Hello, everyone. Welcome to Plenary 5. My name is Ruthie Solani, and I will be moderating this plenary session alongside with Dr. Keta LaRusso, and we are so happy that you've joined us here today. Today, we have four abstract presentations and two distillations. Let's get started. And to avoid delays and lengthy introductions, I'll turn the screen to Dr. Emily Thompson to present her abstract. Dr. Thompson, if you'll please turn on your camera and please go ahead and start. Thank you for that lovely introduction. I'm delighted to speak to our work today, elaborating the clinical significance of in situ margin status for molecular high-risk vulvar squamous cell carcinoma. I have nothing to disclose. So we've been acculturated to the idea that morphology and margin status are integral to risk prediction in cancer excision specimens. Increasingly, pathologists and clinicians alike are stepping into a new and exciting paradigm, which emphasizes the role of molecular features that predict tumor biology. This Venn diagram depicts the intersection of these and will be used as a framework to orient us to past and present research that's relevant to the study. As we heard earlier today in the vulvar master session, vulvar squamous cell carcinomas and their precursor lesions can be stratified using immunohistochemistry or p16 and p53. These stratify vulvar squamous lesions into three clinically significant etiologic subtypes. These are HPV-associated, HPV-independent, and within the HPV-independent subset, we see segregation between p53 abnormal and p53 wild-type cancers. This stratification is clinically significant and our colleagues in Leiden have recently demonstrated worse outcomes for those with HPV-independent p53 abnormal disease, and this has been demonstrated in several cohorts as well. The WHO has integrated etiologic subclassification into its recently updated classification of female genital tumors. For both non-invasive and invasive vulvar squamous neoplasia, pathologists are now tasked with classifying lesions by HPV status. Updated ICCR guidelines recommend that for HPV-independent vulvar squamous cell carcinomas, the presence of in situ lesions at surgical margin be reported. It is suggested that p53 IHC staining may be of value in assessing margin involvement in these cancers, but this is not a requirement, it's just recommended at this stage. Non-invasive HPV-independent vulvar squamous neoplasias are amongst the most challenging lesions encountered by anatomical pathologists. In 2000, Yang and Hart, in this seminal paper, first described the morphologic features in this most often encountered HPV-independent lesion, that is, differentiated intraepithelial vulvar, sorry, differentiated interepithelial, vulvar intraepithelial neoplasia. Here, they emphasize the importance of basal atypia seen on the top right hand side, together with other features such as elongation and fusion of reti ridges, thickening and hyperkeratosis of the squamous epithelium. Yang and Hart also recognized that overexpression of p53 was frequently encountered in deep in. Switching gears, we've known for some time that global trends towards less radical surgery have come at a cost in terms of recurrence risk. McAlpine and colleagues in 2017 demonstrated clinical significance of etiologic subtype and findings hinted at the impact of extent of resection in this retrospective cohort. This KM plot depicts disease-specific recurrence. The blue lines depict HPV-associated recurrences, whereas red lines depict HPV-independent cancers, the majority of which are p53 mutated. Solid lines indicate cases treated before 1995, an era in which radical resection was offered as standard of care and adjuvant radiation was infrequently used. Hashed lines depict cases treated after 1995, an era characterized by more conservative surgical excisions and increased use of adjuvant radiation. Here we see significant divergence in cancers treated after 1995, and those with HPV-independent disease, the majority of which are p53 mutated, experience significantly worse outcomes. And so that brings us to the current study. We hypothesized that the presence of a p53 mutated in situ lesion at surgical margins may account for increased risk of recurrence in those with organ-confined disease. Our objective in this study was to assess the clinical significance of in situ margin status in patients with HPV-independent p53 mutated vulvar squamous cell carcinomas confined to the vulva. We also sought to define the clinical significance of morphologic D-VIN versus lesions with abnormal p53 staining, but insufficient morphologic features to justify a D-VIN diagnosis. We restricted our cohorts to patients with, our cohort to patients with organ-confined primary vulvar squamous cell carcinoma. Only those with HPV p53 abnormal disease were included. Only cases that were reportedly clear of invasive disease at margins were included, but we allowed for those reported with D-VIN at margins, and margins were evaluated with p53 IHC. 57 cases were identified within our institutional archive, and among these, 16 had D-VIN present on the margin. 11 cases had abnormal p53 IHC staining at a margin without sufficient morphologic features to justify a D-VIN diagnosis, and 30 cases were margin negative when evaluated by p53 IHC. So these, here we have examples of these immunohistochemically positive but morphologically subtle lesions. You can see that there's a distinct lack of basal atypia. We don't see acanthosis or thickening of the squamous epithelium, and only, barely do we see elongation or fusion of the reti ridges. All of these show basal abnormal overexpression of p53 IHC status, sorry, p53 IHC, and as I said, we had 11 such cases identified in our cohort, representing 19.3% of the total cohort, so one-fifth of these patients had a morphologically occult lesion at margin. No significant differences were observed across the three subsets of patients with respective duration, follow-up age at first presentation, or tumor size, but we did observe a significant difference in recurrence rate when stratified by margin status. Indeed, this is our most significant finding, that in situ margin positive status, whether it was morphologic or molecular, significantly associated with recurrence, and this is what that looked like. In this far graph, in situ margin positive status, be it morphologic debin or abnormal p53 staining, without morphologic features of debin, is depicted in dark gray, and we can see here where the impact of these recurrences was seen. Yeah, isolated in situ recurrences were observed in similar proportions in both groups, whereas margin positive primary excisions in those, we saw twice the number of local invasive recurrences, and we saw three times the proportion of recurrences in the nodal or advanced disease, with a trend towards clinical significance in this small retrospective cohort. In terms of delineating risk associated with morphologic debin compared to morphologically occult p53 abnormal lesions, we see segregation, which is significance for recurrence free time, but statistical significance was not maintained in overall survival. It's not surprising given small number of cases we evaluated. In summary, in situ margin involvement by HPV-independent p53 abnormal, in HPV-independent p53 abnormal vulvar squamous carcinoma associates with recurrence. P53-IHC is critical for accurate assessment of margin status, and that we see therefore is a need to evaluate biologically informed treatment approaches in prospective interventional studies. Such a study is currently planned, STRIVE, which stands for stratification of vulvar squamous cell carcinoma by HPV and p53 status to guide excision. In this multi-center randomized controlled trial, we'll stratify those with organ-confined disease by HPV and p53 status to direct care, including extent of surgery, use of adjuvant radiotherapy, and frequency of surveillance. Participating sites include gynecologic oncology units in British Columbia, Australia, New Zealand, and the UK. If any of you are interested in learning more, I encourage you to contact Drs. Jessica McAlpine and Lois Eva from the Hanscom Group. I'd now like to thank my colleagues and collaborators. If there's time at the end, I'd be delighted to take your questions. Thank you. Thank you, Dr. Thompson. You know, there is a chat feature, and we have about 30 seconds. I'm wondering, Dr. Thompson, if you could answer a quick question. Do you have any data about molecular non-squamous cell vulvar tumors? This research was restricted to vulvar squamous neoplasia, and so that was the focus of our work here. Non-squamous cancer seen in the vulva include both mesenchymal and epithelial tumors, but yeah, that wasn't the focus of our research here. Maybe a future collaborative project. Well, thank you and congratulations on your work. Next up, we have Dr. Ting Wang. Dr. Thompson, if you could stop sharing. And Dr. Ting Wang, if you could put on your welcome. Great, great. If you'll share your screen, we'll let you get started. Okay, dear chairman, ladies and gentlemen, good evening. I'm Dr. Wang. Dr. Wang, I'm sorry to interrupt you. We cannot see your screen. Oh, sorry. Is it okay now? Not yet. Not yet. Sorry. Is it okay now? Oh, sorry, sorry. Perfect. Okay now? Yes. Thank you. Okay, thank you. Okay. Dear chairman, ladies and gentlemen, good evening. I'm Dr. Wang Ting from Sun Yat-sen University Cancer Center of China. It's an honor to show you our research in this way. The topic of our research is multi-omics characterization of molecular features related to perineural invasion in cervical cancer. The instructor of this research is Professor Liu Jihong. There are nothing to disclose. Cervical cancer is the fourth most common cancer in women. It remains a serious health problem in developing countries. In China, it represents approximately 18% of the global cervical cancer deaths. Perineural invasion is a newly identified risk factor for recurrence of cervical cancer. It was defined as cancer cells infiltrate in the layer of nerve fibers, including epineurium, perineurium, and endoneurium, also running over one-third of the outer diameter of nerves. Perineural invasion, PNI, has been detected in 7 to 45% of the patients with cervical cancer. The incidence rate of PNI in our center is around 9%. Both the previous study and our published data has demonstrated that PNI is associated with a poor prognosis of cervical cancer. At present, in some other malignants, such as colorectal cancer and head and neck sperm cell carcinoma, PNI is an indication for postoperative adrenal therapy, but there's no relevant recommendation in cervical cancer. Moreover, there's enough bearing radical hysterectomy, NSIH, for cervical cancer. PNI may be a relative contraindication for NSIH. A study in 2019 found that patients with positive PNI receiving NSIH has a tendency to worse survival when comparing to those patients who are receiving traditional radical hysterectomy. All of the statistical differences were knowledge because of the simple science. So, it would be useful if we could identify those patients who are prone to appear PNI before the surgery. In our series study, we have explored PNI prediction model with traditional pathology features, but it's not satisfactory enough. Further, we want to identify the underlying molecular determinants of PNI. So, we carry out this study. DNA and RNA samples from cervical cancer patients were applicated from the Sun Yat-sen University Cancer Center from July 2016 to December 2018. Finally, 20 PNI positive patients and 22 PNI negative patients samples were obtained for the whole exome sequence, the whole genome sequence, and RNA sequence. Based on the multi-omics sequencing resulting in a public database information, the underlying molecular features of PNI patients were analyzed from the multi-dimensions. So, here are the results. First, we analyzed whether there were differences in mutation pattern between the two groups. We found that the most common mutation pattern is missing mutation. The most frequently mutated gene were PIK3CA, KMT2C, FBXW7, and so on. These findings were very consistent with the result reported in the literature and the COSMIC database. However, the mutation of PIK3CA and KMT2C were not statistically different between the two groups. The mutation rate of FBXW7 was significantly higher in the PNI group, which was 30%, but it was only 4.5% in a non-PNI group. FBXW7 is considered to be a classical tumor suppressor gene. The mutation rate can lead to tumor proliferation and invasion. In terms of the copy number validation, PNI tumor have a significantly more copy number gain of NKX21 and PDGFIA. In previous study, the NKX21 gene was found to be associated with the migration of neural cells, and the PDGFIA was found to be associated with tumor angiogenesis. Next, we analyzed differentially expressed genes. We identified 318 genes significantly in the PNI group, comparing to non-PNI group. The upregulated tumor number is 118, while the downregulation is 200. And the downregulation includes two tumor suppressor genes, SOX17 and PDCH1. The downregulation of SOX17 gene expression can activate the WNT signaling pathway, leading to the development and progressing of malignant tumors. And the PDCH1 gene was found to be related to the EMT pathway, which can promote tumor cell metastasis. In addition, we found tumor immunosuppressive environment may be a contributing factor for PNI. PNI tumor shows significantly lower tumor mutation burden than non-PNI, and fewer CTA-positive cells in the tumor microenvironment, but there's no significant difference in the micro-satellite suitability. So, here comes the conclusion and discussion. First, in the journal analysis, lost function mutation in FBXW7 was found in PI-positive patient. In the literature, FBXW7 mutation could promote self-proliferation, migration, and invasion in cervical cancer cells. Copy number gain of NKX21 and PDGFIA was found. It has been reported that the ESACS NKX21 axis can regulate the FOXM1 gene and lead to tumor progression and poor outcome in HPV-positive patients. In the transcription analysis, downregulation of SOX17 and PDCH1 was found. Downregulation of SOX17 expression by promoter methylation can result in activation of the VIN signaling pathway. And the PDCH1 gene was also found to be related to the EMT pathway. These pathways can help to promote the invasion and metastasis of cancer cells. Finally, a tumor immunosuppressive environment can contribute to the development of TNR. Thank you so much. Thank you for your attention. Thank you, Dr. Yuan. Excellent work. And both these highlight the changing molecular profile for these tumors. I'm really excited to announce that we'll now hear from Dr. Kathleen Moore, presenting a distillation on these first two abstracts. Dr. Moore, you'll turn on your camera, and I will turn the screen over to you. Dr. Yuan, if you could please stop sharing. Yeah, okay. Thank you. Thank you. There we go. Well, it's my great pleasure to have been asked to distill these two very interesting abstracts for this IGCS meeting. And I have only seven minutes to do so. So I'm going to get started. These are my disclosures. And so both of these abstracts are, you know, they're very different in different disease types, but they really are trying to ask the question about individualization of surgical care, potentially adjuvant care for women with relatively rare tumors. And so this idea of individualization of surgery, or really even de-escalation of radicality of surgery is actually not new. We've been working on this across disease sites, you know, since Halstead. And so the best example of this comes from breast cancer. And this is a beautiful review article for those who are interested, which kind of goes through the history of where we started and where we are today in terms of individualization of surgical care for women with breast cancer, to a point that we're even considering not operating on women who get neoadjuvant therapy for their breast cancer based on a circulating tumor. Not there yet, but that's where we're going. So complete de-escalation of radicality individualized to the patient. Now, are we there yet in some of the gynecologic cancers? Well, sort of, you know, we can look at vulvar cancer and we've absolutely seen that same individualization of surgical care. This doesn't even include radiation across time for vulvar cancer from the big butterfly incisions that were started in the forties to today. And congratulations to Brian Somovitz who just got the groin study open through NRG, another example of trying to individualize the adjuvant therapy and the surgical management for women with vulvar cancer and really trying to decrease mortality and decrease morbidity more correctly. But that comes with a cost. And the cost is, and we all know this, potentially some failures, failures in the groin with sentinel nodes, local failures because of less radical surgeries. And what do these positive margins mean? And there's lots of literature on that. And so Thompson et al asks an interesting question. I actually had to learn about DVEN quite a bit, looking at these HPV independent vulvar cancers, and really asking the question, does margin status matter and how to best assess margin status? And should it increase the radicality potentially of how we take care of this rare subset of women? And so this idea of DVEN, differentiated VIN, again, isn't new. There's a lot of literature out there on it. But what you can see here is kind of looking at a registry from the Netherlands where they had 1,100 patients who came in with either with H-cell or DVEN. And you can see the breakdown. DVEN is pretty rare. So this is a rare subtype of high-grade vulvar intrapathial neoplasia. The median age differs. These are found in older women. You find concurrent squamous cell cancers much more commonly when the precursor, or what you're going to the OR with, is DVEN, 62% versus 21%. You find incident cancer, and that's the figure here on the right. You can see in the middle that if you have a precursor lesion that's DVEN, your likelihood of developing a cancer over time is 60%. And the kind of risk factors on multivariate analysis for developing vulvar squamous cell carcinoma on this analysis really comes down to the type of vulvar intrapathial neoplasia. Is it just H-cell, HPV-related, or this DVEN age? And then the presence of lichen sclerosis, which is also associated with DVEN, this sort of chronic inflammatory condition. And so the aggressive nature of DVEN might be explained by a relatively short intraepithelial phase before progression to invasive carcinoma. And that's really what's supported, again, in this trial, by the finding that the interval to vulvar carcinoma was only one and a half years if you had a precursor of DVEN versus four years for H-cell of other indications. And you had a much higher number of patients with DVEN with concurrent cancer as well. So this is a much more aggressive lesion. So this idea of this TP53 mutation association with DVEN is relatively recent, not brand new, but relatively recent. And so this is a paper that was actually cited in the presentation that among HPV-independent cases, TP53 was present in almost all of the cases that had a precursor of DVEN. And so that's what you can see here in the red box in the middle column are those patients with an in situ lesion. And I've circled the ones that are DVEN. They're in the black and gray boxes. And then what you can see on the right-hand side of the column are the subsequent invasive tumors and TP53 mutations are in green. And so you see this quite striking association between DVEN and having these TP53 signatures. And further, this does seem to correlate with outcomes. And I think you can see this here, although it's a little bit blurry and I apologize. On the top, it's TP53 mutated versus non, overall survival. And you can see the subsequent, the difference in patients in red that have a TP53 mutation, much poor overall survival. In the bottom is progression-free survival where you don't see as much a difference but you do see it really separated out in overall survival. So this is pretty striking. So you have this whole range of morphologies and this is just a figure again from that same paper that's kind of hard. That's what I learned from this talk. It's actually hard for pathologists to diagnose DVEN. And so you may miss this lesion. And the importance of that is not really well-known yet. We don't really know the full prognostic significance of this finding. We don't know whether or not this sort of TP53 mutation represents a field effect that's related to that chronic inflammation that you see with lichen sclerosis. You see this in the field effect in colorectal cancer. We haven't proven it here yet, but it's an idea. And so the best current utility of this TP53 signature maybe is a molecular adjunct to the difficult morphologic identification of DVEN. So if you have an HPV independent lesion, if you have this TP53 mutational pattern, it kind of helps you make the diagnosis of DVEN if it's not otherwise known. And this is a figure from the presentation. Now, when I got the slides, it didn't say I couldn't copy, so I do apologize because I copied it. But you can see here, these are three different pathologies that may be difficult to identify as DVEN, but they all stain for this TP53 at the margin and identify it as such. But the question now is, so what? So in the presentation, we saw that this positive in situ margin for P53 was significantly associated with disease recurrence. 67% versus 30%. But what do we do now with the data? Do you re-resect all the positive margins for this kind of premalignant condition? That's certainly not what we do now, but should we? Or do you just wait and watch and re-resect at the time of recurrence? Should all patients with HPV independent squamous cell carcinoma undergo a more radical primary excision? Should we be striving for bigger margins knowing this is a possibility? And even going back to the premalignant lesions, you know someone has an HPV independent VIN, should you be doing a bigger wide local? These are the questions, and some of this will be answered by the STRIVE study that was described here, which I think is fantastic. This is sort of the thing we need to do to really validate these very interesting pathologic findings, and I really look forward to hearing the results of this in the coming years. Now, the second article is kind of another variation on this theme of de-escalation of radicality. Here's the similar slide I made for cervical cancer. We've certainly come a long way in terms of decreasing radicality of cervical cancer, not quite to minimally invasive surgery yet, that's still ongoing and beyond the scope of this talk, but sentinel nodes, less radical surgeries, nerve sparing surgeries, that's most germane to this talk. So Dr. Wan et al are suggesting that this perineural invasion, if identified, may be a marker for actual re-escalation of surgical radicality in cervical cancer, and maybe not doing these nerve-sparing surgeries. So perineural invasion in cervical cancer isn't new. There's lots of data on this, and it's kind of all over the map. You have the incidence here on the left. It's, as he points out, up to 35%, but really the prognostic relevance is all over the map. Some of the studies find no prognostic relevance. Two of the studies on multivariate analysis do find prognostic negative relevance. And so what's the truth here? We do know that perineural invasion is significantly correlated with deep cervical invasion, LVSI, large tumor size, et cetera, positive resection margins. So a number of things that portend a poorer outcome. And further, PNI is also associated with the sort of grade of tumor cell dissociation, strong peritumoral desmoplastic stromal reaction, and reduced peritumoral inflammation, which is consistent with what Dr. Wan and his colleagues were looking at trying to find out mechanistically what's going on in these tumors. And they do find, as demonstrated on the left, this immunosuppressed environment in PNI tumors. And then also, interestingly, identifying this FBXW7 loss of function mutation as more commonly found in PNI tumors. And as we, just to remind you, FBXW7 is a tumor suppressor gene that's really nodal. It acts through all the oncogenes that we know, C-mix, cyclin E, Notch, mTOR, June, and it can have oncogenic properties in and of itself. It's not yet targetable, but this may be something important that we look at in the future. And so the question from his- Dr. Moore, we're over time, so if you could just wrap up, that would be great. Okay, the present, sorry, I thought I was on time. So the presence of PNI at this point probably should not be used to alter surgical therapy, especially making a decision between nerve sparing and not, and really kind of figure out how much of the poor outcome is related to other associated factors may give us more information on how to individualize therapy for patients with cervical cancer. And with that, I thank you for your attention. Thank you, Kathleen, for this excellent, excellent distillation. Thank you so much. We will move forward to the next presentation, which is Dr. Bradley Monk. Please, Brad, the stage is yours. Greetings and welcome. My name is Brad Monk from Phoenix, Arizona. On behalf of NGOT and the GOG, it's my privilege to present these data. I recognize my coauthors here on this slide and all the collaborators and investigators and patients that contributed to this successful scientific observation. I wish we were together, but I'm glad that we can still share this information. So Tizotamab-Vdotin plus Bevacizumab or Pembrolizumab or Carboplatin in recurrent metastatic cervical cancer, this is a phase 1B study, trying to look at dose-limiting toxicity and to come up with a recommended phase 2 dose. These are my disclosures, speaker consultancy fees and so on. This study was funded by GenMab and CGen. We're very grateful for their support trying to help our patients battling cervical cancer. I think we're all aware of the results of 204, which showed that platinum taxane doublets are the standard. And then the results of GOG240 that shows that Bevacizumab can be added. And that led to the first global approval of a targeted therapy in cervical cancer, but that hasn't been enough. These patients continue to recur and die and there remains a high unmet medical need. We need more effective and safer agents in this setting. Tizotamab-Vdotin, I think as many of you know, or TV as I'm gonna call it, is an investigational antibody drug conjugate that is directed to tissue factor, which is highly expressed in many solid tumors, but particularly cervical cancer and releases the tubulin inhibitor MMAE. And then it's internalized and results in cell cycle arrest and apoptotic cell death. And the direct cytotoxicity, I think, as you know, can be augmented by a bystander effect and maybe even immune related activity. So in a recent pivotal phase two trial, Rob Coleman is the first author, probably includes many of you in the audience as coauthors as well, published in the Lancet Oncology, it showed that single agent TV in a previously treated population had a 24% response rate with metastatic or recurrent cervical cancer. These responses were durable. The safety profile was acceptable. We've submitted that to the US FDA. And I think many of you are aware that the action date has been announced to be October 10th. And we remain optimistic that we'll soon have this agent in the clinic. In this study though, we evaluated the feasibility of new combinations, combining TV with other agents with non-overlapping mechanisms of action, which are known to be active in cervical cancer, trying to improve activity in a safe way. So we conducted a two-part multi-cohort, phase one B and then a phase two trial to evaluate the safety and tolerability of combining TV with other agents. And these agents are pretty obvious, right? Bevacizumab, okay? The PD-1 checkpoint inhibitor pembrolizumab, and then the DNA damaging chemotherapeutic carboplatin. And as I mentioned earlier today, I'm gonna present the dose finding part of this study, which led to the recommended phase two dose. The primary objective of the study was to determine the maximal tolerated dose, as well as to recommend a phase two dose. Of the TV combined with either Bevacizumab, pembrolizumab or carboplatin. We enrolled women 18 years old or older that had failed either a platinum taxane doublet with or without Bevacizumab, okay? Now for the Bevacizumab combination, there was the potential, because both potentially are associated with increased risk of bleeding. We used a very conservative approach with a three plus three dose escalation design. But in TV plus Pembro and TV plus Carbo, we followed a six plus six dose escalation design. And to go to the next dose, obviously you had to have a few, if any DLTs, basically one or fewer, okay? This slide shows the demographics. You can see that this represents a mix of the sorts of patients that we see in the clinic. The majority of patients had either failed first line or second line treatment for metastatic disease. At the time of the data cutoff, which was March 1st of 2021, the median duration of follow-up was 8.6 months in the TV plus Bevacizumab arm, 16 months in the TV plus Pembrolizumab arm and 12.5 for TV plus Carbo. And as you can see, the most common reason for discontinuation was disease progression. In all of the patients with TV Bev, two thirds of the patients had progression and came off studying TV plus Pembro and 73% of all the discontinuations in TV plus Carbo. The rate of discontinuation to AEs was acceptable. In fact, there were none in TV plus Bev and it was 15% for discontinuations due to AEs in the TV plus Pembro and TV plus Carbo arms. This is really the key slide. There were no instances of dose limiting toxicity in any of the cohorts based on the review of the data monitoring committee. In other words, we never got to a maximum tolerated dose. In other words, you can combine full dose TV with full dose Bevacizumab, Carboplatin or Pembrolizumab. So full dose TV is two milligrams per kilogram. And we generally use Bevacizumab at 15 milligrams per kilo every three weeks. And you can combine them at that doses. Carboplatin AUC of five, again, added to full dose TV two milligrams per kilo and then full dose Pembrolizumab 200 every three weeks. So you can use Bev 15 every three, Carbo AUC of five every three or Pembro 200 every three weeks. There were no fatal adverse events related to TV and grade three or worse adverse events related to TV. I just wanna point out was 30.1% for anemia and 15.4% thrombocytopenia when combined with Carboplatin obviously the marrow suppression and sensor neuropathy was 15.4% in the TV plus Pembro. This slide shows the adverse events of interest, specifically ocular, bleeding and peripheral neuropathy. As you can see in the purple color, most were grades one or two in the green is the grades three or worse. Although preliminary, this is some exciting data, I think for us to examine looking at tumor response. Again, the primary end point was to come up with the recommended phase two dose, but we can't really avoid looking at those patients that were treated and look for anti-tumor activity. And I think it's very exciting to see that the majority of patients had a decrease in their tumor burden from baseline. And in fact, more than half of them had a 30% or greater reduction at their respected recommended phase two dose. So five patients in the TV plus Bev arm had a confirmed objective responses that included one CR and four PRs. And in the other arms, two out of 11 in the Pembro arm and four out of 12 in the Carbo arms. And those were all partial responses. I note that only 11 of the 13 patients and the 12 in the Pembro arm. So 11 of 13 in the Pembro arm or 12 of 13 in the Carbo arm I had post baseline scans. So the maximum plan dose of TV and these combinational agents was feasible. And we developed a very conservative and safe plan to show today that the recommended phase two dose for these three doublets is full dose. And that these combinations were adequately tolerated, had an acceptable safety profile with the majority of AEs being grades one and two. Acknowledging the limited sample size, all combinations showed some promising although preliminary anti-tumor activity in this group of recurrent metastatic cervical cancer second line and beyond. I think we'd all agree these data are encouraging. We're excited for dose expansion cohorts. And as you know, this is happening and ongoing and these will be presented at an upcoming meeting. I really appreciate your attention. Most importantly, I appreciate you as investigators and colleagues, both the GOG and NGOT and I'm certainly grateful for the patients and their families. And again, without GenMab and CGen this would have never been possible. Thank you. Thank you, Brad. We agree with you. These data are very interesting. Congratulations for your study. And the next presenter will be Dr. Han. So please, the stage is yours, Dr. Han. Okay, thank you for your lovely introduction. Good afternoon, everyone. I'm Dr. Anne from GO department, National Cancer Center Cancer Hospital, Chinese Academy of Medical Science. On behalf of our research team, I'm very honored to be here to give the presentation of our study. And this is a open label, non-randomized multi-center phase one and dose expansion study to evaluate the safety and the preliminary efficacy of PD-L1 antibody, so Casolimab in recurrent or metastatic cervical cancer. About this research, I have nothing to disclose here. Cervical cancer is the first most common cancer in women worldwide. In 2018, China yearly instance of cervical cancer was 106,000 cases. Surgery or radiotherapies are the major treatments for primary cervical cancer. For patients with metastatic or recurrent cancer, the prognosis is very poor. Primary treatment is usually platinum containing chemotherapy. After the failure of the first line treatment, the objective response rate of the second line chemotherapy is even lower. We can see from the table, most of the drugs lower than 10%. Immunotherapies such as the immune checkpoint inhibitor, that is ICIS, has improved survival of several malignancies, such as lung cancer and the melanoma at all. Several trials in metastatic or recurrent cervical cancer have reported the preliminary efficacy outcomes. They all are among 10 to 20%. It seems to be a promising brand new treatment for cervical cancer. In 2080, FDA approved Papiro-Lizumab as the second-line treatment strategy for the patients with MISI-high or PD-L1 positive in recurrent and or metastatic cervical cancer. In China, studies of ICIS in gynecological cancer lack sufficient efficacy data and have not been approved as indiction. So we call for the relative clinical trials and the results. Our research drug is Socasolimab. It's a humanized antibody PD-L1 IgG1 antibody. It's screened from the largest human GMAP antibody library. It has dual mechanisms. Firstly, as PD-1, PD-L1 checkpoint inhibitor to avoid the cancer immune escape. Secondly, it's strong ADCC function to further strengthen NK cell to cure the cancer cell. In China, there are several ongoing studies of Socasolimab in different kinds of cancers, such as esophageal cancer, lung cancer, and urosteroid cancer at all. Outcomes are expected too. Our studies divided into two stages. In the dosage escalation stage, we have three escalated dosage of Socasolimab that was given every two weeks. The primary endpoint is to determine the maximum tolerated dose and the dose limited toxicity. And finally, to determine the dose for the next stage. In the next stage, that is dose expansion stage, Socasolimab was given in a fixed dose every two weeks continually until the dose progression or intolerable toxicity, whichever comes first. The primary endpoints for this stage is to determine the objective response rates. And the second endpoints to determine the PFS and the duration of response, overall survival, and also the best overall response. The correlation between the PD-L1 expression and the efficacy was also evaluated. Totally 18 investigational sites in China participate in our study. In dosage escalation stage, we have a conventional three plus three studies that design. That is with five, 10, 15 milligram per kilogram were given intravenous drip every two weeks. No PLT was observed. And the half lifetime of the drug is around a 10 to 12 days. The receptor occupancy is saturated among all doses. We have four PR and three ST cases in this stage. And finally, five milligram per kilograms was determined to be the dose for the expansion stage. Finally, expansion stage was completed. Totally 94 cases are fully evaluated, the safety and the efficacy. Most patients were younger than 60 years old or a squamous cell carcinoma type. Previous treatment were one or two lines and 60% patients has a PD-L1 CPS score more than one. And we can see the results of the efficacy. The media follow-up period for all the patients were 40.7 months. There are three cases for CR and 14 cases for PR. And ORR for all the patients was 80.1%. And ORR in PD-L1 positive group was 19.6% and 20.7% for negative group. The media PFS was 4.5 months. The overall survival was 50.8 months. Until now, the DOR was not reached yet. For the safety results, instance of adverse events are more than 10% including anemia, a low white blood cell count, hyperuricemia, a urinary tract infection, hypothyroidism, elevated transaminase. Treatment-related adverse events raised more than 5% including hypothyroidism, a low white blood cell count, and elevated transaminase. And the most, the TRA rate, grade one or two grades. For TRA of grade three or four, total instance was 7.7% including high transaminase, intestinal obstruction, anoesia, allergic pharyngitis, high directed bilirubin, myocarditis, and anemia. There was no treatment-related deaths. We also compare our results with stats in paprodizumab in cervical cancer. The TRA rates is comparable in both two drugs, but we have a lower grade three or four TRA rates. For the efficacy, we have a higher ORR regardless of PDR1 status. There was a research conclusion for present. The TRA of sulcalazumab are similar to other ICS products, mainly in grade one to two. There is no treatment-related deaths. In those state expansion stage, the confirmed ORR was 18.1% and the PFS was 4.5 mgs. The DOR has not been reached yet. It should be noted that the comparable ORR regardless of PDR1 status with sulcalazumab was observed in our study. So sulcalazumab has good safety and efficacy in metastatic or recurrent cervical cancer and was thus carried out for the studies. Finally, I would like to express my sincere gratitude to the leading PI, Professor Wu Linyin and all the PIs of participated sites for all the support from our research team. So my report is completed. Thank you for your attention and your time. Thank you, Dr. Han. Congratulations for this very interesting study and for this very interesting data in cervical cancer. It is my great pleasure to invite Dr. Lesley Randall to have a distillation of these two very interesting study. Lesley, it's a pleasure. The stage is yours. Thank you so much, Keta. These are great presentations. One of the big themes of the meeting is the evolution of cervical cancer therapy that's happening so quickly. So it's my great pleasure to be invited to discuss these two very interesting and innovative abstracts. These are my disclosures. So as Dr. Oakman presented in our master session, it's really a seismic shift in the standard of care in cervical cancer. And I think it was, I can't remember who said this at ESMO, but the immunotherapy era in cervical cancer is happening. And that was with the presentation of Empower by Dr. Tiwari. So really looking at moving immunotherapy into earlier lines of therapy, which makes both of these presentations very relevant to our current and evolving treatment paradigms. Single agent PD-1 agents are active in the second line cervical cancer. Again, we saw that with Empower with the first abstract of this meeting. And I wanted to take you back to Pembrolizumab as Dr. Ahn presented so eloquently that when all this work started, really we only had Pembrolizumab. And our impression was that based on this small 98 patient trial was that Pembrolizumab was not active in PD-1 negative patients. But as we do more trials with these agents, we're learning that it is in fact active in PD-1 negative, not as active, but it is in fact active. And so interestingly, Dr. Ahn presented today. So Kezolamab, she pronounced that differently than I am pronouncing it. But Sokezolamab does have a high rate of response in the PD-1 negative population in this study. And so we'll talk about that as we go along. But as you can see here, we have four very active anti-PD-1 or now PD-1 with Sokezolamab therapies in cervical cancer. And to the tune of, here's the only progression-free survival and chemotherapy comparison data that we have in power, again, presented at this meeting where the median PFS time for checkpoint in this population 2.8 months for Sokezolamab was 4.5 months. And it doesn't look like, there's so much debate and many have talked about at this meeting, is response rate and PFS really the end point that we need to look at with these agents because even when the PFS is short, the overall survival time can be long. And in my impression, this is because of the responders who have long durations of response as we've seen in multiple trials. This is translating into this overall survival benefit. And so I do think that response rate remains a relevant end point for checkpoint inhibitors as was reported today with Sokezolamab. And here you see Simplamab having a 12-month median overall survival time and Sokezolamab reporting a 15.8 month in a smaller population without a comparison group, but yet in the same ballpark. So as Dr. Solani talked about in her eloquent debate against Dr. Tewari, we are really moving these agents into the front line. And so a lot of the second line, a lot of the second line trials are going to be important, but potentially for a shorter period of time, depending on when we get the results of these trials. So we've got three in the front line. We've got Keynote 826 that recently reported that it met its primary end point at an interim analysis. And this is going to be presented at the ESMO meeting and one of the presidential abstract sessions. But we don't know the degree to which this was effective, just that it was effective regardless of PD-L1 status and regardless of whether patients had received Bevacizumab with their treatment. And also as Dr. Solani presented to you, we have this in the locally advanced setting with chemoradiotherapy with the CALA trial using Dervalimab maintenance, having already completed its enrollment. And Dr. Ketai is leading this Keynote 818 study, which is enrolling currently. And we're very anxious to see those results as well. And this is the bulk of our cervical cancer patients. So these are almost all of our patients who go on metastatic trials and all those who go on second line or greater therapy or those that have previously received chemoradiotherapy. So this will have, again, another seismic shift in our treatment landscape. So where does that leave us? You know, we're looking at IO combos. So not just the PD-1 or PD-L1 inhibition, but also looking at combining this. So we know that if we combine PD-1 inhibitors with other agents, we can get higher response rates, certainly in the PD-L1 negative population. But, you know, and several of these trials are ongoing and not yet reported out. We've got several of these bi-specific antibodies now in the pipeline. We've got a PD-1 CTLA-4, PD-L1 TGF-beta inhibitor, and not a bi-specific, but also a combination of a different agent is a tezolizumab, a PD-L1 in development with teregolumab and antitiget. So a very active menu of ongoing trials with combinations. Now, sokazolumab, I scoured the internet and tried to find a picture of this molecule and really couldn't find that. So I think the antibody drug conjugate portion of this molecule is not necessarily in the public domain, but it is clearly active with a 20.7% response rate in the PD-L1 negative population. And so this is just sort of an example of where a PD-L1 inhibitor went in non-small cell lung cancer with the Cityscape trial using a tezolizumab with or without teregolumab. Here you can see the benefit of adding the antitiget agent to the tezolizumab alone. And this was much more pronounced in the very high PD-L1 positive patients. And so I don't think for cervix that we've quite worked this out as well, this PD-L1 positive negative to this level of granularity by magnitude of expression. But certainly we need to look at that because as you can see here, if the PD-L1 expression was under 50, there really wasn't much of a difference. And that likely a tezo, there was no non-tezo arm here, but likely a tezo had an effect in that population, but the tiget didn't add much more to that. So interesting things to come in cervical cancer because a similar trial is ongoing for our cervical cancer patients. So again, bringing up this antibody drug conjugate activity, it's clear that this agent has some other activity aside from the checkpoint by its heme toxicity. And so if you look here, and Dr. Ahn eloquently just presented this rate of anemia and low white blood cell count, though most of this was low grade in nature, it was present, which we wouldn't typically see with an immune inhibitor alone. So that brings me to tesodimab. Tesodimab, Vodotin, or TV is really, as I keep saying, the only non-IO game in town right now, except for maybe the ADC component of Socoselumab. But this is, as Dr. Monk described, this is an antibody drug conjugate that targets tissue factor, which is pretty ubiquitously expressed on cervical cancer surface. And it carries an MMAE payload. So when the drug binds to the tissue factor, it is endocytosed into the cell and causes microtubular disruption both in the receiving cell and as the cell lyses by apoptosis, it releases MMAE molecules into the bystanding cells causing what's called a bystander effect. And Dr. Monk also referred to the Inova TV 204, another study that we did in collaboration with our NGOC colleagues through the GOG, a single arm study showing a 24% response rate with a median duration of response of 8.3 months for tesodimab in the second line or greater setting. So this is gonna be an extremely important therapy moving forward. And as Dr. Monk also mentioned, the PDUFA data set for this in October, where in the U.S. and other sites that are covered, other countries that are covered by our accelerated approval programs may have access to tesodimab vedotin in the clinic as soon as the end of the year. And this is where tesodimab as a single agent is going. Currently, it's in a phase three trial, GOG NGOC collaboration versus investigator choice chemotherapy to, this is a confirmatory trial for its accelerated approval, but we're interested in TV outside of second line. And that's why we're looking at these combinations. So the most common adverse events that we're seeing with tesodimab vedotin, and this was in the phase two single arm trial, were alopecia, though not to the degree of a taxane, epistaxis, nausea, conjunctivitis. And these are the pre-specified AEs of interest of tesodimab vedotin. It has ocular adverse events. And most of these are keratitis that can be mitigated with a prevention eye care plan that's fairly easy to follow, but also bleeding adverse events and peripheral neuropathy. So when combining these with other agents, these were of interest and needed to be looked at very carefully, specifically with bevacicimab. And so Dr. Monk explained to you that the bevacicimab cohort enrolled slower than the other cohorts. And that's because tissue factor is involved in the maintenance of hemostasis and blood clotting. And so there was concern that if we disrupt it, even though we weren't directly, we're just using tissue factor to get the drug into the cell, we're not directly inhibiting tissue factor, that there might be some overlapping bleeding toxicity observed with bevacicimab. And certainly in this cervical cancer population, that could be catastrophic. And so there was great care taken with that combination. And then with carboplatin would have been the peripheral neuropathy and heme toxicity overlapping. And there wasn't really much expected to overlap with the pembrolizumab. And so that one went ahead much faster. But this is the toxicities that Dr. Monk presented. And I put here the toxicity from the TB alone that was observed in the larger phase two study. And these are still small numbers and need to be borne out more in the larger expansion cohorts, which are ongoing. But here you can see that, and as Dr. Monk told you, you could combine these drugs at their regular doses and schedules. And the combination, there was no overlapping toxicity and the receipt of the combinations didn't compromise the dose of either drugs. And so these are well tolerated at the standard dose levels. So in conclusion, you may be asking yourself why another checkpoint inhibitor? Well, more data is better and combinations are coming. And really we've talked a lot about low and middle income countries during this meeting. And this just creates market competition and potentially drives down the cost. And a lot of this is driven by like access. You may not be able to access the same drug in China as you can in the United States. And lastly, TB is a very pivotal therapy. And as it can be combined with other agents, we can potentially move this earlier on into therapy. So thank you so much for the invitation. Thank you, Leslie, for this excellent talk. And thank you for all the presenters for sharing with us their very strong data. And this concludes our session. Thank you for the attendees. Thank you to Dr. Salani for sharing with me this session. Please move to the industry hall because we have two very nice industry symposium that will start in one minute. Thank you so much. Bye, bye-bye.

Dr. Brad Monk

tizodimab vedotin

bevacizumab

pembrolizumab

carboplatin

recurrent cervical cancer

metastatic cervical cancer

response rates

PD-L1 negative patients

so-casolamab