Good morning. We're off to a great start. Welcome to Seoul, Korea. My name is Brad Monk. I'm a gynecologic oncologist from Phoenix, Arizona, and the vice president of the GEOG Foundation and the director of the GEOG Partners organization. It's my pleasure to welcome you here. It dawned on me that my first visit to Korea was 20 years ago at the IGCS in 2003. So it's good to be back. I've been back several times. It's been amazing to see the advancement, not only in surgical, but also radiation and medical innovation. The title of this session is the non-surgical management of cervical cancer. Why non-surgical? Well, surgery is, first of all, very, very important in cervical cancer. And if it hasn't dawned on you, it's been more than 30 years since the introduction of minimally invasive surgery. To my best estimation, the first minimally invasive laparoscopic surgery hysterectomy, if you will, was in 1989. That's my best estimation. The first radical minimally invasive surgery is in 1992. So again, about 30 years. And here in Korea, the da Vinci robot was introduced in 2004, 20 years ago. So I think the techniques are well established, but the innovation in the technique has not necessarily evolved anymore. You guys know how to operate. But the question is when and what to do. And you saw earlier today the SHAPE trial, but also the LACK trial in 2018. And I just reviewed the state of the science, and so that's not what we're going to talk about. So we're going to talk about the non-surgical treatment. Again, surgery is important. We do it well. We're still debating what to do. But when we have consensus on what to do, I think we do it with great skill. I invite you to converse with us, to utilize the IGCS 2023 mobile app. We have established an elite group of panelists from all over the world. We're going to talk about, obviously, biomarkers. We're going to talk about radiation, because that's non-surgical, and actually the radiation technology continues to evolve, and we're so happy to be here with you. We're going to talk about immunotherapy. We have international experts, and then ultimately beyond immunotherapy and anti-angiogenic. So let's kick it off. I'd like to introduce Jiahong Liu from China to begin this conversation about biomarkers. Thank you and welcome. Thank you. Thanks, Meng. Good morning, ladies and gentlemen. It's my great honor to be here to present this talk. I appreciate the organizing committee to give me this opportunity. The aim of this presentation is mainly to review the evidence of biomarkers in advanced and recurrent cervical cancer. I have nothing to declare. We know the prognosis of cervical cancer patients is largely affected by a fecal staging. That's about 8% to 26% of cervical cancer patients will develop the recurrent disease within the first two years after primary treatment. Recently, immunotherapy has emerged as a promising option of treatment for the recurrent and the metastatic cervical cancer. Some biomarkers have been indicated as a companion diagnostic for the immunotherapy or target therapy. So we know that PtL1-positive, TMP-high, and MS-high may predict a good response to immunocheckpoint inhibitors. And the PtL1-positive can be seen in up to 85% of cervical cancer cases. And TMP-high occurs in 21% to 25% of cases. And the MS-high-positive is quite low in the cervical cancer patients. So we use immunohistochemistry to measure the PtL1 expression using the different antibodies. But there are four FDA-approved companion diagnostic tools to determine clinical PtL1 expression. But only the antibody 22C3 is approved to use for the cervical cancer, which detects the both membrane and the cytoplasmic PtL1 expression. In this picture, we can see the PtL1 just strongly expressed on the membrane of cervical cancer cells. So there are three scrolling methods, including the TPS, CPS, and the TAP to evaluate PtL1 expression. CPS is commonly used in cervical cancer. And the scrolling one or more is considered for the PtL1 expression positive. The maximum score is defined as CPS 100. Another biomarker for the immunotherapy is DMMR and MSI. DNA mismatch repair is a highly conservative mechanism used to restore DNA integrity after the occurrence of mismatch errors. Four genes play a critical role. If one of the genes is inactivated, it will result in the defective MMR mechanism may cause the MSI presence. So far, we use IHC to detect DMMR clinically. And the PCR is a good standard for the MSI testing, which is normally just indicated when IHC results are not determined. And just a little data available on the reliability of IHC detect and MSI PCR. So NGS is an alternative test. Tumor mutation burden is a total number of somatic mutations per coding area of tumor genome. So three FDA-approved companion diagnostic tools are used to examine TMB according to the different types of tumor. WS is a good standard method to measure TMB. But this method is cost too much and takes time to analyze. So NGS panel is more widely used, and they are highly consistent with WES. And so far, the most optimal cutoff point for TMB are not well-defined and may vary across different platforms and states. So expression reach of these three biomarkers in cervical squamous cell carcinoma is much higher than that in cervical adenocarcinoma, but no larger sample data available now. What about the relationship between the MSI-high and TMB-high and the PD-L1-positive? So we can see that TMB-high, MSI-high, and the PD-L1, these three biomarkers' co-expression was observed in only less than 3% of all cancers, about 2% in cervical cancer. MSI-high generally occurred as a subset of high TMB. 83% MSI-high samples also had a high TMB, more than 20 mutations per MAC base. Only 16% high TMB samples were classified as MSI-high. So in cervical cancer, co-occurrence of these two biomarkers was not that common due to the low incidence of MSI-high in cervical cancer. So we use IHC to evaluate HER2. So because HER2 pathway becomes very hyperactivity in many cancer cells, also in cervical cancer. So I just briefly introduced HER2 gene variations, including the amplification or expression and the mutation. So IHC was used to evaluate HER2 protein expression levels, and we use in situ hybridization to assess HER2 gene status. And HER2 gene also can be tested by NGS. In terms of the prevalence of HER2 in cervical cancer, you can see the HER2 amplification can be seen in cervical cancer in 0.5% to 14%. And HER2 protein expression can be seen in cervical cancer of 21% of cases. But HER2 mutation rate is quite low. This slide shows ASCO and the CEP HER2 scoring and the interpretation guidelines for gastric cancer and breast cancer. So we can see there are two status for the HER2 positive. One is IHC2+, combined with FISH positive. Another one is IHC3+. There are some small trials to investigate the treatment targeting the HER2. Some of it is FISH2 single-arm basket trial using the neratinib. Neratinib is oral pain-herd TKA drugs. In this study, 16 patients with advanced cervical cancer were included. Response rate in this cohort can reach the 25% PFS seven months and OS nearly 17 months. So the neratinib showed the promising clinical efficacy in heavily pretreated cervical cancer patients. Another FISH2 multi-center FISH2 study is DP02. You may be familiar with that. This study includes seven cohorts, including the cervical cancer patients. 40 patients with metastatic and recurrent cervical cancer patients are included in this study. You can see the response rate reached 50%. If we look at the subgroup with HER2 expression three plus, so the response rate is even high to the 75%. Just two weeks ago, we noticed the PFS results of this trial are reported at a small meeting. Cervical cancer cohort also had PFS benefit. So in conclusion, PDR1 positive TMB high and DMMSI presents current biomarkers for the effects of immunotherapy in cervical cancer. Also the PDR1 alone might not be a good enough predictor. PDR1 tested by IHC with a CPS scoring and the TMB detection can use either WES or NGS panel, while the NGS is recommended to detect MSI high. HER2 IHC detection has not yet established a unified interpretation standard in cervical cancer. Treatment targeting the HER2 have a significant clinical effect on the cervical cancer. Some other biomarkers, such as TROP2, ARIDA1A, something like that, have been seen in advanced cervical cancer. They have a high expression rate, but we don't have time to talk about today. So this supports the design of a clinical trial for the further investigation. Thank you very much for your attention. Thanks. Thank you, Dr. Liu. Please join us at the table for a short question and answer. Let me ask if there are any questions from the floor for Dr. Liu. Can I ask you something? I mean, first of all, thank you for a very thorough presentation about the biomarkers in cervical cancer. Do you know, we discuss a lot about PDR1 in cervical cancer, particularly because, of course, immunotherapy is the star, OK, right now. And so do you believe that you mentioned that CPS, for you, is probably the best biomarker to predict efficacy of immunotherapy. So do you believe that really we should use CPS to select patients, which antibodies, because there are different antibodies, there is different methodologies, different algorithm. And actually, even today, we heard in keynote 826, as you know, we have 89% of patients with positive CPS score. So it's different to understand how you can discriminate since the prevalence of CPS1 and higher is so frequent in cervical cancer. Do you still believe this is a good marker, or we should look for a different one? OK, thank you for your questions. Just like I have mentioned in the summary, I don't think that PDR1 alone is a good predictor for the cervical cancer patients to use immunotherapy. Of course, in some phase three trial, such as keynote 828, so we can see the patient with a different CPS score in the specification. So you can see the PFS and the OS are almost the same. So I don't think that PDR1 alone is good enough for the predictor of efficacy for immunotherapy. I think we need to explore more other interesting biomarkers, such as I just mentioned RAID-1a. So we have seen this marker has a very high expression in a cervical adenocarcinoma. So maybe we need to do something about that. Thank you. Hi. Good morning. Regarding the positive result of the DESTINY trial presented at Osgoode this year, if you have access to both ADCs, which would be your sequencing, when are you testing for her to cervical cancer patients? Thank you. Leslie, you want to take that? Yeah, I can take that. Hi, Angelica. I will address this a little bit in my talk, but yeah, I think that the best data that we had, do you mean to Zotamab, Vedotin, and sequencing that with HER2, is that what you mean, or do you mean immunotherapy? No, after immunotherapy. After immunotherapy. I think at that point you'll have TV and the HER2 ADC, and right now the best data that we have is with Tizotamab, Vedotin, and that's more broadly applicable than the HER2 will be, and I don't think we truly know the frequency of HER2 expression or cervical cancers. We do know that it's higher in adenocarcinomas, lower in squamous cell carcinomas, so not all patients will be eligible for the HER2 opportunity. I think in terms of sequencing, I'm not sure which one to do first or second, but I know that the TV will be more widely applicable across the board. Yeah. Great question. Could I comment on that? And thank you for that question. Remember, HER2 plus is about twice as common as HER3 plus, and there is apparently a big difference in the 2 plus and 3 plus, and the NCCN recommends 2 plus and 3 plus, but the FDA has breakthrough therapy only in the 3 plus. So I think the answer to your question, in my opinion, is in a 3 plus patient, you probably should prioritize HER2 first over Tizotamab, Vedotin. In the 2 plus, it's a very tough question because the activity in the 2 plus is very similar, particularly from a progression-free survival standpoint, disease control, not just ORR, very similar to TV, and TV will probably be more widely available, so I would probably prefer TV in the 2 plus, probably HER2, Trastuzumab, Daroxetacan in the 3 plus, but that's a really, really good question. Thank you for that. Could I ask Nicoletti? Can I make one comment? Yeah. Yeah. I think that I agree with that. So as long as the Destiny data is confirmed, it is still a small subset. Forty patients. Right. Nicoletti, I'm so happy. We have so many smart people from the audience in here. So Nicoletti, your wonderful study, A26, had 11% negative rate, but A18, it was only 5%. Yeah. I get it. It's not perfect, but is the difference, and maybe there's not a difference, maybe 11% is the same as 5%, but do you think there's antigenic decay in the A26 PD-L1 antigens because they sat around for a long time versus the A18, the patients newly diagnosed? Is that a thing or am I making that up? I don't know. Maybe Dr. Liu can answer that, but I don't see a big difference between 5% and 11% actually. And this is, in fact, a different population probably. Keynote is a more advanced persistent recurrent disease, and this was kind of newly diagnosed in A18. But I don't know if you have a more reliable answer to that on the different expression of it. I'm going to throw in an alternative hypothesis. I mean, it's potentially tumors get immune exhausted over time, so possibly biology, but I bet I wouldn't be surprised if it was a combination of both the antigenic, just the practical antigenic decay, and then potentially changes in the biology with exposure to repetitive cytotoxic treatment. Zhihong, what do you think? Do the antigens, are they unstable over time? I don't think so, but I'm not an expert. You are the expert. What are you talking about? Okay. So, I think we should move on, and so it is my pleasure to introduce Remy Noot from the Netherlands, and he will present the Evolving Standard of Care in Locally Advanced Cervical Cancer and the Role of Radiotherapy in Oligo- and Metastatic Settings, please. Thank you very much for the introduction, and I would like to thank the organizing committee for the opportunity to discuss this topic with you this morning. These are my disclosures. So today, we will discuss locally advanced cervical cancer, advances in chemoradiotherapy and brachytherapy, but also new emerging evidence in systemic therapy, and on the last part, the role of radiotherapy in the oligo- and metastatic setting. So, to introduce the Evolving Standard of Care, we go back two decades, and the 1999 NCI alert, and later, you see the results of the meta-analysis for the addition of concurrent chemotherapy, and weekly cisplatinum has become the new standard, and the results in this meta-analysis of 18 randomized trials indicate a five-year overall survival benefit from 60 percent to 66 percent. And now, we are more than 20 years down the road. If we talk about Evolving Standard of Care, we can look at it in a broad way. When we look at radiotherapy before the century, but this is a slowly transitioning technique, it was mainly x-ray based. External beam radiotherapy was four-field technique, and brachytherapy was prescribed to point A using standard plans. Over the last 20 years, we see, of course, the introduction of imaging, CT, MRI, PET-CT, which has greatly also improved our diagnostic accuracy, which impacts on radiological staging, and it has been incorporated now also in FIGO. From radiotherapy perspective, we've seen the introduction of IMRT, VMAT, more conformal radiotherapy techniques, and image-guided radiotherapy treatment delivery, but also the introduction of image-guided adaptive brachytherapy. It's good to realize that we have two phase three randomized trials that have demonstrated the superiority of IMRT over 3D conformal radiotherapy, indicating decreased late morbidity and better physical functioning. When we look into brachytherapy, we've seen the introduction of MRCT-compatible applicators, and very important also the introduction of intercavitary and interstitial combined applicators, and that has resulted in more conformal treatment. And when you look at this image, in the top two panes at the moment, you see a standard point A-based plan, and you can see that using a standard point A dose plan, in this case with a residual tumor in the parametria, you do not cover the complete tumor with the desired isodosis, and at the same time, you're creating an overdose into the bladder region. So a standard plan in such a patient is very unfavorable. When we look what we can do nowadays using combined intercavitary-interstitial techniques, you can really see in the lower two panes that you're able to use this combined intercavitary-interstitial technique to cover the tumor more adequately, while at the same time sparing sensitive organs at risk. And when we look into recent data, and this is from the retro-embryo study, we can see that in larger tumors, on the left-hand side, and defined as tumors with a residual high-risk clinical target volume larger than 30 cc, a combined intercavitary-interstitial technique also resulted in a better local control, whereas in smaller tumors, the prognosis local control rate is already very good, and there is no additional benefit of interstitial technique, but we should look more into morbidity. Moving on towards EMBRACE 1 results, EMBRACE was a prospective study on the introduction of MRI-guided, image-guided adaptive brachytherapy and the introduction of that, and here we see now that a great improvement in local control, as you can see on the right-hand side, also now in higher stages, so stage 3B, 4A disease, also having local control rates of 90%, and this altogether, if you look on the left-hand side, resulted in local control rate of 92% at five-year, pelvic control of 87%, and overall survival of 74% across all stages. Important to realize that now in EMBRACE 1, approximately 40% of patients were treated with combined intercavitary-interstitial technique, so this is an evolving radiotherapy practice. Looking into risk factors in EMBRACE 1, it's very clearly lymph node status, we know that very well from other major series, also histology, adenoscomas, carcinoma, but interestingly, also necrosis on T2-weighted imaging. And now we finally are also arriving at data where we can look at response to treatment, because we looked at the residual tumor volume at time of brachytherapy, in this case defined as high-risk clinical target volume greater than 45cc, which was also a significant, important predictive factor. So taken together, when we look at the whole population of locally advanced cervical cancer, there are several risk factors present, and they indicate that there is a more favorable group and a more high-risk group, and favorable outcomes have been seen in lymph node negative and squamous cell carcinoma patients. And also these results have indicated, for instance, the importance of some quality parameters like overall treatment time. When we move on to adjuvant systemic therapy, and this was a recent meta-analysis, many studies have been done over the last two decades, and there was no significant benefit in unselected patients, but we did see added toxicity of adjuvant systemic therapy. One of the largest studies recently performed was the OUTBAC trial, randomizing standard chemoradiation versus chemoradiation, followed by adjuvant carboplatin and paclitaxel, and five-year overall survival in this trial was around 70% in the standard arm, with no significant improvement of adjuvant carboplatin and paclitaxel, and also no indication of differences in patterns of disease relapse. Moving towards neoadjuvant treatment, and this is just one slide on the role of neoadjuvant chemotherapy followed by radical surgery versus concurrent chemoradiation, and the survival curves are from the Indian study, but the ERTC 55994 on the same topic found very similar results and was published this year, and here we also do not see a benefit from neoadjuvant chemotherapy plus surgery. It was not superior to the standard chemoradiation, and note the five-year overall survival in this slightly more favorable population is 75% at five years. So this brings us to the next combination, and that is neoadjuvant chemotherapy followed by standard chemoradiation, and it was very exciting two weeks ago at ESMO presented by Mary McCormack on behalf of the Interlace group, the Interlace trial, and here today in the previous session she also received the Global Impact Award, and it's highly deserved and we want to congratulate also Mary McCormack and the Interlace team on that. So in Interlace, 500 patients were randomized between induction chemotherapy followed by standard chemoradiation or chemoradiation, and patients were included over a 10-year period 2012 to 2020, and of course in that period there is a diverse array of radiotherapy techniques, and the study team has paid great attention into doing quality assurance across these techniques. Importantly, this trial included a range, a wider range of locally advanced cervical cancer, so 1B1, no positive, 1B2, 2B, up to 4A, and when we look into disease characteristics, the majority of patients were 2B, 70%, and around 14% 3B or 4A, 82% squamous cell carcinoma, and a majority around 57, 58% were not negative. Looking into the results of Interlace, there was a clear benefit in progression-free survival, 9% increase from 64% to 75% in five years, and an 8% improvement in five-year overall survival from 72% to 80%. Importantly, when we look into patterns of relapse, there was a decreased crude rate of distant relapse from 20% to 12% in the neoadjuvant chemotherapy arm, while there was no difference in pelvic recurrence rate across both arms. So moving into the discussion, importantly previous adjuvant and neoadjuvant surgery trials were all negative, and now we have a first level one clinical trial demonstrating an overall survival benefit from neoadjuvant chemotherapy followed by chemoradiation, and importantly, again, less distant relapse, which is intuitively, of course, what we want to see. So a point for discussion. It's not easy to compare the trials if we want to estimate the five-year overall survival in the chemoradiation arm, because you have to combine T and N stages across the different trials, and that's not easy, especially also with the evolving FIGO stages. Furthermore, there is an inclusion of different radiotherapy techniques over this period, as already discussed. Of course, this has been randomized, so that's taken care of, and for instance, there are interesting questions as regards to the delay start of chemoradiation in the standard arm. Importantly, this treatment is feasible from a global perspective, and it was demonstrated in this study. So can we learn more, for instance, about these diverse techniques? And I think one of the most important questions from my side is, do we need now induction chemotherapy in all patients, because we know there were also favorable patients in this study, for instance, in node-negative squamous cell carcinomas? And hopefully, a future publication will elude into some of these questions. Another important study that was also today presented and presented at ESMO was on the combination of chemoradiation and immune therapy in the form of PD-1 inhibitor. So this was the Keynote A18 study, a randomized double-blind phase 3 study comparing chemoradiation plus concurrent pembrolizumab followed by pembrolizumab, or chemoradiation with placebo. And Keynote A18 demonstrated, with a median follow-up of almost 18 months, a progression-free survival benefit, an increase in two-year progression-free survival from 57 to 67 percent. So for Keynote A18, a strong point is that they included higher-risk patients in the study, and I think that is a trend that we see now in adjuvant studies. Two-year outcomes are promising, but we have to realize the duration of active treatment in the experimental arm is almost two years, and we're looking at a median follow-up of 18 months. So there is definitely a need for also longer-term follow-up, especially, of course, if we want to evaluate overall survival outcomes in this study. And then also important, can we better select patients that benefit? The majority of patients, more than 95 percent are CPS, more than 1 percent. And that's, of course, then a difficult parameter, I think, to use, and that was already also discussed previously. And another question is, can we better understand the benefit of the concurrent phase versus the adjuvant phase of NTPD1 treatment? And putting it into perspective, the CALA trial with Dufralumab was negative, and there is one other study with Atezolac that is still ongoing. So this is an interesting development. So moving towards radiotherapy in the metastatic setting, this was a large NDCDB analysis in metastatic cervical cancer, where there was clearly demonstrated benefit, also looking into a propensity score match analysis of radiotherapy and chemotherapy compared to chemotherapy alone. And looking a bit more into detail, of course, there is bias due to selection. And they have done a propensity score matching. But patients that received relatively higher doses towards standard of care definitely had better median survival at two years. So the take-home of my presentation is that chemoradiotherapy and image-guided adaptor brachytherapy is the current standard of care. Publications of interlaced and keynote studies are eagerly awaited to evaluate more detail. And I think one big question is, can we better select patients that benefit from these more intense therapies? And finally, there is emerging evidence for the integration of high-dose radiotherapy in the oligomeric static setting, including brachytherapy. Thank you. Thank you. Thank you, and congratulations. That was excellent. These slides are so fantastic. Thank you. We don't have a lot of time, but I have some quick questions. So let's have some quick answers. So let's talk about prognosis. Prognosis in locally advanced cervical cancer is based on three factors, the primary tumor, the size, if you will, the type of local spread, and I'm going to get back to that, and then the nodal status, the number, the size, and the location. Let's talk about this type of local spread. I have been taught that uterine corpus extension, the type of local spread, is a bad thing. Kailash Narayan has talked about that from Melbourne. Is that a thing? Well, we definitely see that infiltration in the uterine corpus has prognostic impact. That's absolutely true. I think so. And we have a lot of very smart people here, David Gaffney and others. Sorry to call you out, but feel free to jump in. The next question is, I agree with you that image-guided brachytherapy is the standard. Just what you said. What percent of brachytherapy is image-guided? And if it's not high, why not? I think that's a very good point, and especially talking from a global perspective. We do see, so of course, there's MRI-guided, image-guided adaptive brachytherapy, and there's CT, image-guided brachytherapy. And recently, there has been also the introduction of guidelines for CT-based, image-guided adaptive brachytherapy. And there's definitely an increase. And CT is used much more broadly when we look at it from a global perspective as compared to MRI. And studies are ongoing, and there have been already studies published on CT-based, image-guided adaptive brachytherapy. So Nicoletta and Leslie, what do you think? Image-guided brachytherapy, how common is that in Europe? I think in Europe, it's quite common. But as Amy said, I mean, we have to think that cervical cancer is actually much more frequent in less developed countries. So I'm not sure how much is frequent to have this kind of technique. May I ask you something about the duration of treatment? Because you didn't mention it, but I think it's quite important. Because this morning, I was listening to the interlace and to the A18. And it was quite a different length of treatment. Because interlace was only 45 days and was 56 days in A18. Do you have any comments on that? Yeah, so overall, treatment time is an important factor. And there are several studies that have indicated that. And that's why also proposed in quality indicators from ESCO is overall treatment time below 50 days. Again, in interlace, there was a lot of attention paid also on QA. And that is, of course, definitely an issue in treatment and management of cervical cancer. But teach our audience. So let me give you the yin and the yang. So generally, high-dose rate brachytherapy started during external beam. If you started earlier, you end earlier. If you start it later, the tumor is smaller and you have better dosimetry. So teach these individuals when the brachytherapy should start and how you make that decision. Because there are no guidelines, but it's judgment. Give them some confidence about how that decision is made. Yeah, so I think we have now a large experience with giving first 45 gray, five weeks of external beam chemoradiation. And after that, you start with brachytherapy. So not together? No. I know that that is also done, right? So it's absolutely not wrong. But you're right. You have maximum regression towards the end of chemoradiation. The most regression is in the first four weeks. There's also very nice evidence on shrinkage of tumor volumes in the first period. But it's very feasible to first complete chemoradiation and then do brachytherapy. And of course, in brachytherapy, there's also evolution. There has been practice of doing five to six fractions, single repeat fractions, while nowadays there's also more push towards, for instance, doing two applications over two weeks time. So also there, there is a lot of evolution and now also stronger data about feasibility and altogether doing the whole treatments within 50 days. Don't go away. I'm going to get to you. But I want a very simple question, Leslie. So all else being equal, you have availability interlaced? You have availability to A18? It's right here, maybe twice, actually. Which one? A18 or interlaced? Either one of you. I'm never going to deny my patient the opportunity to do better. This is the curative setting, right? So you're never going to deny them that opportunity. So I think both trials are very important. So which one? They could be combined. Yeah. If you both approach it. That would be my answer. Go ahead. Thank you. I love it. I would answer the same. I would combine them. Excellent presentation, Ramin. So at Tata, we did the new adjuvant and surgery trial. And it was all conventional technique, simple treatments. And PFS at five years was 75%, 74%. And interlaced has almost similar population, but their PFS is 64%. So we find it very hard to understand how to interpret this. We have waiting lists also. Yes, so I think that this is on? Yeah, now it is. I think that's a very good question. And I focus now on overall survival rates. I think moving towards PFS and also, yeah, it is, again, not easy to compare different populations. For instance, how was screening done, imaging done prior to inclusion when you compare trials? So it's not so straightforward to compare these different studies. That's my argument. But again, it's a valid point for discussion, absolutely. So hopefully, we can learn more from the eventual publication. I have a perspective. I mean, I think that you sort of presented why this could be, because your techniques have improved so much over time. It's taken us 20 years to show improvement, survival in the locally advanced setting. And a lot of that has been because the control arm patients have done so well, especially when the majority of them are in stage two without nodal or with minimal nodal involvement. So we don't talk about radiation enough, but it's so fun, right? Let's have these two very quick questions, and then because I want to hear about immunotherapy and all the hard work that Professor Colombo is doing. Go ahead. Hi. Kelly Cole from Melbourne, Australia. I'm a radiation oncologist. Thank you, Brad. Yes, we do need more radiation oncology. Just a couple of comments. Firstly, the push towards image-guided brachytherapy is wonderful, but we have a disease here that is predominant in low and middle income countries. They have really big tumors. They also don't have access to a lot of the imaging that we take for granted in developed countries. And I think we need to bear that in mind as we push forward. Similarly, with the two studies that were presented this morning, I would comment that interlace is a wonderful study for that reason because it could potentially be very useful in lower income, middle income countries for them. But I'm not sure we could use A18 in a country that can't access those sort of drugs. Not yet. Not yet. But thank you. Good seeing you. Thank you. Last comment. Thank you. Maybe just briefly to comment on lower middle income countries because, of course, this is obvious. At the same time, especially in locally advanced disease, we see benefits of combined interstitial, intercavitary techniques. So I think we do have to also confront ourselves with these data because it points us towards where we can improve, right? Thank you. Thank you. Hi, how you doing? Hi, Mike Saud from Mayo Clinic Abu Dhabi. Previous trial with neoadjuvant chemotherapy were all really not very effective. And the problem was those patients who progress on neoadjuvant chemotherapy. So my question with the interlace, how many of these patients really progressed? And how was their prognosis when they progressed? Because with the previous trial, even those patients who had the complete clinical response, and a very large number gets complete clinical response to the neoadjuvant chemo, this really did not affect their either disease progression or overall survival. So how can you explain? I mean, what's the difference? Mike, it's a good seeing you. And that's an excellent point. The good news is it was a very progressed weekly treatment. So the number of patients that progressed were very low. But we have to see the paper. And I think there's still some questions. But I like what was said about the applicability of this. So thank you. We're so happy to have so many experts and conversations from so many continents. It's really fun. So we're going to pivot now to Professor Nicoletta Colombo, whose, quite frankly, life has been devoted to better systemic therapies, and hear about her wonderful work in cervical cancer with immunotherapy. Thank you, Nicoletta. Thank you. Thank you, Brad. And thank you for giving me this talk, 12 minutes to cover immunotherapy in cervical cancer. So bear with me if I won't be so deep in the details. So look at this. This is what we have done in terms of progress for the treatment of cervical cancer over 30 years until 2013. And we started with single-agency splatting, and then added something. And finally, Bevacizumab came. And this was, of course, a big step forward. This was the new standard of care, because it was demonstrated that the addition of Bevacizumab to chemotherapy could improve overall survival in patients with cervical cancer. Now, I'm going to tell you what has happened in the next 10 years, after 2013. We learned that immunotherapy could be a very good option for cervical cancer for several reasons. There is a strong rationale for using immunotherapy, because, as you know, HPV infection is the cause of more than 90% of cervical cancer. And HPV-positive tumor microenvironment is rich for PD-1-positive T cells. And so we know, also, there is a high expression. We talk about that, of PD-L1 in cervical cancer, but not in normal cells. And we do have drugs, anti-PD-1 and anti-PD-L1. So why not testing this drug in cervical cancer? And this was done, starting from second-line treatment. These are phase two, looking at the monotherapy, anti-PD-1 and anti-PD-L1, in patients with cervical cancer failing chemotherapy. And here you see the response rate was OK, not outstanding, ranging from 14% to 26%, slightly higher in tumors with PD-L1 over-expression, as you can see. But the most important trial in the second-line setting was, of course, the Empower Cervical 1-GOG306-NGOT69, because this was a large, randomized study, 600 patients receiving either semiprimab or standard care chemotherapy. And this trial clearly demonstrated superior overall survival. Again, we are talking about overall survival, not progression-free survival, in patients with advanced cervical cancer with the use of semiprimab compared to standard of care chemotherapy. And what, for me, is even more impressive in this study in cervical cancer is that they all demonstrated also an improvement in quality of life, which is so important in this patient. These patients are really miserable most of the time, because this disease is terrible. And with this drug, you may improve quality of life, which is, of course, extremely important. But having said that, of course, this was nice. But you recognize that monotherapy is probably not enough for these patients. So we started looking at combination therapy. And the first combination we looked was with chemotherapy. And this is Keynote 826, as you know, published in 2021. And we looked at patients with persistent recurrent metastatic cervical cancer without prior chemotherapy, except for chemo given together with radiotherapy. And they were randomized to receive standard of care chemotherapy with or without vivacizumab plus pembrolizumab or placebo. And the dual primary endpoints of this study were OS and PFS. So again, we were looking not only at PFS, but also at OS. And then response rate, duration of response, and so on. As you know, the study was positive. When we published the study in 2021, we clearly showed that at the first interim analysis, it was clear about progression-free survival was improved and overall survival reached statistically significance at the first interim analysis that was published. Also, response rate and duration of response. But very recently now, in these days, you will see the publication, JCO, of the final overall survival, which confirmed an incredible increase in overall survival for the PD-L1 positive population, which is the label population. As you know, the approval was only for the PD-L1 positive. And here you see for the PD-L1 positive, but also for the old camera population. So this is the new standard of care for sure. And here in this study also, we were able to demonstrate an improvement in quality of life. So once again, we were able to improve PVFS, OS, response rate, duration of response, and quality of life. A super positive trial. Now, I want also to point out that this is the forest plot. You see the benefit is consistent across all the pre-specified subgroup analysis. But I also want to point out this aspect. So the trial is positive for patients who receive bevacizumab, but also for those who did not receive bevacizumab. And this is important, because you know that at least 30% of these patients cannot receive bevacizumab because of contraindication. So it is important to see that if you add the pembrolizumab to chemotherapy, even though you cannot use bevacizumab, you still achieve a better outcome. So I think that's very important information. But of course, this morning, you heard about the BIT-CC. Very similar, but different, because atezo was used instead of pembrolizumab. And all patients received bevacizumab in this study. This was a randomized non-placebo control, and the PVFS was assessed by investigators. But they show overall survival, also improvement. So confirm, really, the activity of anti-PD-1 and anti-PD-L1, in this case, together with chemotherapy. So here you see the incredible progress that we have made. Look at the PFS, which is platinum 2.9 months. Now we are 10.4. And the OS, 6.5. And now we're at 24.4. Actually, this morning, you saw with bevacizumab, 32 months. And even in the keynote 826, if you look at the subgroup of patient treated with bevacizumab, it's 36 months. so it's really incredible the improvement that we were able to make. So having said that, of course, what about other possible combination? Because this was with chemo, but there are other combinations that can be tested. For instance, look at the CTLA-4 blockade. Why is this important? Because when you use a PD-1 inhibitor, you are acting at the effector phase when the activated T lymphocyte should attack the tumor. But then there is also the primer phase when the T lymphocytes should be activated. So it makes sense to combine these two agents, and it was done. You see here the combination of nivolumab and ipilimumab, two different doses, quite large number of patients, nice response rate, apparently higher than the single agent. Also, this combination, which receive a fast-track designation by FDA. Or you can use a bispecific antibody targeting simultaneously PD-1 and CDLA-4. This is, in fact, a Chinese compound, the cadolidumab. As you can see, it was designed to bind both to TILs, co-expressing PD-1 and CTLA-4 with higher affinity. And a phase three study now has been completed with this compound, a similar design as the Keynote 826, but using this bispecific antibody instead of pembrolizumab. And also, as much weeks ago, we see the results of this study. This is a non-randomized phase two. This is another bispecific antibody, similar to the previous one. And they added to chemo, with or without vivacizumab. The response rate is good. The feasibility, the tolerability is good. Difficult to say anything, but a phase three study is now planned. Another possible combination is the anti-TGIT with anti-PD-1. TGIT is a co-inhibitory receptor that is highly co-expressed with PD-1. And so it makes sense to combine these two different drugs. At last year, AACR, the results of this study were presented. Two different doses of Vibostolimod, which is an anti-TGIT together with pembrolizumab. And here you see a response rate, 23%, with a higher dose of Vibo. I would say not impressive, not outstanding, 23%. It's probably slightly higher than monotherapy, but not so much. And then this was presented at ESMO. Again, another anti-TGIT together with anti-PD-1. And again, the response rate is 23%, and 26% in PD-L1 positive tumor. But this morning, you've heard the presentation of the Skyscraper, another combination of another anti-TGIT, the tiragolumab together with atezolizumab. Again, a very large study. And here the response rate, 19% in the overall population. 25% in the PD-L1I population. So I'm not sure if this is the right combination. The results are, yes, okay, numerically higher than single agent, but probably not exactly what we were hoping to achieve with this combination. Another combination which is very nice is the combination with the anti-VEGF, because as you know, VEGF promotes an immunosuppressive state. So it makes sense to block VEGF together with the anti-PD-1. And we had some reports showing a very high response rate, 59% and 56%, but with a very, very high toxicity. And the same is true, we heard two weeks ago, as well, this is nice because it's a randomized phase two, combining VEGF inhibitor with anti-PD-1 inhibitor. And you have the combination, the single agent, and the investigator choice, chemotherapy. And as you can see, there was a higher response rate, 43% compared to single agent and compared to chemotherapy. Also, the PFS was definitely prolonged, but unfortunately, toxicity was extremely high. So I think this combination works, but it's very toxic. So we have to work out a way to overcome this problem. And finally, just two seconds to say that this is, of course, another interesting perspective for the future, which is the adoptive cell therapy. There is one trial ongoing with the tumor infiltrating lymphocytes by Iovans. And basically, you excise the tumor, you expand the lymphocytes in vitro with the interleukin-2, and then you re-infuse the lymphocytes after lymphodepletion. And preliminary data were very encouraging, 44% response rate. Reported back in 2019, so a few years ago. Updated in 2021 in patients without prior chemotherapy, 57% response rate. And the study's now ongoing for the IO pretreated patients. So we'll see what's coming up. So to conclude, is immunotherapy beating advanced cervical cancer? I think the introduction of ICIs in the treatment of cervical cancer has led to significant improvement in progression-free survival and overall survival, both in the first-line treatment and in the relapsing setting. Despite encouraging data, several open questions remain. Is PD-L1 a reliable biomarker to select patients, or can we do better? I think we can do better. Which combinations will be more effective, particularly after immunotherapy? Will adoptive cell therapy become a real option, and how to address affordability and access issues in populations with the greatest need? Thank you for your attention. Thank you. Wow, that's a lot. Thank you, Nicoletta, for your hard work. You know, I have a question here, and this is actually common in my country. We're gonna hear next, I can't wait, Leslie, to hear about antibody drug conjugates and other opportunities. But IO after IO continues to be common. I think, quite frankly, half of the gynecologic cancers in my country are treated by non-specialists, non-gynecologic oncologists. They know immunotherapy well, and so they give it again. So in this setting of A18 or A26, we've had TV in the US now for two years, and I think we're gonna hear, Leslie, your wonderful experience. Does it make any sense to give IO after IO instead of TV, or is that just irrational? I want both of you to, because it's done. It is done in a common scenario, and I don't know whether it's because they don't know about tizotamabidotin, or tell us what you think. I think it could make sense, actually, if you have like an interval between the treatment. But in Europe, we cannot do that. So I don't have any personal experience. Maybe you have, because you can do it. No one does yet, right? We just don't have that experience yet. I think if you do IO after IO, especially for a patient who's progressed on checkpoint, and even if they haven't progressed on checkpoint, they've been exposed, my bias would be to use it in combination. So we've got these amazing combinations, and I'll talk about combinations as well. So I think that I would focus on combination. So I knew that's what you were gonna say, Nicolette, and I don't ask easy questions. If you guys know me, I know what I'm talking about. I'm not gonna ask easy questions. And I don't ask easy questions. If you guys know me, if it's an easy question, you guys don't wanna know the answer. So what percentage of Keynote 826 patients then, and you don't have to give us the exact number, but finish their two years, and then go a time, and then recur, is that common, or is that rare? It is rare, actually, it is rare. I know that there are patients in CR now still ongoing without treatment for many years, because now the trial is closed a few years ago. So I think the duration of response and benefit is incredible, really, with this combination, yeah. And thank you, and congratulations. The other message is that in 826, we haven't really disclosed this much, but 40% of the patients never get another line. So we have to do the best we can. And this is a Leslie Randall message. We have to do the best we can, the earliest we can, to give the patient the best opportunity. So thank you, and that was a wonderful presentation. Thank you, Dr. Glomberg. So our final presentation is Dr. Leslie Randall, who will talk about treatment beyond immunotherapy and anti-angiogenesis in recurrent cervical cancer. Please, Dr. Randall. Great, thank you so much. So, so great to be here. Thank you for the invitation, Brad, and this is, I'm gonna try not to talk about immunotherapy, but it's gonna be hard, because even in the recurrent setting outside of immunotherapy, immunotherapy still pops up. These are my disclosures. So you see how this treatment landscape is evolving, and we anticipated this, that the immunotherapy is so effective that the priority was to move it up into the most curative intent line of therapy, and that's been accomplished now with the Keynote 18 results. So now we're kind of left with, as we move these great options to earlier lines of therapy in the recurrent setting, we're left with fewer options, but the future's very bright for us to develop other opportunities, and so the current opportunities are Tisodamabidotin, and that's been available for us in the United States since September of 2021, and hopefully the TV301 data will bring that to the rest of you in the world, and I'm really excited to see, because I've felt very guilty that I've had that all this time and know that others do need it. And then we've got some, the tissue-directed treatments. So this is really interesting, and Brad, you alluded to this, most of the, this is U.S. data, and in the left, you can see the patients that are treated with first-line therapy, and then on the right, you can see those who cross over to second-line therapy. So my talk is about recurrent setting in less than half of patients in the United States who may have some therapies available or actually even getting therapy. I think this is complicated. I think this is lack of knowledge of existing therapies, it's lack of access to existing therapies, it's cost or perception of cost in a patient population that is already somewhat marginalized, especially in the U.S., but I think across the globe also. So this is complicated, and I think as we get more options for these patients, we really need to not forget the big picture here and remember that patients are not necessarily getting these treatments. The current NCCN guidelines were updated in September of this year, and they, the preferred regimens in the recurrent metastatic setting are in the box at the top. Two of them are checkpoint inhibitors, and they're single-agent checkpoint inhibitors. So, you know, again, my bias is to give a combination if you're doing checkpoint after checkpoint, but that kind of knocks out really two of the options right off of the bat, and so what we're left here with in the preferred is the tesotamabidotin opportunity, and then at the bottom here, you see the HER2 that we've been talking about, the destiny pan tumor results led to this listing. And I don't know that I've ever seen, and I could be wrong here, ask you all if you've seen an NCCN listing of a therapy with such little, with little data that's not yet published in a peer-reviewed journal. So clearly, these results have generated a ton of excitement. So really, and so the bottom line you can see here is that the antibody drug conjugates are really kind of the next wave of opportunity post-IO and post-antiangiogenesis. It's kind of mostly, not completely, and I'll show you about antibody drug conjugates, but mostly about antibody drug conjugates. So here's tesotamabidotin, and hopefully you're familiar with it and have saw the 301 data presented earlier this morning, but this is a tissue factor-directed ADC. Its payload is MMAE, so it's a microtubule poison. It gets into the cell by binding to tissue factor, which is pretty ubiquitously expressed on the surface of the cell over 90%. So a tissue test is not required for use of this agent. It's not discerning in this setting. And it not only gets into the cell and releases its cytotoxic activity, but as the cell dies and releases drug, active drug into the tumor microenvironment, it has a bystander killing effect. And then we think that it's uptaken into antigen-presenting cells and has an antibody-dependent immunotherapy-type reaction in the tumor microenvironment. So this drug is thought to act in four different ways, and we'll look at the comparison against chemotherapy, and it's evident that it's doing more of a lift than chemotherapy alone is. So this was the initial trial that garnered the US accelerated approval, and it was the preliminary data that gave support for the phase three trial. This is Innovative T04. This was a GOG NGOT collaboration, which you'll see a lot of at this meeting. These patients were second and third line patients, so they had progressed after the GOG 240 regimen at the time because at the time this was designed, the Keynote 826 regimen was not yet available. Those results weren't completed yet. Patients received TV, two mgs per kg, IV every three weeks until progression or unacceptable toxicity, and the primary endpoint was response rate, as is common for an accelerated approval opportunity. And these were the results. There were seven complete responses, 17 partial responses confirmed, overall response rate of 24%. Now, this was a bicker. This was a central independent radiologic review, and so when you look at the response rate of the TV 301, which was an investigator-assessed, I just want you to remember that this is a bicker ORR. But this did lead to the accelerated approval, and the uptake of this has been quite high in the US, so my hope is that when we relook at that figure I showed you in the beginning is that we'll see more patients treated in the second line in the US. The pre-specified AEs of interest are ocular toxicity, bleeding, and peripheral neuropathy. The first two that are related to the tissue factor target, the last is related to the MMAE payload. You can see here that in the smaller study that most of these toxicities were of low grade, with the exception of a 7% of a higher grade peripheral neuropathy, and a 9% grade two peripheral neuropathy is clinically significant. So the ocular toxicity was the learning curve for this drug, but in my experience, the peripheral neuropathy is what you end up spending more of your time managing because there is a mitigation strategy for the ocular toxicity. So patients need an ophthalmologic exam, it's very difficult, I still can't say that, it's been two years. Ophthalmologic exam for before they start TV and before each cycle, the toxicity is mostly a surface, conjunctivitis, keratitis, and prior, on the day of the infusion, you use a vasoconstricting eye drop to limit the uptake of the drug in the eye. You use steroid eye drops to reduce the inflammation. We also use cold packs during the infusion to reduce the influx of the drug into the eye, and then continue the steroid drops for 72 hours after. Patients use lubricating eye drops throughout the cycle, really all the time, and the drier the climate, the more they need them, and they're supposed to avoid contact lenses and not wear mascara and do things that make them feel like women, which is a little tough for them trying to cope with this. But if you do this, the incidence of the ocular toxicity is actually very low in my practice experience, is much actually lower than what was presented or reported in the study. So this is TV301. Hopefully you saw this this morning. It's the confirmatory trial for TV in this setting. This was TV at the same phase two dose that was randomized to investigator's choice or against investigator's choice chemotherapy, and you can see the agents that are listed here. The primary endpoint of the study was overall survival, and the key secondaries were PFS rate and safety. This was the population that was studied. There was a high contribution of the Asian population from Asia, which is excellent. That lends to the diversity of the enrollment of the trial, which is clearly one of our more contemporary initiatives to try to improve that. Most of the patients had squamous cell carcinomas as expected, and pelvic recurrence only was in 10%. The study met its primary endpoint, improving overall survival. The hazard ratio was 0.7. That was statistically significant. It also showed a benefit in progression-free survival as a secondary endpoint of 0.67. That was also statistically significant. And the forest plot, if you had had prior anti-PD-1 therapy, the drug was still efficacious, as was in prior bevacizumab therapy. Unfortunately, there was a signal for no prior bevacizumab, but these are exploratory endpoints and really can't draw conclusions. Based on these, the bottom line is that it was efficacious in the entire population. These are the adverse events, so chemo clearly contributing more of the heme toxicity, and then the adverse events of special interest showing up, again, in the TB301 data with the ocular toxicity. Again, this is manageable. And here you see, again, the ASIs, but we're very consistent with the Phase 2 dataset. The eye care protocol for the study differed just a little bit in giving a steroid dose before the chemo day, so the day minus one steroid dose, and the toxicities are similar. In my opinion, it didn't seem to make a difference. So you just have to get into a routine with the ocular care. So can't get away from immunotherapy, the TB205 study looked at multiple combinations, and this was a two-phase protocol. So the Phase 1 looked at the combos, TB with PEMBRO or CARBO or bevacizumab, and these are very tolerable at their normal doses when combined. And that was presented by Dr. Munk at the IGCS a couple years ago. And then Professor Vergoot has since presented the efficacy. I want to just draw your attention to the bottom, the TB PEMBRO in the second and third line, because that's my talk and I'm going to stay focused here, overall response rate of 38%. So you remember PEMBRO for PD-L1 positive was 14%, TB alone was 24, and so that's at least an additive benefit. And that may be relevant in the post-IO, and those were IO-naive patients, but that may be a relevant combination for IO-exposed patients moving forward. And we've since published the overall efficacy of that TB PEMBRO combo in the recurrent setting and it still is very favorable. So another IO, because you can't get away from it, Dr. Colombo presented the TILS data. TILS is complicated. You saw the process that it takes to get TILS therapy. It can be toxic to patients. Vaxibody treatment is a way of engaging the same T-cells that TILS therapy engages. They're just not as personalized. So this is a technology that engages the HPV-16 positive tumors and can combine this with either alone or with a checkpoint inhibitor. This has been studied in an early phase setting with a 19% response rate in all comers and then 29% in PD-L1 positive patients. And in the GOG, we are looking at taking this into a larger study where we are doing a randomized study, randomized phase two, to look at the vaxibody alone or with atezolizumab in that. So another IO combination that has potential to benefit. And this is in the IO-exposed population. So now we're in the era where we really need to study these recurrent therapies in the context of having had prior checkpoint inhibitor. So what do you do after you've exhausted those options? We've talked about HER2 as a target. This was identified in the TCGA. We heard about the SUMMIT trial. And then the trastuzumab durextacam, which is also an ADC, against HER2. This has nothing to do with the HER2 pathway, unlike the SUMMIT trial, where neratinib actually inhibits the HER2 pathway. This just uses HER2 to get into the cell. So it's sort of a different approach. And you saw the design of this study. And you also saw these results earlier, where this was very effective. And so even though, and even I said that this is early data and needs to be confirmed in a larger subset, it's so overwhelmingly positive that it made its way into the NCCN. And if you look at the PFS that was also presented today and from the ESMO meeting, you can see that it appears that it may be most relevant in the IHC3+. So Brad, I agree with your comment earlier that we may need to prioritize this therapy for the IHC3-plus patients, because it does have not only a high response rate, but a very impressive duration of response. So we need to figure out how we assess HER2. And in SUMMIT, it was assessed by the breast criteria. And with the DESTINY, it was assessed by the gastric criteria. So was the benefit that we saw in DESTINY versus SUMMIT, was that because we assessed HER2 differently? Or was it because it was a more active drug? I think maybe both are at play in this setting. One last thing to mention before I close is TROPE2 is a target. You're going to be starting to hear about this as the next ADC target. This is also highly expressed in cervical cancers. A lot of this work has been out of the lab of Dr. Alessandro Santin. And he's now leading an expansion phase. We had a large phase one study with all tumor types. There was one cervical cancer patient who achieved a stable disease. But this has moved forward into phase two. So that data will be forthcoming in the future. And I'm excited to see that. That's the end of my talk. Thank you. It's my email if you have questions. Okay. Thank you, Dr. Randall, for your wonderful talk, very comprehensive, and a lot of information in it. So now, take the questions. So Leslie, that was great. I saw a patient last week. Tell me if this makes any sense. So she failed TV, but she was HER2 negative on IHC, adenocarcinoma, but had a mutation. Because you told us that there are mutations, but also there are different ways. Does that make any sense to give that patient something like neratinib, even though she's IHC negative? In other words, are there complementary ways to engage HER2 if, in the absence of a HER2 expression, the pathway is amplified or mutated? Yeah. I think that it's a great question, right? And I think we need to learn and answer this question. To me, as I said, if you want to engage the pathway, you're using a pathway focused, like a neratinib, like a trastuzumab, like a pertuzumab. But if you are just using the ligand to get the drug into the cell, you're more likely to use a trasturuxicin. But if you have no expression on the cell, then the trastuzumab trastruxicin is not going to get into the cell, even if you have an HERB2 amplification. So then you need to actually engage the pathway. That's what I think. I don't think we know. But we have to be very flexible. Angelica, hi. No? Okay. Thank you. Regarding the PD-L1 negative population, would you anticipate the approval of a TISO for them, based on BIT? And which are your impressions about the differences in the drug, the testing? I think you should ask Roche Genentech, of course, for the approval. I cannot say anything right now. So really, I don't know. It would be a pity, because as actually Anna concluded this morning, she said this is a new standard of care. So it is not the new standard of care, but can be another standard of care, of course. But this depends on the company. And what is the other question? The difference between... Just because it was tested for Alzheimer's, but would you think that it may work differently, the drug in PD-L1 negative patients, pembrolizumab, compared to a TISO? No, I don't... You know, these are two different drugs. You know. I mean, we have the same discussion for endometrial cancer, where pembrolizumab and dostalimab were used, and then also atezolizumab. And I know that Brad believed that anti-PD-L1 are less effective than anti-PD-1. I don't think you can say that in cervix. I think the B-C data are very strong. Yeah. Yeah. So... That's right. But, you know, it's difficult to say. But it looks... The results are very good. So, Mike, before we get to you, let me give you some things to think about. So, on the September 20th, NCCN, semiplimab got approved, regardless of PD-L1. But the FDA did not approve it at all. No question. Right. So, I don't think, personally, in your opinion, believe is a sort of faith belief. We could talk about what the difference is between belief and faith, but I don't think there's really such a thing as a PD-L1 negative patient. And I predict, believe, that A18 will not have a PD-L1 restriction. So now I have semiplimab, A18 really didn't show it, and here's some evidence. So, you saw on Wednesday that Nicoletta and the rest of the 826 team published the final overall survival for 826. And initially, there was no benefit to the judgment of the regulators and the clinical trial data of impact in PD-L1 negative. But in that paper, you can read it. It's free online for the Journal of Clinical Oncology. There's a .87 improvement in overall survival in 826 and PD-L1 negative patients. So now I'm starting to accumulate some evidence that the imperfect biomarker that you beautifully described is inaccurate. And so, as you said, Dr. Randall, let's give every patient a chance. If it doesn't work, then stop it. But I think there's some accumulating evidence that in the PD-L1 negative, however you measure it, and the biomarker that picks up the most positivity is the CPS greater than 1, as you nicely described. So I don't really think it's that big of a deal. I think we got distracted, because in the 77 patients in the keynote 158, there were no responders in the PD-L1 negative, but I think that was probably false discovery, in my opinion. But I'm not always right. Yeah. No, absolutely. You know, there were very few patients to look at the forest plot and just decide not to prescribe, you know, this drug to the PD-L1 negative is absolutely, also from the methodological point of view, completely wrong. I mean, I never understood the FDA decision and AMA decision, actually. In 158, the Bevacizumab pretreated patients. There were no responders. So we could have said, oh, if you got Bevacizumab, checkpoint's not going to work. Well, obviously, that's not true either. So Mike, go ahead. Yeah. Just in the context that most of these cervical cancer occur in low-income country and low middle-income country, with the expense of this new medication, what would you define as a clinically meaningful response? Because we've heard the difference between 2.9 and 4.2 months. I really don't think this is a clinically meaningful response. And do you really have, for this trial, to come up with a definition that would, you know, suit this low-income and middle-income country? Because nothing of what you have presented this morning will be available in this country. So respectfully, that's not true. Not available today. So there was a time that cisplatin was very, very expensive and not available in under-resourced countries. It went away because it became generic. I get it that antibodies are more complicated to produce than cis-di-amino-di. So how would you define a clinically meaningful response? I mean, 2.9 and 4.2 months. It's called value. I really would not define this as a clinically meaningful response. Every day counts. So that's clinically meaningful. But it's value. And the cost of these medicines is in evolution. And I predict that one day, these antibodies, which are relatively inexpensive to make, when they go off patent. So today, it's not, there's no value based on the cost. But I think over time, and again, you know, the solution for cervical cancer, let's just admit it, is prevention. When there's a spore grant, there's a spore grant in the, you know, the spore grant, it's a program project grant between Hopkins and Alabama for a heat-stable virus-like particle vaccine that can be rolled out into Africa or other countries. Africa's not the only opportunity. So that's the science. So I think we get caught up too much in, and I live in the wild, wild west, trying to figure out what to do once the horse is out of the barn. So we need to focus on prevention. But I hear you, and I like that, and I'm interested to hear Toon's perspective. Hi, Toon. Yeah? Can you turn the microphone on? It's open. Thank you. I just want to join my colleague. I'm from Belgium, the middle of Europe. And even for us, this might be a problem to get the reimbursement. So it's a valid question. I mean, which benefits do we accept? Yeah, it is a valid question, and I don't mean to minimize it. But I don't understand why you focus on months. I mean, you have to look at the overall pictures. I mean, these trials show you a benefit in overall survival, which is so difficult to achieve. I don't know why people are focusing on PFS. PFS, you know, you have OS, you have response rate, you have duration of response, you have quality of life. I mean, you have everything. All the endpoints, the primary, dual, and the secondary endpoints are met. So for me, that is much more convincing than just looking at two months or one month or two months or three months in the PFS. Look at the OS, yeah. I fully agree. I mean, there is a benefit, that's for sure. But that's not the way how the governments think about reimbursement. And that's not how, I mean, even for us in the Western world, this is becoming a problem. We have so many drugs, we have so many expensive drugs at the moment that our governments need to make a decision. It's completely different in the United States because due to the insurance companies and so on. But in Europe, this is a problem. And thank you for both of you for acknowledging it. So Dr. Randall, we're going to give you the last word. Okay. Well, my last word is that if we're not going to advocate for our patients, our governments, and who will, like, and not that they always listen to us, you know, I would not have supported restricting the Pembrolizumab approval in the 826 space, based on a forest plot, as you say. But I think that, and I think that we just have to keep fighting the fight. I mean, if we know what is going to benefit our patients, we wouldn't want to deny them that benefit. And, you know, the trials don't tell the whole story. I mean, I have patients, I haven't used the Trastuzumab directs to Kenya, but I have two patients who had malignant bowel obstructions over a year ago that are still on Tizotamab, Tizotamab, Avodotumab, and Pembrolizumab combo for the TB205. And I know that I'm privileged to be in the U.S. and to have access to that combination. But, you know, my patients made graduations and other things that were really important to them. So I think as we develop these more effective therapies, it's just up to us to push the importance of them. So thank you for this robust discussion. Thank you to this exceptional international panel. Please join us in the grand ballrooms, this one and also the 103 for the industry-supported symposium. Let's grab some lunch. Thank you, everyone.

Immunotherapy

immune checkpoint inhibitors

cervical cancer

PD-L1

targeted therapy

clinical trials

Pembrolizumab

combination therapy

tumor-infiltrating lymphocytes

vaccines

optimization

access to treatment

research