like to thank the program committee, the authors, Dr. Gordhandas, Dr. Guillen, for their excellent presentations addressing a critically important topic, specifically clear cell ovarian cancer. My disclosures are listed in the slide above. We understand that clear cell ovarian carcinoma represents an unmet medical need. Earlier today in the presidential session, Annie Ellis, who's an ovarian cancer advocate, says, I'm tired of hearing about prognostic markers. Cancer is bad and people die. And I told her I put this comment in my slide today because it resonated with me, and it speaks to the fact that we have to continue to drive the science and move forward with respect to therapeutic and effective interventions. Clear cell histologies are unique histologies. We have gone from disease homogeneity to molecular granularity and understand that the mutations that drive epithelial ovarian cancers are not identical. We understand that ARID1A, PIK3CA, P10, CTNNB1, and PPP2R1 mutations are more common in clear cell histologies, yet despite that, historically, we've lumped them together. In GOG218, only 3% of patients had clear cell histology. In the Aurelia trial, which is our standard of care in the platinum-resistant population, 2% of patients had clear cell histology. So for us to make the assumption that these treatment modalities are effective for these patients is naive. We've already heard that this is an uncommon histology, although accrual was feasible. Younger patients are diagnosed. It's an endometriosis-associated ovarian cancer, and clearly effective treatments are needed because chemotherapy response and retreatment is less than 10%. Antiangiogenic therapies has been examined in ovarian clear cell carcinomas. In GOG254, single-agent sunitinib was explored. It's a VEGF and PGF inhibitor. The objective response rate was 6.7%, and the median progression-free survival was 2.7 months, and if you look at that Kaplan-Meier curve, you see that almost everyone dropped off at first assessment. In the NGOT-OV36 randomized clinical trial, really the first randomized trial for clear cell patients, looked at nintetinib in chemotherapy, and the median progression-free survival was disappointingly 2.3 months versus one month. Median overall survival, nine months versus four months, and if you look at the overall response rates, zero to 2%. Now importantly, the rationale for immunotherapy has emerged over the last several years. This has already been reviewed by Dr. Guillen in her presentation. We know that in the clear cell microenvironment, we tend to see immune-suppressive signatures, increase of immune inhibitors, increased LAG-3, increased TIM-3, increased PD-1 expression, but we also understand that there may be DMMR patients within an ovarian clear cell population cohort. And we know from the Hamanishi trial that there was a clear cell patient out of complete response, and more recently, there was a publication reviewing ovarian clear cell carcinoma patients treated with immune checkpoint inhibitors out of Memorial Sloan-Kettering, showing five patients that had a dramatic response lasting greater than a year. Interestingly, none of these were DMMR patients. One had a biallelic BRCA1 mutation, three had ARID1A mutations, and two had ERBB2 amplifications. So we have a lot to learn about the biomarkers that are predictive of response to immunotherapy across our diseases. And we also know that signals have existed in alternate clinical trials, although I will caution you that some of these are very small numbers. Yet repeatedly, in each of these clinical trials that were conducted, if we pull out the clear cell histology, we see a suggestion of an improvement in response to immunotherapy driving and motivating our exploration of this treatment strategy. And it goes beyond these studies. We know for the LIOS study of lucitinib and nevo, that clear cell carcinomas of the ovary appeared to respond better than alternate histologies. And we also know for the cabozantinib and nevo trials, we have analogous indications. But importantly, within these cohorts, what is the molecular characterization of these responders? We deserve to know. These patients were accrued. We have samples. And it would be informative to sequence these. And the PCOG and the ANOVA results recently presented at ESMO in Paris in 2022. We studied pembrolizumab for advanced stage clear cell gynecologic malignancies. These were mixed clear cell, including 41 ovarian clear cell carcinomas. The median PFS in the total population was 12 months, and the ORR was 25 percent. But it was unclear to us which of these were endometrioid ovary, excuse me, ovarian clear cell, and which of these were endometrioid, endometrial clear cell carcinomas, and what were the biomarkers. In the ANOVA phase three trial, sunlitinib and bevacizumab, 26 patients, this was preliminary results with an ORR of 38.5 percent and a median duration of 12 months. But there are several unanswered questions. Molecular characterization, are these confirmed responses, whether they're central pathology review, and what is unique amongst these responders? For the sake of time, I will pass over the MOCA trial, which again was a dervilumab study showing an ORR of 10.7 percent. And now we will transition to the pembrolizumab epicatastatile of Dr. Gheons. Again, you understand the rationale of combining an IDO inhibitor with pembrolizumab in this patient population. I want to highlight and congratulate the authors. 2.3 patients accrued per month. The line of accrual was almost straight up in the graph that was showed, and that really highlights the fact that these rare histologies, we can effectively do clinical trials. We can accrue, and potentially via cooperative groups, we can achieve satisfactory accrual in a rapid amount of time. The ORR was 21 percent and the median duration of response, 6.9 months. But I will ask, is this the right combination? We don't know. Interestingly, when you combined IDO with anti-CTLA-4, there was suggestion of efficacy, but there was significant immune-related toxicity. So do we need to think about dosing? Do we need to look at novel combinations? What do we know about the patients who responded who were not DMMR? The confirmed responses, biopsies that were done on trial to help define the patients in which we had effective treatment approaches. And we need to define and better identify patients who are going to respond to either single-agent immune checkpoint inhibition or combinatorial approaches. What are the implications of ARID1A mutations in these patients? And most importantly, not only prognostic biomarkers, but we need to identify biomarkers that predict response. In the paper that was presented by Dr. Gord Hondas et al., we looked at molecular subgroups in ovarian clear cell carcinoma patients, over 100 patients. I applaud them in the context of a large sample size such as this with a rare histology. Over a percent of these were MSI high and 1% pole E, suggesting that we need to make sure we don't miss these patients and we identify them in our clinical practice. So sequencing for these patients is critical. We identified the most frequently altered genes, and this will hopefully drive future investigation. I will just say that this was a small exploratory subgroup with respect to OS and PFS, and more needs to be learned to better define the relevance of stage, the association with endometriosis, and the relevance of the molecular biomarkers on outcome. I will end by saying that we are in an era of molecularly targeted therapy for ovarian clear cell carcinomas. Eight ARID1A and ATR targeted therapies are emerging. We know that ARID1A NGS does not correlate with IHC expression. We're looking at novel IO combinations, and I understand in the context of time we can't review all the active trials. Again, I would like to thank the authors for sharing their important data, and I look forward to questions from the audience. Thank you. Thank you very much. That was brilliant. Are there any questions? If not, then I think we should proceed, otherwise we are running really late. Thank you, Dr Gihyen and Dr Kodandas and Skanda. The final abstract presentation is from Dr Irene Luong. Thank you for staying late until the very end and thank you for the amazing conference and for the opportunity to speak at this conference. I'm speaking on behalf of the COVID Search Cancer Gynaecological Cancer Collaborators on COVID Search on the impact of COVID-19 pandemic on gynaecological cancer surgery. I've got nothing to disclose. COVID Search is a platform study across different specialty looking at specifically surgical patients and services during the first wave of the COVID-19 pandemic. I'm pleased to tell you that the collaborative work has been published in American Journal of Obstetrics and Gynaecology recently and can be reached by the QR code here. And I would also like to thank all the collaborators across 227 centres in 55 countries. And I also want to take a moment to think about the patients and their families who experienced cancer and COVID at the same time in the past few years. And I would like to thank the British Gynaecological Cancer Society for the funding of this study. So this is an international multi-centre prospective observational cohort study. We identify adult patients who were meant to have curative or life-prolonging operation for their gynaecological cancers and other cancers in other subgroups during this time. The primary outcome were COVID-related pulmonary complication. And secondary outcome is more to 30-day mortality. In our gynaecology cohort, we focus on the change in care as well. And that was designed prospectively, and we add an additional question in order to answer the summary data we are presenting today. There are numerous papers and output from this collaboration. One of the key one is COVID-free surgical pathway was associated with lower pulmonary complication that was published at the beginning of the pandemic. More recently, we also confirmed that lockdown is not without cost. The more stringent the lockdown, the more likely the planned cancer operation would be cancelled. And that has impact on services worldwide, and we know that that's linked particularly in low and middle income countries. So today I'm going to specifically look at the data from our gynaecological cancer cohort. Just under 4,000 patients were recruited during the first wave of the COVID-19 pandemic. I want to highlight that one in 20 of these patients were from Middle East and Africa, an area that normally have very limited research infrastructures. When we look at income groups, one in four patients were from the low and middle income countries, and that reflective of the fact that we have got a relatively high cervical cancer rates in our cohort, but the commonest cancer type was uterine cancer. Compared to the other solid cancers, we have actually had a lower COVID-19 infection rate even during the first wave of the pandemic, one in 200, that was associated with poor performance status. More likely those patients had bowel surgery, longer stay in hospital, and more likely they have other complications. And roughly one in five who had COVID after their planned operation during the first wave of the pandemic would die from within 30 days of their operation. The headline of our study is really about one in five patients experienced changes in their management during the first wave of the pandemic, and there were no significant difference between different cancer subtype. So what were the changes? One in 13 end up not having the planned operation, which were meant to be curative and life prolonging. For those who had an operation, one in 10 had delayed in their operation or being operated on in a different hospital. Roughly one in 40 would have a change in operation choice compared to what they would have had before the pandemic. Another thing is delay. It's probably echoed with many of you sitting here. One in nine patients had to wait more than eight weeks for an operation, and that increased to one in six for those who had ovarian cancer during the COVID-19 pandemic. I just want to reiterate, this is a group of patients that specifically is meant to have curative and life prolonging surgery. They were meant to live. There's a higher proportion of patients who had earlier diseases, but even then, one in 10 had neoadjuvant chemotherapy during the first wave of the pandemic. And when they experienced the delay, even with early ovarian cancer, one in four would have neoadjuvant chemotherapy. We have roughly half of the patients who had advanced ovarian cancer. In this group, neoadjuvant chemotherapy rate was 36% overall, and that increased to over 18 in 10 for those who had experienced a delay. But does it matter waiting for a little bit longer? So we think it does. In those patients who were not operated on, about one in 40, unfortunately, died within three months of the decision to operate by their tumor board or by their clinical team. For those who didn't have an operation, who had a delay in the operation, about 22% would experience a first outcome, and that's a significant increase compared to those who didn't experience a delay. And that included, when you open up, unable to resect the disease, disease progression, emergency surgery, or death. So obviously, we didn't design this to design well, what causes these at first event, but in low and middle income country, those who had more advanced cancer, and in areas where there was a full lockdown that was associated with more likelihood of not having an operation or a significant delay in operation, which is consistent with the previous in other solid tumor subtype. So in summary, this is the largest completed international multi-center study for gynecological cancer surgery completed during the COVID-19 pandemic. One in four patients were recruited from the low and middle income countries. Reassuringly, even during that time, the perioperative COVID-19 infection rate was low. And just to summarize, one in five people had a change in care plan. One in 13 did not end up having an operation, despite it's meant to be curative or life-prolonging. One in nine had to wait for more than eight weeks for their operation, and that was linked with poorer outcomes. But I think the positive note is that actually, now we have a great network of collaborators in areas that may not have been exposed to research before to do a collaborative study like this. And our upcoming new collaborative work based on this model using the same network, using the same data management system to look at outcome of secondary debunking surgery in patient with positive AGO score after exposure to PARP inhibitors. And I'm sure you guys will all hear more about that in the near future. Again, I would like to thank everyone, many of you involved here in contributing to this study during a time that is so challenging for everyone, for both patients and health professionals. Thank you very much for listening. Thank you, Dr. Luan. And now for the final distillation of IGCS 2022 from Dr. Kevin Holcomb. Good afternoon. Thank you to the program committee for this opportunity to offer this distillation of a very important study. And here are my disclosures. I think it's quite fitting that this final presentation is related to, and I think in a great example of the importance of international research collaborations, particularly at a time of such an adverse event as a public health emergency like COVID-19. And I'd like to congratulate Dr. Luan and her colleagues for being able to pull this off. And I'm particularly impressed when I think back to the environment in which this was done. If you go back January 3rd of 2020 is when China first informed the WHO that there were 40 cases of a pneumonia of unknown etiology happening in Wuhan. Almost a month later, the entire country was impacted with COVID-19. The first case is being reported in the U.S. by January 20th. A month after that, the epicenter has moved to Europe and Italy is locking down. And by March 11th, you have the WHO declaring COVID-19 a global pandemic. At that point, there were already over 4,200 deaths. And if you look at the timeframe of when this study was done, the start date was the first confirmed case of COVID-19 in each of the participating sites. They followed the surgical patients for 30 days and the nonsurgical patients for 90 days. And so with a data lock date of August 31st, 2020, this study was conceived and conducted during a time of no vaccines, no effective therapeutics, and largely overwhelmed healthcare systems in the countries that were participating. But we didn't know a lot about COVID-19, but we did know a few things. And I think it informed the study design. One of the things that we knew was that nosocomial COVID-19 infections were occurring. By this point in 2020, there were numerous reports of this happening in various settings. There was a report of 28 healthcare providers, 13 patients, and seven visitors that were infected in a pediatric dialysis center in Munster, Germany. There were cases being reported, 196 nosocomial infections out of 1,500 patients from 11 hospitals in the UK and Italy. And that bottom citation was from Wuhan, where there were 57 people who were infected through hospital-associated transmission among 138 hospitalized patients. And so the concern that healthcare settings could be sites of spread of COVID-19 were well-founded. There was also emerging data that cancer patients with COVID-19 do worse. This data is from nine hospitals in the Wuhan district that were designated to take care of COVID-19 patients. And you can see under the COVID-19 patients who did not have cancer, about 12% had severe disease and the death rate was about 2 to 10%. Among the patients that had cancer in COVID-19, the severe status was about 64% and the death rate up to 20%. One of the things we learned early, unfortunately, here in New York City is that there were great healthcare disparities associated with this pandemic. When the earliest data on fatalities that were stratified by race and ethnicity came out in New York City, it became very obvious that the brunt of this pandemic was being borne by Hispanic and African-American New Yorkers who had much higher rates of fatalities. And although these are ethnic and racial disparities, the underpinnings were really socioeconomic. It was multi-generational living, overcrowded housing, people whose jobs did not allow them to work remotely and often put them at risk. And so any study looking at a COVID-19 experience would have to have diversity in the socioeconomic status. Also, we know that treatment delays lead to worse outcomes. This is a study from 2020. It's a meta-analysis including 34 studies from 17 tumor sites. And it shows the impact of delaying either surgery or adjuvant therapy in a number of solid tumors. And you can see in bladder, breast, colon, head and neck, non-small cell lung cancer, that for every four-week delay in treatment, you see a worsened outcome. And these authors, they estimated in a population of 1,000 theoretical breast cancer patients. If you assume a 12% mortality, every four-week delay in treatment would lead to an additional 10 women dying. A additional 12-week delay would lead to 31 extra deaths from breast cancer. And so we were in a time period where there's a concern about infection in healthcare delivery sites and yet there's a concern about delaying healthcare. And so some of the earliest advice we were given was to use some sort of stratification where we focus on high-priority patients. And these are people with curative potential who have and sometimes rapidly growing tumors and that we lower priority for those receiving adjuvant therapy or just purely palliative. And so Dr. Lung's study is looking at that priority A group. These are people with curative potential. And I think that's important to keep in mind. This was a large prospect of truly international study. It had over 4,000 patients from 227 centers, 52 countries, seven world regions. Only 5% of these participants were from Africa or the Middle East, but there was really good socioeconomic diversity with 27% of patients coming from lower middle-income countries. The primary endpoint was 30-day COVID-19 infection following elective cancer with the secondary endpoints being 30-day mortality and interestingly the impact of resource constraints on patient treatment. There's a lot of good news I think in this study. One is that despite all the concern of healthcare hospitals being sites of COVID spread, that is not what was seen in this study. The COVID-19 infection rate was only 0.6%. Interestingly it was much lower for GYN patients than for other solid tumors in the study. I think that remains unexplained. There was a low 30-day mortality in operated patients, less than a percent. A low 30-day mortality even in non-operated patients, which is 2.7%. And also if you looked at mortality in patients who had a delay in surgery for more than eight weeks there was no difference. It was 0.8 versus 0.9% which was reassuring. The bad news is that the pandemic was extremely disruptive. As Dr. Lung pointed out, one in five had treatment changes compared to pre-pandemic. One in 13 didn't have an operation. One in nine waited more than eight weeks for surgery. It was even worse for the ovarian cancer patients. And although there was no difference in mortality using a composite negative outcome that looked at unrespectable disease, progression, emergency surgery or death, you saw a 24% increase in these negative outcomes because of the pandemic. And for that few patients that did get COVID-19, they had longer hospital stays, higher morbidity and mortality. And this sort of mirrors what we saw in New York City. Our group at Weill Cornell looked at the same time period, similar time period between March and April 2020 at three affiliated hospitals here in New York City, one in Manhattan, Brooklyn and Queens. And we saw about 40% of our patients experienced a COVID-19 related treatment modification, whether it was surgery, radiation or systemic therapy. Interesting difference is that we saw higher rates of impacted treatment in areas with higher incidence of COVID-19, whereas as Dr. Lung pointed out, in some of their areas with the biggest delays in treatment, they actually had low disease burden. And I suspect it was the lockdowns that was leading to the delay. So what did we learn? Good news, steps taken to prevent nosocomial COVID-19 infection works in participating hospitals in this study. Surgical morbidity was similar to that seen before the pandemic. Treatment delays resulted in more unrespectable disease, disease progression and emergency surgery. And so in future healthcare emergencies, which unfortunately I believe there will be, we have to really surge resources to the women requiring the most complex surgery to avoid delays in those planned procedures. Again, I'd like to congratulate Dr. Lung and her colleagues for this important work. Thank you, Dr. Lung and Dr. Holcomb. I think it's a very symbolic, Brian's selection, this abstract is the last abstract of a meeting. Well, this concludes the IGCS 2022 Annual Global Meeting here in beautiful New York City. And thank you to everyone who presented today, this session and the audiences. We wish you a safe trip back home and we will see you all next year in Seoul. Thank you.

Dr. Irene Luong

IGCS 2022 Annual Global Meeting

COVID-19 pandemic

gynecological cancer surgery

impact

study

patients

55 countries

first wave

COVID-related pulmonary complications

30-day mortality

changes in management

operation

delay in treatment