Good morning, good afternoon, and good evening. My name is Brad Monk. I want to thank the program committee for allowing me to be here with you. I'm a gynecologic oncologist from Phoenix, Arizona. This is my favorite meeting. This is my 11th International Gynecologic Cancer Society meeting. I'm so happy to be with you from around the world to discuss cervical cancer, which is, of course, a very serious global problem. I'm joined here today by my co-moderators, Professor Mary McCormick from the University College London Hospitals in the United Kingdom, Professor Anna Oetkinen from the Val de Hebron Institute of Oncology in Spain. I hope you've all enjoyed these master sessions presented throughout the meeting. I also hope that you agree that these master sessions really are an excellent way to comprehensively discuss gynecologic cancers with the experts. I'd like to kick us off here with Dr. Katie Moore, who's a professor in Oklahoma City. I'd like her to discuss with us today the histologic subtypes and molecular features. I know her as Katie. Katie, share your screen and welcome, and thank you for kicking us off today. Thank you for having me. Good morning to everyone in room. It's my pleasure to be invited to this session. I'm going to kick us off with just an overview, really the histology and targets surrounding cervical cancer as we know them now. These are my disclosures. I'm going to frame this discussion because it's a little bit of a dry topic. I'm going to frame it around a case to illustrate how we use histology and markers to make decisions about our patients. This is a real case. This is a patient of mine. She's 42, a black woman. She presented as most of our patients do with an extensive history of vaginal bleeding, in this case, two years. She'd been seen at multiple emergency rooms, had received 32 transfusions without a pelvic exam for this time, and eventually was finally transferred to our facility in February of 2016. We took her to the operating room and did an exam under anesthesia, cystopracto, and found to have, at that time, staging 2B. Cervical cancer and biopsies were consistent with an adenosquamous carcinoma of the cervix, and she underwent a PET scan at our facility to complete her clinical workup. The first thing to think about- Sorry to interrupt. Put that in presentation mode, if you wouldn't mind. It's not in presentation mode? I don't think so. We can see the next slide that's coming up. Sorry to interrupt. Very sorry to interrupt. No problem. Thanks for letting me know. Is that better? Yeah. Thank you. Okay. Thanks for letting me know. I'm doing a PET-CT. The first thing we need to ask ourselves is, once you get the histologic diagnosis for your patient, does that histologic type determine therapy? Does it help you pick what you're going to do? I've just put up this slide of some of the more common histologies, and this is not anywhere near exhaustive, but if you start in the top left, what you can see is large cell non-keratinizing, and then clockwise, you see keratinizing, which is probably the most common thing that we see, endocervical adenocarcinoma, and then coming to the lower row, adenosquamous, which is what our patient has, and then these uterine corpus-like cervix cancers that are HPV negative or HPV positive. I can't, in the interest of time, even get into neuroendocrine tumors, mucinous tumors, although I'll mention them at the end. There's a number of histologies that expert pathologists will arrive to a diagnosis, and what does it tell us about how we treat the patient? Really, it doesn't influence how we treat the patient, at least in the frontline at this time. I'm showing you two sets of data on the top here. What you can see is data from Dr. Burke, where he's looked up here at the top at three-year recurrence of squamous cell, and in the middle, this is three-year recurrence risk factors for adenocarcinoma. The interesting thing about this, these are local regionally advanced tumors in each case. There are different prognostic markers for squamous cell and adeno. Adeno, it's primarily the size of the tumor, whereas a squamous cell tumor, as you can see in red, it's a variety of things, the more classic risk factors that we think of, vascular invasion, depth of invasion, and size. Different prognostic markers do exist, but it doesn't change how we necessarily would treat the patient. More recently, on the bottom right, what you can see is data from Dr. Levinson et al, that was presented just this year at ASCO, where they did an ancillary analysis of trials performed through the gynecologic oncology group, now the NRG, and looked at how histologic type was influenced response to therapy. I have that in the red bar. Adenosquamous, adenocarcinoma, and squamous in orange are all on the same side of the bar. This adenocarcinoma, the confidence intervals overlap, so really statistically speaking, they may do a little bit differently in terms of outcomes, but it doesn't influence how we treat the patient. The patient is treated the same way, with the exception of neuroendocrine, either local regional advanced or metastatic disease, regardless of histology. Certainly, it doesn't mean histology is not important, and I'll come to that, but in terms of frontline therapy, at this point, it doesn't determine what we do. Coming back to our patient, I mentioned to you that she had a PET-CT, and I've outlined in the white arrow what was the surprise to us, because we thought initially she was a stage two, and it turns out she was actually a stage 4B by virtue of liver metastasis. She was started on paclitaxel cisplatin and bevacizumab in April of 2016, and did about what we would expect. She was treated for about 11 months, at which time she progressed in the liver, and was referred to the phase one unit where I work, and at that point, 2017, we were very excited about immunotherapy, and so we put her on a novel anti-PD-1 monoclonal antibody in April of 17, and on her first scan, she had eye unconfirmed progression, and we kept her on. I probably wouldn't do that today, but we kept her on so that she could have confirmed progression disease at the next line of therapy, and so the question is, how do we select immune checkpoint therapy for patients with cervical cancer? Can we select, and we can, and we can now, and potentially we can even better, so this is just a table of all of the biomarkers that are in use and under study for use of immune checkpoint inhibitors, and the ones that I want to point out are tumor mutation burden, of course PD-L1 expression, and then this T cell inflamed microenvironment, which we look at with a gene expression profile, which I'll talk to you about in a minute, but it's important to know that these aren't really independent biomarkers from one another. They overlap considerably, and so combination biomarkers may really help us identify those patients who would best be served with immune checkpoint inhibitors in a recurrent setting where we use them now, but potentially in the future, and so this may make a difference in how we look at patients for frontline therapy in the future. So the PD-L1 testing is really kind of our key asset right now for selecting therapies, and this is a really complicated biomarker, I think, as we're all increasingly aware in gynecologic cancers. On the top left of this slide, I have the myriad of assays that are available and cut points that are available just for lung cancer, which of course has the most data, and we try to apply this to the cervical cancer arena, which has some limitations. PD-L1 does seem like kind of the most logical biomarker to use in this setting, but it's really had some issues. What do you measure? Do you measure PD-L1 on tumor cells or inflammatory cells? How do you account for tumor cell heterogeneity? What is the standard for testing PD-L1 in terms of which antibody to use? And what's the real cutoff that we should be using for the various gynecologic cancers, including cervical cancer? And of course, we use the combined positivity score instead of the tumor proportion score, which we use in other solid tumors, and that combined, or CPS score, the combined positivity score, just to remind you, is the percent of PD-L1 stained cells, tumor cells, macrophages, and lymphocytes, divided by total viable tumor cells times 100. So why do we use that? Where did that come from? Why aren't we using any of these other myriad of tests? Well, it came from Keynote 158, which I'm sure one of the speakers to follow me will mention. This is the study that led to the approval of pembrolizumab in second-line cervical cancer, at least in the United States, and it used the CPS score greater than one, only in squamous cell cancers. The study was only for squamous cell, and you can see in the red box why this was picked, because the response rate of about 15%, which is what we talk about with this indication, was only in that group of patients who were PD-L1 positive by this immunohistochemistry test, and those that were CPS zero, or less than one, had no responses. So that's where that biomarker comes from, and so this is one of the key biomarkers currently that we use in cervical cancer. So can we improve on that? Maybe, and all of these studies that are ongoing, there's fortunately a lot of translational work being done. Tumor mutational burden is of interest in lung cancer, so is that something we can use in cervix cancer? Well, the arrows here point, I included vulvar squamous cell cancer just of interest, that's the one on the left, but in the middle is the percentage of patients that have tumor mutation burden high for squamous cell carcinoma of the cervix, so it's just shy of 20%. So does this correlate with response to immune checkpoint inhibitors? That's actually unknown at this point. We haven't correlated this well yet, so this is one of the things that's sort of under study and under development as a potential biomarker. And then I mentioned this gene expression profile, and it's really a T cell gene expression profile, and there's a number of these that have been developed by different companies. This is the 18 gene signature that has been, probably has the most data behind it because of the amount of patient pool data that's available from the keynote studies, but this is really the 18 gene signature, again, that has the most data. And these, what we call GEP scores, are truly associated with patients who have responded, not only responded, but responded the longest across disease types in the keynote program. And so you see this heat map, which does show an analysis of the T cell inflamed gene expression profile, and you see a higher frequency of responses in patients who have this higher gene expression of these individual genes in this GEP, such as CD274, which is actually PD-L1, so that makes quite a bit of sense. You can see this right here. And so in the future, when we're looking at trying to select patients for immune checkpoint inhibitors, this kind of combination biomarker approach may make sense. Will it make sense in cervical cancer? That remains to be seen. It will certainly have to be validated in tumors that have a larger footprint first in immune checkpoint inhibitors. But what you're seeing here is this, so in the y-axis is tumor mutation burden, and the x is this GEP profile. So pink is tumors that have both tumor mutation burden high and GEP high, and gray, both are low. In blue, you have tumor mutation burden high, but GEP is low, and purple is the reverse. And so right here, you see cervical cancer. And of the patients who were included in the keynote study, so it's not a huge number, about 40% of patients have neither elevated GEP or tumor mutation burden. About 35% are in this purple group that have an inflamed GEP, but low tumor mutation burden. Little bit here, 5% have the reverse. And in pink, it's probably about 15% are high. Then overlay on this, and this is kind of what's missing from this really interesting paper, would be the PD-L1 positivity, which certainly overlays a lot of this gray. And then we have to figure out, does this really matter? If 80% of patients, at least with squamous cell, have PD-L1 positivity, which they do, do we care if we can predict better those patients who are really gonna respond for a long period of time, or is PD-L1 alone enough? And these are the things we need to think about. I think especially if we are going to incorporate immune checkpoint inhibitors into earlier lines of therapy. But for now, CPS is the test that you would send, at least in the United States. And so coming back to our case, as I mentioned, she had progressed on her immune checkpoint inhibitor. And in fact, the liver metastases that she had had grown substantially. She was very sick. But at the time she came to phase one, we also sent her tumor for next generation sequencing. And this is the report. We sent foundation one testing, and she has this IRBB2 amplification, come to find out. And so we did have a clinical trial, a basket trial at that time, of trastuzumab and partuzumab for patients with IRBB2 amplifications. And we kind of slid her right on at the last minute. She was getting pretty sick to see if this might salvage things. And here's just two cuts of what her liver looked like at the time we put her on trial. So really extensive. And this really was her only site of disease, but really extensive liver metastases. And this is just pre-treatment and post-cycle two. So eight weeks later, you can see the marked reduction in her liver metastases. And she actually walked in on Kintea for her CT review and told me that she knew it was working, which is sort of one of those golden moments in clinical practice that makes you want to come to work every day. So she ended up staying on for 28 cycles. She had an 88% response, never quite went away. And her liver metastases, and was great back at work, doing fantastic until unfortunately in May of 19, she was diagnosed with cerebellar mats. Given her great extracranial control, we elected to have them resected and then radiated, which took some time to get her recovered from that. And then we put her back on therapy in September of 19. We only got a couple months in and she had progressive disease, which was unfortunate. But we did have quite a benefit with use of this targeted drug. And so what's in with that? So here is the TCGA data from her cervical cancer. You can kind of see the distribution up in the upper left-hand side. And there's not a lot yet that we can target. But things to talk about would be, we do see molecular alterations in the PI3 kinase pathway, about 42% of the time in both squamous cell and adenocarcinomas, which hasn't been really targetable yet, but it may be in the future. That's something to keep in mind. But you do see about 26% of adenocarcinomas by TCGA. It's higher in other series, which I'm going to show you, have ERBB2 pathway alterations, either amplifications, mutations, or these BKAR4 fusions. The fusions are rare, but what happens when you have these fusions is that you kind of have this BKAR4, which is a metastasis-promoting, non-coding RNA that promotes cell proliferation because it activates ERBB2 and 3. And so by all of those combined, you can target ERBB2 in cervical cancer. And so here's the only place where really we've seen efficacy yet with NGS-identified targets. And so when you look across the literature, you'll find mutations, most commonly S3104F in about 6%. And then you'll find amplifications in overall about 20%. You do find them in squamous cell, about 18% of the time, 30% of the time in adenocarcinomas. And then in these other subtypes, serous carcinomas of the cervix, mucinous gastric type, you'll find ERBB2 mutations or amplifications 17% of the time. And so when we think about what's coming in terms of biomarker or not biomarker-directed therapy, you're going to hear these. There's tissue factor, the new drug Tizotimab, and this is just information from Dr. Hong's paper. And what I want to draw your attention to in the lower right is that tissue factor levels by immunohistochemistry do seem to correlate with response, with best overall response, but the confidence intervals here clearly overlap. And so this is one of those therapies where it may be more empirically selected than biomarker, but that remains to be seen, whether or not you guys are going to be sending tissue factor IHC on patients when you're looking at this therapy and these trials are ongoing. Kind of the same story with this one, with TGF-beta, there's an interesting agent called ventrapas, hard to say. TGF-beta alterations are common in about 30% of squamous cell carcinomas. Does that presence of those molecular alterations matter in terms of the efficacy of this drug or not? Is this an empirically driven drug or a biomarker directed drug kind of remains to be seen as well. And so those are kind of TBD sorts of new therapies that I think you'll hear about as we're moving along. And so in conclusion, number one, don't give up on your patients with recurrent metastatic cervix cancer. We do have lots of options for them. For our patient, just to give you a summary of her, once she came off trastuzumab, she went on Pemetrexid and then now on Abraxane is responding well. And we have novel HER2 agents for her next. For immunotherapy, our best predictive marker thus far is PD-L1, but more to come and we should be able to do better in selecting patients for these therapies. And next generation sequencing may identify targetable mutations or amplifications, specifically ERBB2. These are found in all histiotypes and finding actionable mutations may be uncommon, but it matters to your patient. And I hear a lot of nihilism from my colleagues about sending NGS on cervical cancer specimens and for patients because they don't find things often. But remember the story of the man throwing the starfish back into the sea. You help the starfish that you can help. And so you can help that patient at that time when you identify that mutation. So keep throwing the starfish back into the sea, look for these mutations and help your patients. Thank you. Katie, that was exceptional and thank you for keeping us on time. Can you guys hear me? Now we can. I want to introduce to you Jalid Sahouli, who is Professor of Gynecological Oncology at the Charity Hospital in Berlin. Staging is still important. We're evolving the imaging and I'm so happy, Jalid, to see you and to have you join us today. Thank you and welcome. Thank you, Brad, and best greetings from the darkness of Berlin because it's five o'clock in the morning. So I'm really happy to talk with you about the possibilities to look on the different perspectives on staging and we start with the new fecal staging because you know that we have a revision in 2018 and looking on 1B1 and much more important even to look that we disseminate the Stage 3 to lymph node pattern and we know that 3C1 is pelvic lymph node metastasis only and 3C2 is including the parotid lymph node metastasis. So the question before we go more in detail is for what we do staging? Do we like to predict, like do we like to have prognostic information for the patient or do we really need to reflect our staging system regarding therapeutic effect? Does therapeutic lymph node dissection, for instance, influence over survival? That's a key question but always even be discussed with our patients and their relatives. So we know that the staging including imaging is feasible and I will show you in some seconds that it's even accurate but the question is who looks at what time with which purposes because the gynecologist is primarily trained to do surgery and you know that even the anatomy of the radical hysterectomy is really changing and sometimes mystic. And the question is if you have a positive lymph node you will stop to do radical hysterectomy. The question for the radio oncologist is also to look on tailored adjuvant radio chemotherapy. Do you need to include the parotid field and that's even one of the key points to decrease even morbidity for our patients. So the question is what is the best method and you know that PET-CT is very sensitive but don't forget that even in PET-CT you need at least seven, eight, nine millimeters of tumor lesions to make them visible. So if you look on the different approaches yes PET-CT is much more sensitive but the negative predictive value is much better than the positive predictive value. So that's a limitation. So if you see something that's maybe cancer if you don't see something that's likely there's nothing there. But again you know even in severe cancer and all the tumor tissue has high key 67 so proliferation rate is not in all lesions very high and that's make the limitation. So don't forget the clinical examination because that's even part of the clinical staging. And even to look on ultrasound by experts CT is not of value in the pelvic region much better is MRI and we have even a big evolution in technique of MRIs and imaging where we just started. So let's go back to the question if clinical staging is much better for the patient than surgical staging and you know the different series from all over the world looking on these and always the story was yes if you do surgical staging is much better. Going back to the conclusion they supported to do surgical laparoscopic mainly staging to have a much better accuracy of the lymph nodes metastasis and even to have a better platform to make a tailored radio chemotherapy. But nevertheless there are several limitations you see in this study because the diagnosis was not really systematic done. Going back to history in 2003 that was the first trial looking on clinical versus surgical staging mainly open surgery and they stopped after 61 patients because there was a crucial difference in both survival curves favoring the clinical staging. So we did in Germany a prospective trial and Simone Amaris at her time at Charité has initiated this trial now showing you some of the results were under revision and the International Journal of Gynecology will come I think very soon and as a full publication. So you see that the study was designed to look on progression over survival and I will show you that this study presents a very good quality and there was no severe complications, no high no mortality and most of the centers included stage 2b until 4. It was primary from the study group not accepted to include earlier cancer that's a pity but that was the time and you see that even parotid lymph nodes dissection was done and if you compare the upstaging it was higher in the surgical than if you did a CT guided biopsy with only 1 to 2 percent of the metastasis. If you look on the clinical outcome there was no overall survival difference but if you look on the cancer specific survival the surgical arm was much better than the clinical base. Coming back to the chemoradiation related toxicity, the toxicity burden I think even a very important goal if you reflect the staging system and even supporting in this case based on this algorithm the surgical staging. The study has some limitations because yes the number of patients was good but if you look on overall survival you need much more to have a robust database basis and there was no PET CT included and as I mentioned the 1b1, 1b2 we have not been enrolled in this trial. We really try to reflect the surgical staging issue. We have even to be aware that this is even an evolution and we know that we have different approach in surgical radicality. We have the TMR, we have much more and more the nerve sparing technique without compromising radicality and that's I think very important that we know many things to less and that even the technique and MRI and even the other imaging technique becoming more and more modern and that even the nerves is a new target in these imaging studies. If we train even radiologists to interpretate this data because what you don't know you will never see, it's very simple. So coming back to the lymph nodes and we know that it's not only pelvic and the parotid regions even the parametri what is really difficult to present even by the clinical examination under anesthesia to discriminate between stage 2b and 1b2 is a very, very big challenge and based on the new ICG technique there's even some advantages to make the lymph node involvement much more visible than ever before. So we use it as a standard of care but again it's still in evolution and have to be confirmed in these trials. So what's the difference between micro and macrometastasis that's even an open question and to stop if you have the positive sentinel node is one algorithm what we have to improve in the ongoing trials but at the moment it looks not that micrometastasis really makes the music and the effect in the clinical pathway. So I think that's one of the most important efforts of the society that we try to implement quality indicators even for cervical cancer and to define a minimal database for surgical staging I think that's minimal and we have to go much more in detail but again we want to reflect it and we discuss with our patients because they want to survive they want to be cured but we have to discriminate the evidence regarding survival you have seen there was not no over survival benefit so far if you do surgical staging what is the meaning of progression for survival and what is the term of time to substitute sequent therapy what is a topic in ovarian cancer but not any at this time for cervical cancer we have to introduce this in our pattern what means tumor control rate mobility quality of life and cost is even important. So to conclude is that we have several possibilities to reflect staging and cervical cancer take your time to make a puzzle to look if this patient is really curable or not and second is how we can implement in most cases we'll see the multimodal approach in our patients to bring at all the best models together so and I think that's a big demand for us at all to make all the clinical trials together to make really the difference. Thank you very much. Thank you very much Dr. Sahouli for that excellent overview on staging and thank you for keeping to time. I'd now like to welcome my UK colleague Dr. Alex Taylor to give us her insights on the state of the science in radiation oncology. Dr. Taylor would you like to begin please? Yeah thank you very much thank you for asking me to participate in this session. I just would like to start going through looking back over radiotherapy for the first 100 years in cervical cancer where we established the principles of radiotherapy including external beam radiotherapy and brachytherapy the radiobiological models but we see by the landmark trials in 1999 of chemoradiation we were still using conventional radiotherapy whereas in the last 20 years there has been an explosion really in the technological developments in radiotherapy and I'll be looking a bit at some of these in terms of intensity modulated radiotherapy image guided brachytherapy and stereotactic radiotherapy. Now with external beam radiotherapy this conventional treatment with radiotherapies use bony landmarks it covers a large volume of normal tissue and that has been improved by using conformal radiotherapy which reduces to some extent the normal tissue but with intensity modulated radiotherapy we are able to conform much more tightly to concave and sort of curved sort of curved shapes with the treatment and therefore reducing the amount of normal tissue that we're treating. The issues that we had when we started using this was defining the target volume as we can see on the first trial of our study comparing gynecologists and radiation oncologists there was a wide spectrum of what was thought to be included in the target volume but with the development of consensus guidelines and atlases with training we now see that there is much more consensus in terms of terms of inter-observer variability as shown here in the quality assurance program for the interlaced trial. Because we're reducing the amount of normal tissue that should relate in to reduce toxicity and certainly in the post-operative setting that is the case. We have one randomized trial where the primary endpoint was patient reported toxicity so an important endpoint which was reduced both for bowel and bladder toxicity. When we're treating definitively it's a larger target volume and we don't have large randomized trials but larger this is the earliest sort of cohort of comparing historical to IMRT and again the grade three toxicity was reduced from 17% to 6% with IMRT. But I think the big advantage that we have with IMRT is it allows us to dose paint. We can pick out areas within the volume that we wish to give a higher dose to and in particular in cervical cancer this would be the involved lymph nodes. As we've just heard when we stage if we can detect lymph node involvement particularly with a PET scan we can then design the radiotherapy treatment to boost that particular region with a higher dose. Whether that translates and what dose we need to be delivering is still under debate. There are many there are a few series that all show excellent local control with an integrated boost and it does not seem to increase the toxicity because you're boosting such a small volume. But when we look at dose response it seems the lymph nodes do not need as high a dose as the primary tumor and once you're above a total dose of 58 gray there's no definite dose response and similarly for the nodal volume we're not seeing a definite size response. The challenges we have with IMRT is we're producing a target volume. It shapes very tightly on the original scan but throughout the treatment you then have impact bladder and rectal filling status on highly mobile structures. We also can find the tumor shrinks as it goes through treatment so again the shape and the volume is changing and to monitor this we probably need to be doing daily imaging if we want to be using highly conformal techniques. We can do this when we're constructing the range of motion to see if it's a mover or non-mover by a non-adaptive approach by pulling in full and empty bladder scans or alternatively adaptive radiotherapies we can have a library of plans and select a plan of the day for each of the challenge for each of the days that we're treating. Looking forward we've now got technology that's going to be coming through in the next few years that allow us to actually do online adaptive re-planning and shaping and integrating that with machine learning so we're going to see further large changes in the next few years. With image guided brachytherapy we're also seeing great change. Now moving from brachy therapy can depend on the resource and the patient whether you use a library-based point-based technique but ideally 3D volumetric brachytherapy. First most simple image guidance we can use is intraoperative ultrasound. We know that doing live guidance improves the applicator placement and reduces the perforation risk so that we wouldn't be delivering a high dose to bowel if there's an unsuspected perforation. Once we are able to take imaging and again with the best soft tissue we see it with MRI we can start individualizing the dose to the target volume and if we have a case like we have here where there's been a poor response to external beam treatment putting a tube into the cavity is not going to give sufficient dose to the lateral tumor and therefore adding interstitial needles into the parametrium can improve coverage and reduce the organ at risk doses. And the group that really took this forward was, uh, Richard Potter's group from Vienna, where they initially published their first cohorts trials where by optimizing and increasing the dose from 81 to 90 gray, you were seeing excellent control, even with the lower doses, um, of small tumors, but, uh, with a larger tumors, increasing the dose improved pelvic control from 70 to 90%, which translated into overall survival benefit. And despite the higher dose, the severe locked late toxicity was reduced. Now group this led to the Geck-Estro guidelines and, uh, the consensus that's widely adopted now in terms of the target volumes that we use. And, uh, we would be aiming to deliver 85 gray to a high risk target volume whilst maintaining sort of adequate doses to the organs at risk. Now, the Geck-Estro group also developed the embrace and the retro embrace studies, which recruited retrospectively and prospectively more than 2000 patients where we have excellent, uh, dosimetric data and outcomes for such a large group of patients. And what this has confirmed is our modeling that there is a dose response for local control, um, that, uh, there is a similarly a dose response for bladder, rectum, bowel, for organs at risk, and also the vaginal mucosal doses. And this has been led into the embrace two study that's now ongoing where they're combining IMRT with nodal boost, risk stratification image guidance, and trying to, uh, reduce the dose to the organs at risk while escalating tumor doses. The last area I'm going to cover briefly is stereotactic radiotherapy. Now this, um, it can be delivered by many platforms, but the most common is probably CyberKnife, which is a dedicated stereotactic machine or linear accelerator, um, toxin sort of approach. And the features of this would be that you have a highly conformal dose, um, distribution, but within that you are able to give a much higher dose to the center of the tumor, um, whilst having a drop off to the normal tissue. Other features are real time image guidance and a large dose per fraction. So these are the features of stereotactic, but I also have to remind you that these are also features of brachytherapy and stereotactic treatment is not a replacement for brachytherapy. As a boost for cervical cancer, we can see that, um, very occasionally it is not feasible to give brachytherapy and some small case theories have shown it's feasible to use stereotactic treatment instead. There was a small trial that was discontinued due to toxicity, um, and particularly with rectal fistulation. And I think it has highlighted the importance of us defining our dose constraints when using these new techniques. Stereotactic treatment is, um, very established for oligometastatic disease. You can get excellent infield control with these. And the question is how to combine that with systemic therapies and the Comet trial, not specific to gynecological cancer, showed that treating oligometastatic disease can result in improvement in both overall survival and progression-free survival. In cervical cancer, we have a particular reason to use stereotactic, which is recurrence within the pelvic lymph nodes. And again, small series, short follow-up, but encouraging local control with treating pelvic nodes. It means when we're thinking about nodal recurrence, particularly in the pariotic nodes, the consideration is do we need to treat the whole target volume of the nodal region with a protracted chemoradiation approach, or would we use SBRT where we treat a single node with three or five fractions? I think it's still a debate, um, but we can use the SBRT in combination. It can be excellent palliation for nodal recurrence and also for re-irradiation. And re-irradiation is something we've avoided due to the risk of toxicity in many occasions, but we now have a technique where we can consider using it for selected cases. Of course, re-irradiation has been used, um, with interstitial brachytherapy and there have been three studies, um, similar results using image guided brachytherapy, which have shown good control for re-irradiation. If we compare this to the outcomes with pelvic excentration, but there is still significant toxicity, which may be acceptable when we're looking at a salvage technique. In terms of re-irradiation of the side wall with SBRT, small series, limited follow-up again, but encouraging that we can achieve some long-term control. And I'm just highlighting one trial, which looked at the impact of volume in that we have small tumors, less than four centimeters, two year overall survival was 89%, whereas it's very poor with larger tumors. And as an example, here's a case of a patient who had recurrent disease involving the side wall and bladder who was treated with CyberKnife five fractions given over two weeks. And she had no toxicity with treatment and has maintained a complete response for four years. Anecdotally, it is an approach for selected patients. Finally, just very briefly, we just always have to talk about how we can combine this with immunotherapy. Now the abscopal effect is a term used when ionizing radiation can have an effect at distance from the aerated volume. We occasionally see regression of the tumor away from where we've treated. Now, if we're thinking about combining that with immunotherapy, it's a very interesting approach. Radiation can be the boost that gives immunogenic cell death that then promotes activated T cells against that tumor. And if it acts on distant metastases, there's an abscopal effect. This particularly can be seen if you then add in a checkpoint inhibitor, which overcomes the immunosuppression that we can see from the tumor. Now, if we think about how to combine this, we're still not certain. It's a technique that's coming through. And we're not sure whether we should be using SBRT or conventional fractionation, but trials are now ongoing looking at SBRT to generate an approach for metastatic disease. So in conclusion, we have had a lot of recent advances in radiotherapy, and we need to be looking at how to combine these techniques with systemic approaches for improving outcomes. Thank you. Thank you very much, Dr. Taylor, for a wonderful presentation and great clarity. And keeping to time now, I'd like to welcome Dr. Linda Meleshkin from Melbourne to present to us an update on systemic therapy with radiation. Dr. Meleshkin, would you like to begin, please? Thanks, Mary. And thank you for having me on this sunny Sunday afternoon in Melbourne. It's nice not to be giving a talk in the middle of the night, Australian time for a change. I don't have any disclosures. So we've heard a bit about the treatment of locally advanced disease already. And we know that concurrent cisplatin with radiation really became the standard of care for treatment after the NCI put out an alert in 1999, based on three trials showing a clear advantage from giving concurrent chemo radiation. And subsequently the individual patient data meta-analysis actually confirmed that this pretty simple and cheap intervention actually significantly improved five year overall survival, the rate increasing by six percent, and also significantly improved five year disease free survival by eight percent. So which chemotherapy do we use? All of the trials used slightly different set schedules, but it's become really a de facto standard to use cisplatin at a dose of 40 milligrams per meter squared weekly during the external beam radiation treatment. And the meta-analysis really suggested similar benefits with non-platinum regimens and didn't really show a significant difference in terms of cycle length or dose intensity of cisplatin that was used with the different trials. But we certainly see patients who are not able to have cisplatin for various reasons, such as renal impairment or pre-existing hearing issues. And so for those patients, we do have the option of using other drugs such as carboplatin or 5-FU. And we know from small studies that both of these are tolerable, but probably they're actually inferior to using cisplatin. So we should have a good reason for not using cisplatin in the individual patient. And we do recognize that there are certain negative prognostic factors for the outcome, which will become relevant when we talk a bit later about some of the ongoing clinical trials. So particularly patients tend to do worse if they have large tumors or if they have a high FIGO stage. Also if there's invasion of the body of the uterus, which can be seen on MRI, if the patient's a smoker. And also there's some suggestion that those with adenocarcinoma probably do a little bit worse. And we've heard about the utility of using PET scanning to look for nodal involvement. And I always tell my trainees that if the lymph nodes are involved, you know that that patient has unfortunately about a 50-50 chance of relapsing with standard chemoradiation. So where do people relapse? So unfortunately distant failure is really the most common site of relapse. This is a figure of some audit from some local data from Melbourne, really showing that when you have good quality radiation to relapse only in the primary site alone is rare, but certainly local relapses do happen. And we know in the meta-analysis that local regional failure was seen in 35%. And hopefully some of those newer radiation techniques we just heard about will make that figure go down over time as radiation technology improves. But unfortunately disease often relapses at multiple sites and really distant failures are what often causes patients to die. So how could we reduce these distant failures? So we got a hint from the JCO meta-analysis in that there are a couple of trials you can see highlighted down the bottom that gave some extra chemotherapy following the chemoradiation, which became known as outback chemotherapy. The idea being that this may treat micro metastatic disease and therefore improve survival. And these two trials actually showed an absolute five year overall survival gain of 19%. So subsequently the Mexican group led by Duenas Gonzalez published this paper of using cisplatin and gemcitabine chemotherapy as two cycles of additional adjuvant therapy. And they actually showed a 9% improvement in the progression-free survival rate at three years, but at the cost of some increase in toxicity. Unfortunately, this trial was only able to follow patients up for one year. So they were unable to investigate the impact on overall survival. But very interestingly, there wasn't a big difference in local failure with the adjuvant chemotherapy, but the rates of distant failure were halved with the addition of the adjuvant chemotherapy. Subsequently we've run through the GCIG, the outback trial, which is a trial that's been testing the possible advantage of giving four cycles of carboplatin and paclitaxel chemotherapy following standard chemoradiation. And this trial has completed recruitment some years ago with everyone anxiously waiting for the results. But they've been a bit slow to come because of better than expected outcomes really in both arms of the trial. But hopefully we're getting closer to running an analysis later this year. One thing that we have been able to look at in the trial was that we noticed that during the trial, a significant percentage of women were not actually starting the adjuvant chemotherapy when allocated to that arm. And in fact, 23% of women allocated to the adjuvant chemotherapy arm didn't receive any adjuvant chemotherapy. And we tried to look at some of the baseline factors in the women to work out if there were particular groups that we were seeing this in. It wasn't just that women didn't want to lose their hair, but in fact what we found that there was evidence of disparities in the trial in that women who were older, more than 60 years of age or those of non Caucasian race were significantly less likely to start the adjuvant chemotherapy. And the other thing that really stood out to me in this analysis was that 25% of the population didn't actually finish the standard chemo radiation component. So clearly there's scope to improve there. And it's very important when we look after these women that we think about all the things that we need to do to try and get them through treatment. We need to look for HIV and hepatitis if this hasn't been tested before and treat those things. We need to treat pain. We need to treat iron deficiency. We need to discuss and manage fertility concerns and the impact of early menopause. We need to help women quit smoking and also manage their psychosocial distress because often this disease sometimes occurs in the history or with a history of sexual abuse and think about their financial toxicity. What about neoadjuvant chemotherapy? So interesting in this came from a meta analysis that was done by the UK group, which included 18 trials with an individual patient data meta analysis performed, and they compared trials that gave neoadjuvant chemotherapy prior to radiation to those that gave radiation alone. The study did not importantly include trials with chemo radiation, but there was a signal that possibly a survival benefit was seen with neoadjuvant chemotherapy for those studies that used a cycle duration of less than 14 days with chemotherapy or used a dose intensity of cisplatin of more than 25 milligrams per meter squared per week. And we have the ongoing GCIG interlace trial, which is looking at these question in more detail, randomizing women to have six weeks of weekly carboplatin and paclitaxel before their chemo radiation and following these women up to see if survival is improved. This trial has a recruitment target of 500 and is well on the way to being close to completing recruitment. An interesting paper that was published in the JCO within the last 12 months was this small study from a Brazilian group that looked at giving patients three cycles of neoadjuvant chemotherapy with cisplatin and gemcitabine prior to standard chemo radiation. It was a small randomized phase two trial with 107 patients and the primary endpoint was progression free survival. And unfortunately what they found was that the response rate to chemo radiation appeared to be lower in those who had neoadjuvant chemotherapy and also the progression free survival rate as well as the overall survival rate was actually inferior in those that had neoadjuvant chemotherapy. So there are some criticisms of the study in that some older style radiation was used and with more than half of the trial population having a prolonged treatment time. And they also noticed that more patients in the neoadjuvant discontinued their current chemo concurrent chemotherapy and in fact the dose intensity of the cisplatin in this trial was less than that 25 milligrams per meter squared that the measure analysis suggested might be necessary to improve benefit. But nevertheless an important study and we await the results of interlace with interest. At ASCO this year we saw the STARS trial presented from a group in China a very large trial that randomized really all comers with locally advanced cervix cancer to three different arms. One was pelvic radiation alone the second arm was our standard chemo radiation arm with weekly cisplatin and the third trial was a slightly unusual regimen of giving two cycles of paclitaxel cisplatin first then radiation and then two more cycles of paclitaxel and cisplatin. And this was presented in the oral abstract session virtually at ASCO this year. These are the patient characteristics which were reasonably balanced but not completely with the authors pointing out that there were less lymph node metastases seen in those patients treated with radiation alone. And another thing that I thought was quite interesting of seeing in this trial was again the rates of people that didn't complete treatment. So most patients completed treatment in the radiation alone but in the chemo radiation. Again we see about a third of patients not completing treatment discontinuing due to toxicities and slightly less in the sequential arm was seen. How about the results. These are really the headline results which suggested that those patients in fact who had the sequential treatment did better and you can see highlighted in the red box the group of those with high risk features. But somewhat surprisingly there was no real difference between the radiation alone in the chemo radiation which you would really have expected to see based on the results of the meta analysis. So perhaps in this trial we're seeing an underperforming chemo radiation arm and probably not hear something that's ready to be implemented into routine practice. Also, just to highlight, again, the highest toxicity was actually seen in the chemoradiation arm in this group of patients, not the radiation alone arm or the sequential arm. So it looks like we need to do better at managing the toxicities during chemoradiation. So we've heard a bit about pembrolizumab, and obviously there's been a great desire to bring this forward in treatment because the response rates in metastatic disease aren't that great, only 14%, but there is a signal there. So could it help with the treatment of local advanced disease? And now we have a suite of trials addressing this question. This is the CARLA trial that Brad Monk, one of our chairs, is heavily involved with, which is picking those bad players. So those patients with node positive disease or advanced stage disease who are randomized to have concurrent divalumab during their chemoradiation, and then as maintenance treatment for a two-year period, with the primary endpoint being progression-free survival. It is a pharma-sponsored trial, but it does include assessment of radiation and quality assurance, as well as health-related quality of life. And then with pembrolizumab, we have this NGOT trial, which is quite a similar trial, really a similar trial population, but in this case using pembrolizumab, again concurrent with the chemoradiation, and then for two years of maintenance. In this case, the primary endpoint is a dual one of overall survival rate at three years and the progression-free survival rate at two years, and again includes detailed assessment of radiation quality assurance and health-related quality of life. And this trial is being run as an NGOT Model C trial involving multiple GCI groups and countries. And the third trial is a smaller trial, which I think is a very interesting trial, the ATOMIC trial, again led by Anna, one of our speakers today, which is a smaller trial, which is looking at using the PD-1 really just as a maintenance therapy. So seeing patients first of all get through standard concurrent chemoradiation and have a response, and then be randomised two to one to have PD-1 maintenance therapy or no further treatment, with the primary endpoint being progression-free survival. So some of the questions I have about these trials are, will the concurrent immunotherapy with the chemoradiation increase toxicities like diarrhoea and lead to early cessation so that people don't get to the maintenance, which seems to be one of the important things that's helpful in other diseases such as lung cancer? Might it be okay just to have maintenance alone as is given in the ATOMIC trial? And maybe there's only a subset that will benefit given that the PD-1s don't seem to work so well if patients have PD-L1 negative or there's adenocarcinoma histology. And what will we do if the outback trial is positive? How will we incorporate adjuvant chemotherapy? And finally, do we really need two years of maintenance immunotherapy? This is a long time to have treatment which is good for pharma but probably not good for patients. And how many patients in the real world could even access this if it's positive? It's important to remember that most cervix cancer is seen in the developing world that can't access many of these expensive drugs. So take-home messages, we await the results of these multiple adjuvant trials with interest. We clearly need to do better at getting women through standard chemo radiation and we need affordable and better treatments that will be accessible to women in the developing world. Thank you. Thank you. Thank you, Dr. Milenski, for this excellent presentation. It's a really wonderful overview. Well, the next presenter is Dr. Leslie Randall. She'll speak on first-line treatment of metastatic disease. Dr. Randall, please go ahead when you want. Leslie, you are mute. Please open your mic. I'm the worst about that. Thank you so much. So hello, everyone, from Richmond, Virginia, where it's midnight. So I've caught up to you next day. And can you see my slides? Not yet. Could you share your presentation with us? I am sharing. Is it working? Not yet. Try again. As you did during our rehearsal, you will be fine. I am doing exactly. Let's see. How about now? No, we are not able to see your screen. Oh, no. No. Your screen thing, Leslie? I'm doing exactly what I did earlier. Send your presentation in your screen and then just click on share screen in the bottom of the bar. How about now? No, we are not able yet. Oh, no. No. I am not sure why it's not working. Let's see. Let me try one more time. Maybe. No. Okay. Now? Now? Now. Perfectly. Now you can go ahead. Excellent. Okay. Thank you. Sorry about that. Thank you so much. No problem at all. So first-line metastatic disease, and I'm already behind here in my disclosure. So we're going to talk about three specific aspects of metastatic disease, GOG240, and then incorporating immuno-oncology agents into first-line therapy, and then a novel strategy of using whole pelvic radiation following chemotherapy. When we talk about patients who are candidates for chemotherapy, we're really talking about those with metastatic, recurrent, and persistent cervical cancer, persistent meaning after chemoradiotherapy. And if you look at most of the clinical trials in this setting, the breakdown of patients in each of the various stages of disease, actually the bulk of patients who go on metastatic disease clinical trials have recurrent disease after either surgery or chemoradiotherapy, followed by stage IV-B, and then followed by persistent. So the inverse of these five-year survival statistics here is where we really have an opportunity to improve upon a treatment for these patients. And you just heard an excellent presentation by Dr. Milishkin trying to really improve on chemoRT, where a bulk of these patients again come from. So this is our high unmet medical need, and this is the evolution of systemic therapy for cervical cancer. And you may not really think about this much, but it wasn't until 2005 that we really had anything that was even somewhat viable treatment over cisplatin alone. And it wasn't until Dr. Monk's trial in 2009, GOG-204, where we broke the 12-month overall survival barrier with cisplatin paclitaxel. And then of course, we added bevacizumab to that, which we'll talk about next. And what's not shown here is the JCOG study showing that carboplatin was equivalent to cisplatin in this setting. So here was our turning point, GOG-240. Everyone probably knows this study very well, but just to review, these women were either stage IVB, recurrent or persistent with measurable disease, and good performance status, and had no prior chemotherapy. And this was a two-by-two factorial study where there were two chemotherapy backbones that were studied, both cistaxel and topaticantaxel, each plus or minus bevacizumab. And this study was open in the U.S., Canada, and Spain. And our next presenter, Dr. Tewari, led this trial. And as most of you know, there was an improvement in progression-free survival that was statistically significant, though some might argue not terribly clinically significant. There were also improved response rates with bevacizumab in addition to chemotherapy, regardless of which backbone was given. And then the overall survival did result in a statistically significant improvement from 13 to 17 months. And this was much more pronounced in the patients who had not received prior radiation, so your primary stage IVB patients. This was met with some significant toxicity. Clearly, all of the toxicities that were associated with bevacizumab, of which we were already aware, most frequently hypertension, but also a new adverse event was noted in cervical cancer patients, whereas the rectovaginal fistula, this occurred in seven of these patients. None were associated with sepsis or death, but certainly this is a concern and something that might be, we could potentially improve upon. So where do we go after GO2-240? You've heard a lot of information tonight about checkpoint inhibitor really being the next logical therapy to incorporate cervical cancer. We have three ongoing clinical trials, which we'll discuss here. So Dr. Moore did an excellent talk and really sort of touched on the markers of immune drivers in cervical cancer. So this is all initiated by HPV E6 and E7 and initially much driven by an increase in IL-6, which activates this inflammatory microenvironment that Dr. Moore mentioned, in addition to upregulating PD-L1. And this is all worse with hypoxia and TGF-beta expression and reactive oxygen species. Also, as Dr. Moore mentioned, cervical cancer, actually of all of the GYN cancers, has uniformly the highest tumor mutational burden of all of our tumors, only outdone by the MSI high uterine tumors. So this is preliminary data showing response rates and with different checkpoint inhibitors. And to the far right there, the Checkmate 358-Ipi-Nevo combo that Dr. Watkins presented at ESMO just last year. But not only are the response rates impressive, it's really the duration of responses that we're seeing. So you saw GO2-240, where we have a median overall survival of 17 months. Here, many patients who are achieving responses to immunotherapy, their duration being very long. And this is the BCC study. So BCC is the first, well, one of the first immunotherapy trials. Dr. Walkman is the global PI of this trial. We're very excited about this study. And this is basically the GO2-240 backbone with or without atezolizumab. And you can use carboplatin or cisplatin in this study. And patients are, this will enrich for the squamous cell histology. And PD-L1, as you heard earlier, is a marker for benefit of checkpoint inhibitor. PD-L1 status is not required for this study, but we will enrich for squamous cell carcinoma 80% of the patients. And the primary endpoint of the study is overall survival. Keynote 826 is a second randomized trial. This is actually the confirmatory trial for the accelerated approval of pembrolizumab, as opposed to BCC where bevacizumab is mandatory in both arms. Here, bevacizumab is physician's choice. And this is chemotherapy, plus or minus bevacizumab per MD choice, and then plus or minus pembrolizumab or placebo. Interestingly, BCC will be better able to tell if there's a synergy between bevacizumab and atezolizumab or checkpoint inhibitor. 826 will not be able to do that. And here, the endpoint, again, overall survival. And then the FERMATA trial is a third PD-1 inhibitor, BCD-100, also a randomized trial with a smaller sample size of 316 patients. And this study is ongoing. Interestingly, a thought. Incorporating whole pelvic radiation into stage IVB cervical cancer, is this a novel treatment strategy? So radiation directed to the primary tumor in the setting of distant metastasis is traditionally considered contraindicated. And as you heard earlier, this is typically reserved for the local control of oligometastatic disease. And it's actually very successful in several different tumor types. And so now we have two retrospective studies, because some of you out there were paying attention and reading the literature in these different tumor sites that show that radiation could be used to control disease, even in the metastatic setting. And these were retrospective studies, both conducted between 2005 and 2015 to 16, and small studies. Each of these studies had comparison groups. So they had two groups in each study, one of which received chemotherapy with definitive radiation. So this is full, whole pelvic radiation with a full dose of brachytherapy. In the YEN trial, they had a group that received palliative radiation as a control group. And in the Perkins study, they had a group that just received chemotherapy per the standard of care. And interestingly, and this is mostly pre-bevacizumab. I mean, the bevacizumab 240 standard of care change was in 2014. But they were able to show an improvement in progression-free survival in both studies. And interestingly, the overall survival improvement in the Perkins study was very significant from 41 months up from 17 months. So they originally intended this treatment to be a palliative benefit to patients to prevent all the pelvic complications that we know of, hemorrhage and fistula. However, they really didn't see any difference in palliation, but did find this fairly impressive increase in survival. Now, clearly, this is all retrospective data, and this would have to be replicated prospectively. But here you can see the survival curves, progression-free on top and overall survival on the bottom for each of these studies showing a fair difference between the two. And clearly, a lot of selection bias going on here as well. However, this data is provocative. It does raise the question of whether this is worth future investigation. I think there was no selection in these studies, but it's important to point out that this likely benefits women most who have a complete response to their systemic chemotherapy. And interestingly, as Dr. Milishkin just mentioned, possibly even more relevant if the systemic therapies improve and the addition of immuno-oncology agents could induce the abscopal effect with radiation, as Dr. Taylor mentioned. So let's stay tuned for this treatment to come potentially online. And I want to leave you with a couple of thoughts. As we incorporate immuno-oncology agents into multiple lines of therapy, and as our treatments get better, I think cervical cancer is going to be met with that same dilemma that we had with ovarian cancer, in which we have potentially multiple active post-progression therapies where our overall survival endpoint is going to become more and more contaminated and more and more difficult to interpret. And so I think in cervical cancer, we may need to start talking about transitioning our preferred endpoint for our clinical trials to progression-free survival with the patient reported outcome or quality of life endpoint, as we did with ovarian cancers a few years back. And then the last thought I will leave you with is that these therapies that we're developing, they're very exciting, and we work on these night and day, literally. But it is important to note that the women who need them are in our most underdeveloped countries and in the places where they're most difficult to gain access to. It's something that we need to consider as we continue to develop these therapies. So thank you for your attention, and I will hand it back to you. I thought I was mute. I don't know if you have been able to listen to me. Anyway, I will repeat. I would like just to thank Dr. Leslie Randall for her excellent talk. Just for those of you who are just tuning in, this is the master session on cervical cancer. Next up is Dr. Chris Tewari speaking on second-line metastatic disease. Chris, when you are ready, I see that your screen is already shared. Please go ahead. Thank you very much, Ana. Thanks for having me on this program. I'm really honored to be a part of this group. I think that my focus is going to be, for the next 15 minutes, to talk about second-line treatment for women with recurrent and metastatic cervical cancer. I think that immunotherapy is very, very promising in this space. You heard Dr. Randall, some of the studies being done in the front-line setting. I think I want to illustrate or emphasize the reason we are hopeful with immunotherapy is that there are really two avenues through which immunotherapy is going to possibly or potentially make a difference in this disease. The fact that cervical cancer is ubiquitously caused by high-risk HPV DNA infection suggests that there is an infectious etiology to this. You can see here, this is the DNA map of HPV and a consistent feature in all of the high-risk DNAs. You can see it here on the right, the E6 and E7 oncogenes. They're conserved in all the high-risk HPVs. Certainly, we've known that the breakpoint in the E2 reading frame is necessary for expression of E6 and E7 because normally E2 prevents transcription of these genes. Once the virus integrates by opening up the E2 regulatory gene reading frame, the virus integrates and these oncogenes are expressed. At 11 and 12 o'clock, you can see where the virus is integrated. You can see E6, E7, the regulatory genes, even the capsid protein genes, L1, L2, and then of course the patient's chromosomes all the way around. You can see the various amplifications and losses. What we've learned, and this is what I think is very striking, when Anna, Monk, Randall, and myself were working on the GOG240 trial over 10 years ago, we were really working blind. We didn't have this type of information. As a result, the use of Bevacizumab was done without a predictive biomarker to enrich the patient population. Now, we're through a lot of sequencing studies and things like the Cancer Genome Atlas. We've now recognized that there's several important amplifications. Of course, two of the amplifications are the PD-L1 gene and the PD-L2 gene. This is important because if you look at where the virus integrates, the integration points overlap with amplifications of a lot of these immune-directed genes. This is a paper from Ojasena's team that was published in Nature six years ago. Like I said, 40 percent of the integration sites overlap with the amplification of these genes. We really have two strategies through which to attack advanced cervical cancer immunologically, through the canonical viral antigen expression, but also through these immune checkpoint transcribed proteins. This is a really good illustration, kind of what Dr. Randall shared with us a little earlier, but in a different format. You can see that cervical cancer has a mutational burden that tracks with head and neck squamous cancer, lung squamous cancer, adenocarcinoma of the lung, cutaneous carcinoma, kidney cancer. They all track and cluster down at the bottom. We've got positive phase three data for all those other cancers with checkpoint inhibitors or immunotherapy. This suggests, because the cervix appears right there with a little asterisk, that we may be onto something. Again, we're not working blindly anymore. We're working using team science. The immunologic networks, of course, include checkpoint inhibition and T cell redirectional strategies. I'm going to just share with you some of the stuff that's happening right now in the second line setting, looking at immunologic checkpoints. Keynote 158, Dr. Randall did mention this. Again, this was a study that looked at different solid tumor cohorts. The cervical cohort was presented a couple of years ago. We were introduced to the combined positive score, which, as you know, is the number of PD-L1 positive tumor cells, lymphocytes, and macrophages divided by the total number of tumor cells times 100. With keynote 158, we saw that amongst the 77 patients that were valuable for the primary endpoint, the objective response was 14%, 2.6% complete responses, median duration of response when the paper was presented had not been reached. This led to the first US FDA regulatory approval of an immunotherapy for cervical cancer. The confirmatory trial is being done in the frontline setting. Dr. Randall and Leslie shared that with you. That's the keynote 826 study. In the second line setting, though, we also have a randomized phase 3 study looking at simplumab. This data was just published in GYN Oncology this month. It's the non-randomized phase 1 expansion cohorts. It was simplumab, anti-PD-1, 3 mg per kg every 2 weeks for 48 weeks with and without hypofractionated radiotherapy. That was administered during week 2. Again, this is non-randomized, but you can see that in the table over here that I've reproduced from the paper. The objective response, there was one partial response out of 10 patients and 3 patients with stable disease in the monotherapy arm. Duration of response, 11 months. This data was used to develop the GOG-3016 NGOT-Cervix-9 Empower Cervical Cancer Trial that me, Anna Oakman, and Brad Monk, and Ignatius Burgotte are running with Regeneron. Again, the primary endpoint for this trial is overall survival. This is the first phase 3 randomized trial of a checkpoint inhibitor for previously treated patients that have failed on platinum-based therapy, whether it was platinum with bevacizumab or not. The control arm is investigator's choice chemotherapy. Given that this trial is being done worldwide, the menu for investigator's choice really had to reflect the drugs that were available in different parts of the world. Beyond that, there's been a lot of interest, not just in cervical cancer, but in other tumors of combining anti-PD-1 and anti-CTLA-4 treatments. The rationale for this can be seen looking at this heat map. Basically, PD-1 blockade is only going to be effective if there are CD8-positive T-cells in the tumor. PD-1 blockade alone doesn't necessarily recruit those CD8-positive T-cells, but if you do simultaneous blockade of anti-CTLA-4, not only do you increase the expression of the CD8-positive T-cells in the peripheral lymph nodes and regional lymph nodes, but that blockade with CTLA-4 drives the migration of CD8-positive T-cells into the tumor, where then checkpoint blockade targeting PD-1 will be effective. You can see here on the left side of this graph, in these cervical cancer mouse models, combined blockade really reduced the tumor volume significantly, as well as had a higher recruitment of the CD4-positive T-cells. So, Checkmate 358 was presented last year in Barcelona. I think that was probably the last live meeting I attended, and, oh no, yeah, I think we went to NRG this year, or I can't remember. Anyway, this was NEVO plus ipilimumab, and there were two cohorts. There was the NEVO three migs per Kg plus ipilimumab one mig per Kg, and then NEVO and ipilimumab flipped, flip-flopped, and you can see objective responses for the two groups, 31.6%, 45.8%. You can see for the previously untreated patients, median PFS was 3.6 months, overall survival 10.3 months, but no prior treatment, and this is in 13.8 months, and overall survival wasn't reached. Very, very exciting data, and you can see the corresponding data on the right side of the table. Another interesting study looking at combined anti-PD-1 and anti-CTLA-4 is the RAPIDS study. The pre-planned interim analysis results were released. The late-breaking abstract is scheduled for presentation at the ESMO Virtual Congress in a few weeks, and again, this demonstrated that the combination of valstilumab plus xaliframilumab and valstilumab monotherapy did have an objective response of the monotherapy of 14%, and the combination objective response of 26.5%. There were four complete responses with the combination therapy, one complete response of the monotherapy. I'm really looking forward to hearing this late-breaking abstract at ESMO. Let's shift from checkpoint inhibition, and let's go to T-cell redirection strategies. Christian Henrichs at the NCI piloted this study where patients had to be sent to the NCI. They had to have a surgical biopsy. The tumor was cut out. The T-cells isolated, grown up, enriched, and then fed back to the patient as autologous T-cell therapy, and what was really interesting about this was not only were there two complete responses that were lasting in excess of a year and a half to almost two years at the time of publication, but these responses were in patients that had been heavily, heavily pretreated. One was a squamous cell cancer. One was an adenocarcinoma, and more importantly, the T-cell directed attack was against the mutated neoantigens that were present, not the canonical viral proteins that had been expressed, so this is basically a different strategy, but it's cumbersome, and having to send your patients to the National Cancer Institute and having them live there to have this done is difficult, and therefore, Iovance got a breakthrough designation for their technology. They're trying to pilot this study and try to bring this technology into the community by running this multi-center study. There's several different cohorts using the autologous TILs, which we refer to as LN145. I just showed three of the cohorts here. The primary cohort are the previously treated patients that are checkpoint naive. They get autologous TILs followed by IL-2, and the primary endpoint is objective response. Cohort two is previously treated patients that had failed checkpoint inhibitors. They get the same strategy, autologous TILs followed by IL-2 primary endpoint objective response. Then, of course, cohort three, there's a few other cohorts, but I just wanted to show this is actually a frontline study, autologous TILs followed by IL-2 followed by pembrolizumab up to 24 months, and safety is the primary endpoint in that group. Iovance study has been going on now for over a year and a half. I'm looking forward to seeing that. What about antibody drug conjugates? God, I just got to pause for a quick second. When Brad and I and Anna and Leslie were developing GOG240, bevacizumab was the only game in town. Now, the space is so crowded, and now we've got antibody drug conjugates coming online. You know the technology. There's an antibody, a cytotoxic agent attached to a linker. Tissue factor is one of the antibodies, one of the proteins that's targeted. This is the rationale for tissue factor expression. It's highly expressed in cervical cancer. On the left side of this slide, you can see the presence of tissue factor in patients that had positive metastatic disease in the lymph nodes in A and B. C and D on the left side are negative lymph nodes, and you can see there's hardly any tissue factor expression. Then on the right side, these are tumors, patients that had distant metastases. You can see tissue factor is highly expressed in the primary tumor of the patients that had distant mets in A and B, but the patient's tumors that did not have distant mets, C and D on the right side, did not express tissue factor. Tissue factor is a key player, key biomarker, prognostic biomarker for lymph node metastases and distant metastases in cervix cancer. We've got another LBA scheduled for ESMO in a few weeks. Again, this is with ticiturabidotin. This is the two megs per kilogram IV every three weeks, 101 patients. We had a press release. These patients had received up to two prior lines, primary endpoint by independent central review, demonstrated objective response of 24 percent, confidence interval 16 to 33, median duration of response 8.3, dry eyes, conjunctivitis, some epistaxis were the most common effects. Again, please register for this meeting. This is going to be very exciting. Another INOVA study, the previous one that's going to be at ESMOs 204, this is 205. This is looking at different cohorts. There's a dose escalation cohort that includes the antibody drug conjugate plus BEV or PEMBRO or CARBO, and then there's these phase two expansion cohorts, and you can see the different arms there. This study is ongoing, looking forward to that as well. Last thing I want to talk about is the HER family receptors. We always think about trastuzumab, you know, blocking the extracellular portion of the HER2 receptors, but you can also target intercellularly with the tyrosine kinase inhibitor, and it turns out that five percent of cervix cancers are HER2 positive. This is how we check for HER2, 3 plus IHC, or we can even use fish using the centromere protein as a negative control. This is the summit study. Dr. Monk and Anna did the study just recently published in GYN Oncology. These are HER2 mutant positive patients, 16 patients, got oral neratinib, the tyrosine kinase inhibitor, 240 milligrams per day. They also got diarrhea, prophylaxis during cycle one, 25 percent response, and for the three patients that responded, the duration response was 5.6, 6, and 12 months, median PFS 7 months, median survival 16.8 months. Again, exciting stuff. This is just about maybe 75 percent of the studies that are currently being done in the second-line setting, and it was my honor to share these with you. Thank you, Chris, for this excellent overview in the second-line cervical cancer. Our final presenter is Dr. Marie Plante, and she will speak on clinical care in under-resourced settings and how to start a clinical trial program. I think this is a very, very interesting talk, so Marie, we are honored to have you on this when you want. Thank you. Thank you. Good morning, good afternoon, good evening, wherever you are in the world, and thanks for being there. I have the privilege to close this session. I have to say that it's a completely different talk from what we've heard previously. You've seen this map over and over. It represents the cervical cancer distribution worldwide, and it's primarily a disease central in South America and South Africa and some parts of Asia as well. It's critical that the mortality in some parts of Africa is at least 10 times that of the mortality in Western countries, which is completely unacceptable. That has led the WHO to issue a global call for action towards elimination of cervical cancer, and particularly of this discrepancy throughout the world. Clearly, to improve patients' care, screening and vaccination are very important, as well as education, but research is also very important. Really, there is a disconnect when it comes to research because research in cervical cancer is primarily conducted in high-income countries and are publicly funded, but the rates of cervical cancer in high-income countries is actually very low, whereas the cervical cancer is a disease of low-middle-income country where the disease burden is greatest with high mortality rates. In fact, it became apparent to GCIG in 2015 that the areas of the world where research is conducted is exactly the mirror image of where the disease is mostly prevalent. This has led Professor Kitchener in 2011 to propose the creation of a cervical cancer research network with the idea to create a network of centers with interest and expertise in cervical cancer to promote research and good clinical practice. We recognize that participation in research yet generally will raise the standards for all patients as well, and it also addresses diverse ethical and cultural backgrounds and realities that are not the same in those countries that they might be in Western countries. The goals of the CCRN truly was to establish a network of sites to promote clinical trials and address their local key issues. We also developed annual symposium conducted in low-middle-income countries, generally sponsored by industry. They were made free to participants. So far, we have had four of those symposium, Bangkok, Mexico, Bucharest, Johannesburg, and we were supposed to have one in Vietnam in February 2020, but due to COVID, it was canceled. Hopefully, it'll take place in 2020. And at the time of those educational symposium, in addition to providing state-of-the-art symposiums, there's also hands-on workshop addressing clinical trials. So the work of the last several years is really starting to pay back in the sense that, as you can see, there are now several centers in many parts of the world that were not represented before and that are currently participating to CCRN trials. So you see them in South America and particularly in Brazil and Mexico as well, as well as in China, Vietnam, Thailand, India. So it is exciting to see that we're really starting to spread out. It is challenging to run international trials, but it's even more challenging when we run trials in low-middle-income countries. There are a lot of issues pertaining to financial constraints, organizational issues, and insurance coverage is particularly difficult, quality assurance, data management, and follow-up translation, and some centers actually have all of these things right, except they don't have funding for academic studies. So language barriers, translation, insurance and identification has been very problematic in some countries, regulatory approval, all of this takes time and it costs a lot of money. So it is challenging, but nevertheless, CCRN was successful in conducting several very important trials and that were with the participation of centers in low-middle-income country, and I would like to share those with you very quickly, but just for your own interest. There was a SHAPE trial, as you certainly know about, randomizing patients between RAD-HIS and simple-HIS in low-risk disease, and the trial finally was completed after seven years, and hopefully we will have the results to be presented in 2023. SENTACOV-3, which is a validation trial, a very important trial addressing Sentinel mapping, a very ambitious trial looking at 950 patients. And we're excited that already 157 patients have been registered, and already there's international collaboration with China, seven centers in Brazil are just about activating, as well as India. So we're excited to see, again in this map, that it's truly becoming an international trial, particularly in areas of the world that need it so much. LENTESA is a more recent trial addressing neoadjuvant chemotherapy in women with stage 1b2 disease who wish to preserve fertility, begin with neoadjuvant chemo and then continue on with fertility-preserving surgery. The protocol was just recently activated in Canada, as well as in the Netherlands. Andy Anderson is about to be ready as well to open up, and it will give us access to several sites in Latin America. We're very pleased with that. And SIGOG, Eastern Europe Centers of DOG, will also be participating. So we're excited about that as well. The TACO trial, which randomized patients between weekly and triweekly cisplatin therapy, has had a very important participation from Thailand, Vietnam, and China. We've heard about Outback participation from Asia, Singapore, and China, Saudi Arabia. Again, it took more than seven years to complete this trial. Hopefully, as Linda presented earlier, we'll be ready to submit or present next year. And then induction interlace trial of induction chemo followed by radiation therapy. Again, an ambitious trial, near completion, almost 85%. Very important participation from Mexico, as well as sites from India and Brazil. But you know, it's been going on for over seven years. It's taken a long time to complete, but it's getting there. And then lastly, there's an interesting palliative radiation therapy proposal out of Africa. Again, addressing their very specific needs. It randomizes patients to receive a single fraction versus five fractions, addressing the problem that they have very limited access to radiation therapy. So it tries to address their own particular issues. So this is to say that through all this background work, there's been a lot of progress and a lot of countries now are participating, such as in two trials, such as in China, India, and Brazil, Mexico. These two countries are now part of GCIG as well. So can you imagine if only 1% or 2% of patients with cervical cancer in low, middle-income countries could participate in a clinical trial? Can you imagine what that would do? I mean, we could do these trials in two to three years, as opposed to taking seven or eight years. But it's not good enough to say that it's important to have these centers participate in clinical trials. We need to take concrete action to engage clinicians in those areas of the world to participate and even to lead some clinical trials. So I would like to complete this presentation by proposing or informing you about four important initiatives, which I do hope will be helpful for clinicians from under-resourced countries. The first initiative is what we call the CCRN Research Grant Initiative. We will soon be announcing a call for proposals to support small research initiatives with the aim to improve the care and outcome of cervical cancer. It will be a maximum of four awards per year, up to $5,000 each, primarily to researchers that registered CCRN sites to begin, but it could also be available to any site where there is no established national research groups. And the initiative will soon be publicized through the GCIG website at the time of educational symposium and through the journal as well. The criteria are pretty elastic, I would say, in the sense that as long as it pertains to cervical cancer and the types of studies are all good, it could be a retrospective or prospective study, quality of life, palliative care, as long as it has to do with cervical cancer. The second initiative is what we call the YIP, which is the Young Investigator Program, which really is a program which was proposed by Andres Porveda in 2018. And the idea was really to mentor young investigators within the GCREG to monitor them to becoming what I call the next gen. In other words, the next generation of investigators. And this program has evolved to becoming an entire day of presentations around the design of clinical trials and execution of clinical trials, very extensive day of presentation. And with the COVID and all that, these presentations and this symposium is primarily now available online and virtual. So it's a unique opportunity for investigators or colleagues from low and middle income countries to participate to these training symposium and to get to have advantage of hearing these presentations at very low cost and to get education. There is the GCIG IGCS Early Career Program as well. The goal is to develop and promote research ideas. We recognize the importance of publishing for career development. And so at the time of GCIG IGCS meeting, it's an opportunity for early career networking and to create a space for young investigators to present their work. And again, it's a unique opportunity for researchers and clinicians from low and middle income countries to participate in those meetings and to network and to have a space as well to present their work. And lastly, what I think is also very exciting proposal and initiative is, as you know, there is currently a two-year fellowship program that is offered through the IGCS to gynecologists from underserved countries or areas of the world. They have access to a complete two-year fellowship program, very high quality with the board examination and all that. And it's been run primarily by Kathleen Schmeller. And we had the idea that within that fellowship program in gynecology, we could integrate a fellowship in clinical research, either as part of the current curriculum of the program, or it could be even an additional six to 12-month training specifically in clinical research. We think it would be wonderful if those young gynecologists, when they return back to their own country, to their own centers, that not only would they be great clinicians, well-formed, but it would have the capacity to develop clinical research in their own centers. And it could be key players for us to link with when we want to develop clinical trials in those areas. So it's a work in progress, but we're excited. And CCRN is keen to support this initiative as well. So as I just said, four initiatives that may be of interest to some of you listening, research grants, young investigator program to get better education, early career program, and a fellowship in clinical research. And all of this is to create a space to network, to present the work, to publish, and to get solid training in clinical research. So with this, I will turn back the screen to Mary McCormack, I think. Thank you for your attention. Thank you very much, Marie, for a wonderful presentation. And thanks to all our speakers for staying on time, which means that we actually have time now in the session for questions. And we have some questions for our panelists. And I'd just like to ask Dr. Taylor if she thinks that there's any role for protons in the treatment of cervical cancer. Yeah, sorry, in the interest of time, I'd removed my proton slide. So, I mean, in terms of primary treatment of cervical cancer, I think there are questions. There have been several dosimetric studies comparing intensity modulated photon therapy to intensity modulated proton therapy with similarity in dose. But the issue is dealing with the robustness of the planning, because with protons, you start considering the impact of the motion and gas. And once we start bringing in those uncertainties, it is still very much selected cases and small numbers that have been treated with protons. I think there's more of a role for it in treatment of recurrence and with re-irradiation because the characteristics of the proton beam is that you can use generally one or more commonly we're looking at using two beams that have very sharp drop off. And so if you're treating the sidewall, then you can get a much drop off in the more distal organs at risk. And so in comparative studies, we've certainly seen that you can have reduction to the organs at risk. But again, comparing stereotactic radiotherapy for re-irradiation and protons often depends on resource and experience. And I know that this is the scope for future trials that are being planned. Thank you, Alex. Thank you very much. Dr. Randall, I have a question for you. Could you comment on sort of KRAS mutations and perhaps the role of MEK inhibitors in cervical cancer treatment? Oh, sure. I think that may be for Dr. Moore, but I'm happy to. Sorry. Apologies. Dr. Moore. So either one of you. Either one, yes. I just had a... I think maybe both of us could answer. I just had a B12V mutation in a cervical cancer, which is a hotspot for MEK inhibitors. Should I try to give her a MEK inhibitor? Well, I think if you've exhausted what you think will work, which is not hard because we can quickly exhaust what we have available right now. I'm all for giving anything that you think will work. And I mean, what a great proof of concept as well. I mean, if it works, share. Have you ever done that, Katie? No. Well, I mean, I've definitely done it in other tumors. I don't know. KRAS mutations in cervical cancer occur in about 8% KRAS and about 8% to 9% in RAS. So there are RAS mutations and they're mostly in non-squamous, non-adenose. They're more common in sort of rare histologies. So I'm trying to think if I've ever seen one. As you just alluded to, G12C is the most common in lung cancer. And so we have the most data about how to think about targeting G12C. Although, as you all know, targeting KRAS, they call it the untargetable target for a reason. So, you know, you can't target KRAS directly, you have to target the downstream, which can be MEK or BRAF. BRAF you don't find at all in cervix, interestingly. So I don't think it's unreasonable, but you're kind of a little bit going outside the realms of data. I don't think there's any, I don't think it's wrong, but I don't think that there's great data to support it. I don't want to belabor the point, stay tuned. And Mary, and for you and many others, I had an interaction today with New Guinea. And they said, look, in New Guinea, we don't have a single radiation unit. How are we supposed to treat cervical cancer without radiation? Mary or Alex or Marie or any, give our listeners an idea what to do when there's no radiation units, which is not uncommon in these under-resourced areas. I mean, one of the areas that obviously people will look at in these situations is they will, if they have availability of drugs, which are cheaper and more widely available, then, you know, the use of chemotherapy to downstage the patients. Yes, it's still experimental, but if there is nothing else available, then a proportion of patients will respond at least to palliate the symptoms. And then if it's at all possible to operate on those patients, again, some will benefit from that approach. But of course, you know, it's not what we would ideally do, particularly with locally advanced disease. But we have to recognize that in many parts of the world, there simply isn't the opportunity to treat those patients as we would wish to do with chemoradiation. Could I just ask Linda, Dr. Milishkin, you commented on your presentation, which I very much enjoyed, and it's really just bringing us back to immunotherapy and where we're going with maintenance therapy. And certainly some of my thoughts have been around the duration of maintenance therapy. And I wonder, you know, this is a very mobile population of patients, young women, they often tend to move around. You know, they're not the older groups that we traditionally treat in ovarian cancer, where maybe it's easy to give maintenance therapy for many years. Do you think this is going to have an impact? And do you really think we need two years? Well, I don't know, but it'd be good to hear from the people involved in the design of those trials. It seems like it was sort of an empirical or best guess decision. Whereas, you know, in the pivotal lung cancer trial, the Pacific trial, they only gave one year of immunotherapy. And certainly in the melanoma space, they're now trying to kind of work out, you know, when they can stop using things like monitoring by PET scan. And if there's no evidence of disease stopping some of these agents earlier, it's obviously much harder in the adjuvant therapy space. But yeah, you would hope that you perhaps don't really need two years of maintenance immunotherapy. Yeah, I think we have to watch that space and see what transpires. For me, one of the other interesting things that we really need to come back to again is to emphasise the importance of really good chemo radiation. I mean, this is the most important treatment modality for the vast majority of our patients with locally advanced disease. So it is absolutely imperative that those patients complete their treatment in a timely fashion. It is imperative that they receive brachytherapy. There isn't a substitute for that. And that's been shown over and over again to significantly improve survival. And of course, where it's available, where possible, they should also have concomitant cisplatin. And I think it's quite eye opening to actually realise that a lot of patients in the 21st century are still not receiving really good radiation. We accept that there are parts of the world where this isn't available. But I think it begs the question that we really need to focus more on radiation quality assurance and ensuring that those people who treat cervical cancer really know what they're doing and adhere to the best practice guidelines. Hey, Jolene, I've seen you operate in your beautiful Charity conference. You're very good at it. You make it look easy. Do you ever, and Chris, you had a comment on this, did you ever debulk nodes? So if you have a four centimetre, you know, lower aortic node, you ever cut that thing out and you say, I'm just going to, I'm going to send it to Mary or Alex and they're just going to take care of it. You ever cut that thing out? So I think maybe there are some very, very rare cases where we have maybe relapse as a single case, PET CT scan, no other, no previous radiation. And then I think in an individual case you can discuss with a patient to do a surgery. But in general, I think to debug largely lymph nodes is not really a benefit. So we change our behaviour in the last years. So I think again, in an individual case in relapse, I think yes, but for the waste of majority of these tumour pattern, I will not believe that surgery is the best candidate for these patients. So Alex, how big of a tumour nodule can you like sterilise with confidence? Well, I mean, as I said, when we've looked at the series of groups, there doesn't seem to actually be a size response as in very large tumours, even above five centimetres seem to still be controlled with not as higher doses we're looking to give to primary tumours. I must say very large doses. That's where, as Mary said, sometimes neoadjuvant chemotherapy may be the approach. My concern about surgery is that you're inducing radio resistance, you're causing hypoxia and the outcome in lymph node debulking where it's incomplete. The outcomes are extremely poor and far worse than you achieve with primary chemoradiation. And as I say, we're seeing that the size doesn't seem to matter. Assessment prior to brachytherapy may predict those that need a subsequent boost if they have not had a good response at the point of brachytherapy. Thank you, Alex. So I think I would just like to say now thank you very much to all our panellists for the excellent presentations. And thank you very much to the audience. I think we've had a tremendous number of people tune into this session. And of course, for any of you that have been unable to see it live, the recording will be available within 24 hours and it will be available and accessible up until September 24th. So if any of you have any additional questions, then please feel free to put them in the link chat feature in the portal and we'll do our best to to get answers to you. So from me here in London, where it's still dark to all of you across the world. It's a shame we're not all together, but have a wonderful plenary session. Enjoy the rest of the meeting and thank you for tuning into the Cervix Masterclass today. Goodbye. Thank you. Thank you. Take care. Thank you. Take care. Bye. Bye bye.

pembrolizumab

checkpoint inhibitor

locally advanced cervical cancer

clinical trials

metastatic disease

adjuvant chemotherapy

chemoradiation

Outback trial

carboplatin

paclitaxel

neoadjuvant chemotherapy

Interlace trial

STARS trial

high-risk patients

low-middle-income countries