We can invite people to take a seat, probably, and we'll start. Good afternoon, everyone. I'm requesting everyone to take their seats, please, because we have a very tightly packed session. And I'm Dr. Supriya Chopra, radiation oncologist from India, and I have very fantastic co-chairs lined up for the session. Dr. Alexandra Leary from Florence, Dominica LoRusso from Italy, and Dr. Glenn McClurge from Ireland. What we've done now is, because the session is a long session, which has locally advanced and metastatic, the first lineup of talks are on locally advanced, which myself and Dr. Dominica would moderate, and the metastatic would be moderated by our other co-chairs, and I would like to invite our first speaker for case presentation for locally advanced cervical cancer, Florencia Nol from Argentina. Good afternoon, well, my name is Florencia Noel, I'm from Cordoba, from Argentina, in South America. I'm really honored to be here, I would like to thank the organizing committee and the chairs of this session for inviting me and for the opportunity to present a clinical case in this important master session of cervical cancer. I have nothing to disclose, so my patient is a 28-year-old nulliparous woman from my city in Argentina, she has no significant clinical or surgical history, and no history of smoking or other risk factors. She presented with a three-month history of vaginal spotting and post-coital bleeding, she had been treated in another hospital with hormonal and medical treatment, and she reported her last follow-up in 2023 with a pap smear with an abnormal cytology, a high-grade scamus interpithelial lesion. She had no colposcopic lesion, and she had not been treated. In the physical examination, she has an ECOG status zero, and we found a didelphys uterus with two cervix and a vaginal septum extending to the lower third. Her left cervix, there is the picture, you can see the septum in the vagina, her left cervix had no lesions, and at the right cervix, we found a five-centimeter cervical lesion involving the upper vagina and also the paramecium. She had no palpable lymph nodes, and the rectal mucosa was free. So we took a biopsy from the lesion, and the histology report showed us a moderately differentiated scamus cell carcinoma, HPV associated with the P16 block staining, and the presence of vascular space invasion. We staged my patient with an MRI, and we found, again, sorry, two cervix with a vaginal septum extending to the lower third, and at the level of the right cervix, this known mass of five-centimeters cervical mass extending to the vagina, the upper third of the vagina, and also the right paramecium. Here you can see the bulky lesion involving the vagina and also the paramecium. We decided to stage the patient with a PTC, so she performed a PTC, and we found a cervical mass, again, the five-centimeter cervical mass with an SUB of 26.3. The lesion appears to infiltrate the upper vagina and also the right paramecium, and also we found a hypermetabolic adenopathy in the right external iliac chain measuring nine millimeters with an SUB of 4.8, as you can see in the picture. So our patient was staged as a FIGO stage 2018 3C1. We discussed this case in a multidisciplinary committee, and we decided to indicate as primary treatment concurrent chemoradiation. Also we offered a fertility sparing treatment, or not fertility sparing treatment, sorry, a cryopreservation of oocytes, but she decided not to do it. So this was the primary treatment, a conformal radiotherapy with IMRT, and also image-guided adaptive brachytherapy, and once weekly infusion of cisplatin for five cycles during the external bile therapy. This is the dose. The definitive radiotherapy dose was 50 grays with an extended infrared field of 42.5 grays, and also a boost with brachytherapy with image-guided brachytherapy. We guided brachytherapy with CT scan, and in this special case, because of the vaginal septum, we decided to place the tandem guided by ultrasound, and then perform the brachytherapy guided by tomography. The duration of the treatment was seven weeks. This is the physical examination after the treatment, 90 days after the treatment. There was no residual disease in the clinical examination. This is the MRI. We performed 90 days after treatment also, and we found a two centimeters lesion, but it was suggestive of post-radiation changes. So we decided to wait. Again, we discussed the case with a multidisciplinary committee, and we wait and repeat the MRI, and then we found that that lesion wasn't anymore, so we interpreted it as complete response. And now she is 18 months free of a disease. These are some points of debates that I look forward to discuss with the experts in the session, but I will bring, I don't know if you want me to leave it like this, because I probably will ask you some of these points. If there is a beneficial in surgical staging in these patients with a positive leaf node in the pelvis, when is the best time for image to evaluate the response rate? If there is a role for transposition in these patients, and comments about additional treatment options and plan for follow-up. Thank you very much for your attention. Thank you very much, Dr. Noll. Please come and join us at the table. And now I'd like to invite Dr. Alexandra Taylor, who will be coming to discuss improving outcome of patients with modern radiotherapy techniques. Thank you very much, Dr. Taylor. Thank you, and thank you to the panel for asking me to speak, and thank you for the introduction of the case. It was really interesting. These are my disclosures, and we're thinking about radiotherapy advances. This is a slide from about five years ago, looking at the advances, but really radiotherapy is evolving very quickly. I'm going to give a really quick overview of where we're going, and we can see some of the changes that are coming through. How do we improve outcomes? Generally, it's improving local control, increasing dose to tumor, improving survival, but also reducing toxicity of treatment. And that's what we aim to do with advances in techniques. So in terms of brachytherapy, we achieve both dose escalation and reduction in toxicity. So moving from point-based brachytherapy to volume-based brachytherapy, either with CT or MRI, we can develop, look at very individualized dose. We follow the guidance from the Geck-Estro group in terms of dose tolerances, and if we need to escalate for bulky tumors, the use now of interstitial with intrauterine brachytherapy applicators let us really increase that dose to the tumor. We've already seen that the EMBRACE study has given us what the standard of care really is with brachytherapy, and they're achieving over 90% long-term local control, even for stage 3, very bulky tumors. What we also get from the EMBRACE group that's really outstanding is the beautiful radiobiology confirmation, dose response curves for control, for organ at risk toxicities, and from that, we've been able to modify actually what the optimal dose constraints we should be doing with brachytherapy. With external beam radiotherapy, we also similarly moving from conventional to conformal to intensity modulated radiotherapy, each time reducing the amount of normal tissue that's getting higher doses, and we know that that does translate into reduction in toxicity, both severe toxicities reduced and also patient-reported outcomes. The other advantage with IMRT is we can dose paint, so we can now escalate dose to involved nodes without impacting on our normal tissue doses, but there are challenges, and the big challenge we have is that if you're going to produce something that's really conformal to spare as much tissue as possible, everything moves in the pelvis, it doesn't stay the same, and you might miss, or you put big margins around it, and then you're not really sparing any tissue. So again, the move forward is to use adaptive radiotherapy. You can have a plan of the day, you do an image each day when the patient comes for treatment, and select a library plan, but I think the game-changer we're going to have here is we now have platforms where we can do real-time online adaptive radiotherapy, and examples are the Ethos system with Varian or the MR-Linac. The issue at the moment with this is it's really resource-intensive, there's still a lot of manual input into it, as you can see, really what's changing is artificial intelligence is coming into radiotherapy. And it's already here, in terms of auto-segmentation, auto-contouring. Manually contouring all your structures takes a very long time, it is also our biggest source of error now in radiotherapy, and so if you've got validated quality auto-contouring systems, they can significantly reduce your time, but also it can support the introduction of more complex techniques. And again, in resource-limited settings, you can think about moving to IMRT if you've got a good auto-contouring system that speeds this up. I'm sort of shouting out to the RPA developed by MD Anderson, because this is a system not only that they've developed for auto-contouring, but as we heard earlier, automated planning is also coming down the line. It's not as advanced, but there are examples both for brachytherapy and external radiotherapy. So where's the future going? And it's here, probably, but we're getting very close. If you've got auto-segmentation, you've got automated planning, that pathway for patients can be significantly reduced from weeks to days, or even hours, once you get QA into this, and that's where we're heading. Similarly, real-time adaptive radiotherapy, if you've got automated segmentation, automated re-planning and quality assurance, you can be doing this real-time, and that's going to move us to hypofractionation. We can treat in a very few fractions. The final thing, I'm just going to very quickly say, is I think we have to highlight in radiotherapy it's not just primary disease, but recurrent cervical cancer, where historically our outcomes have been pretty dismal, but with the advances, we can escalate dose, and also with the new techniques coming through interstitial brachytherapy, but also stereotactic radiotherapy, protons, we can do re-irradiation, so we can salvage patients that we couldn't before, and we also have stereotactic radiotherapy as options for oligometastatic and oligoprogressive disease, thinking about changing our paradigm for follow-up. So in conclusion, radiotherapy is rapidly evolving with these advanced techniques. I know we're about to hear about all these new developments with systemic therapy, but we have to make sure we don't compromise the radiotherapy. That is our therapy with the highest response rate, and we need to make sure we are delivering it optimally, but we then think about how we combine different modalities to achieve best outcomes. Thank you. Thank you, Alessandra. Please join us. It's my pleasure to introduce Mary McCarnick, that will deal with interlace update on induction chemotherapy before concurrent chemoradiation in locally advanced cervical cancer. Mary, welcome. Thank you. Thank you to the committee for inviting me to present something on the interlace trial. Thank you. These are my disclosures. So cervical cancer in 2024, as we were hearing earlier in the first session, despite vaccination and screening programs, which we know are not that widespread, remains a global health issue. Chemoradiation is the current standard of care for patients who are not deemed curable with surgery alone. But relapse beyond the irradiated area continues to present a challenge to oncologists. So chemo before radiation, or before chemoradiation, referred to as neoadjuvant, or as I prefer to call it, induction chemotherapy, is an old concept, but we've revisited it in the context of the interlace trial. We've used dose-dense taxane-containing regimens. We've minimized the gap between completion of chemotherapy and chemoradiation, and we've delivered the course of chemoradiation within 50 days. So the interlace trial, the key eligibility criteria were patients with newly diagnosed histologically confirmed usual adenosquame or adenocarcinomas, 1B1 node positive, and 1B2s, 2s, 3Bs, and 4As. We did not include patients with periortic nodes. We did not include patients with lower vaginal involvement. Patients were stratified according to the factors here, site, stage, nodal status, type of external beam, tumor size, and squamous versus other histology. Primary endpoints were progression-free and overall survival. 500 patients were randomized one-to-one to induction chemotherapy with carboplatin AUC2 and Paclitaxel 80 milligrams per meter squared for six weeks, followed by standard chemoradiation with weekly cisplatin or the same standard chemoradiation alone. So I'm not going to go into all the details because there's five minutes to do this presentation. So with a median follow-up of 67 months and 151 progression-free survival events, there's a hazard ratio of 0.65 with a p-value of 0.013. So this is a 35% reduction in the risk of progression or death with an additional six weeks of chemotherapy. The five-year progression-free survival rates were 64% in the standard of care arm and 72% that's incorrect, in the intervention arm. Similarly, for overall survival with 114 deaths, the hazard ratio is 0.6 with a p-value of 0.015. So a 40% reduction in the risk of death. The five-year overall survival rate in our standard of care arm was 72%, but this was 80% in the interventional arm. So we also have now presented, my colleague Dr. Menevitz presented it at ESMO, the quality of life outcome for entelace. The addition of induction chemotherapy led to small reductions in most quality of life parameters, but the majority of these were non-significant differences and they were in keeping with the toxicity data. The symptom experience, emotional functioning and pain improved with induction chemotherapy, but what's most important is that the differences between the groups had resolved by 12 months. So what are the limitations to the entelace trial? Well, the trial took 10 years to accrue with changes in practice during that time. Only 40% of patients were treated with IMRT, but there's no evidence that IMRT per se improves survival. We know it certainly has a significant impact on toxicity. Only 30% had current standard image-guided adaptive brachytherapy, but when the embrace protocol is fully employed, and I'm a big fan of it, there's significant benefits in terms of local control and they're excellent, as Alex has just shown. But despite that, up to 25% of patients experienced a distant relapse. So exclusion of patients with periortic nodal disease, and there were only 43% of patients who had node-positive disease in the entelace trial. However, if you look at figure 2018 staging, 49% of patients had stage 3 and 4 disease. So what are the strengths? Well, it's a randomised phase 3 trial with mature follow-up data. The trial met both its primary endpoints with highly statistically and clinically significant differences in favour of induction chemotherapy, and most importantly, no evidence of a detriment to this short course chemotherapy. More than 96% completed external beam, and over 97% received brachytherapy. And they did all of this within 56 days, in fact, 96% completed radiation within 56 days. We also found that induction chemotherapy led to fewer distant relapses. So in conclusion, induction chemotherapy delivered according to the entelace protocol led to a significant improvement in both progression-free and overall survival rates. Induction chemotherapy before chemoradiation did not prolong the overall radiation treatment time. In fact, the median was 45 days. And it can safely be combined with both IMRT and image-guided adaptive brachytherapy. So this short intervention is cheap, readily available, and now supported by a published manuscript, it can be incorporated into clinical guidelines. I'd like to acknowledge all my co-investigators, the TMG, the UCL trial staff, and of course all our patients who participated and their families. Thank you for your attention. Okay. Thank you, Mary. Can you come to the table? It's now my pleasure to introduce our next speaker, one of my co-chairs, Dominica LaRusso, who will talk about a trial update in locally advanced cervical carcinoma. Thank you, Glenn. Thank you to AGCS for inviting me. As has been reported, the locally advanced cervical cancer still represents an unmet need and reflects the implementation of primary and secondary preventive strategies. And when this works, only one patient out of four is diagnosed with locally advanced in Europe, for instance. But in low- and middle-income countries, the problem is much larger, and up to 100% of patients present locally advanced disease. Since more than 25 years, concurrent chemoradiation is the standard of care. Based on five randomized trials reporting 60% overall survival advantage when chemo was combined with radiation therapy. But when you look at the stage of disease for higher-risk population, there is still a large room of improvement. And what improved so much in the last period? What was Alexandra reported in terms of modern radiotherapy that actually is able to cure 75% of patients at five years? I discovered the Bible, the benchmark of radiation oncologists, the EMBRACE trial that reported impressive control of disease and impressive overall survival. On the top of that, there were some rationale in combining immunotherapy with radiation therapy. Radiation can induce immunogenic death, and that's the reason why potentially when we combine immunotherapy, we can further increase the benefit of radiotherapy. And in the CX11 trial, Keynote A18, GOG 3047, we explored if the combination of pembrolizumab 200 mg every three weeks for five cycles, followed by pembrolizumab 400 mg every six weeks for 15 cycles, in comparison to concurrent chemoradiation and brachytherapy, could increase progression-free end-of-life survival. We selected a high-risk population according to FIGO 2014, FIGO Stage 1b, 2, and 2b, providing the patient that is not positive, or FIGO stage 2014, stage 3 and 4A, regardless of lymphonodal status. And stratification criteria were represented by the technique of radiotherapy, high MRT or VMAT versus non-high MRT and non-VMAT, the stage and the planned dose. We put a cutoff of 70 because we had several Haitian patients, and 70, it was considered an appropriate dose. The trial has two primary endpoints, progression-free and overall survival, analyzed in a hierarchical way. First, PFS, and only if PFS positive, all the alpha was recycled in overall survival. And the trial had two pre-planned interim analyses. The first one, with a follow-up of about 18 months, to evaluate if the addition of PEMBRO to concurrent chemoradiation increased PFS and OS. And the second, with a follow-up of 30 months, to evaluate if the addition of PEMBRO to concurrent chemoradiation was able to increase overall survival. I just want to point out that in order to have reliable results in the interpretation, we agreed since the beginning, as also Mary said, on the necessity to have good quality of radiotherapy in our trial. We have an external quality assurance that qualifies the center before starting the study and also reviews any single treatment plan. And we enrolled 1,060 patients that were randomized to receive PEMBRO plus concurrent chemoradiation or placebo plus concurrent chemoradiation. At the time of this data presentation, 40% of patients, around 40% of patients in the two treatment arms completed treatment, and 42% and 44% of patients discontinued treatment in PEMBRO and placebo arm because mainly of progression of disease. The trial enrolled a high-risk population. 56% of patients were FIGO stage 3-4a, 85% of patients had no positive, and 22% in the parahortic area. And in terms of planned radiotherapy, up to 90% of patients received IMRT or VMAT, and more than 90% of patients had a dose above 70 gray. The total treatment time that was planned to 56 days was 75% in our population. And I have to say this is remarkable, considering the trial enrolled during the darkest phase of the pandemic and during the Ukraine war. And I will spare you all this detail just to say that all this qualifies with the good quality radiotherapy with the high-risk volume total EQT2 dose of 87 gray. And we met at the first interim analysis PFS primary endpoint with the significant reduction in the risk of progression of 30% At two here, 57% of patients in placebo arm and 68% of patients in pembro arm were free of progression. At the longer follow-up, the benefit of pembro at three here is confirmed with another ratio of 0.68, and 57 and 69% of patients in placebo and pembro arm respectively free of progression at three here. And when I look at the forest plot, I just want to point out forest plot are descriptive, haven't driven analysis. And the longer the follow-up, the higher the number of events, the better the other ratio also for stage 1b, 2b, not positive, suggesting benefit in this patient. At the second interim analysis, we met the second primary endpoint overall survival. At the three here, 75% of patients in placebo arm and 82.6 patients in pembro arm were alive with another ratio of 0.67 describing 33% reduction in the risk of progression. And again, no difference according to pre-specified subgroup analysis. When you combine immuno to good quality, no good quality, modern radiotherapy, the toxicity profile is really manageable. And serious adverse events were 32% versus 28% in pembro and placebo. And the discontinuation was 20% versus 15% in pembro and placebo arm. As expected, the immune-related adverse events were higher. The type incidence and severity were very similar between the two treatment arms, particularly diarrhea and colitis. We were quite scared of the possible overlapping toxicity, but no signals from this point of view. Thyroid dysfunction were, as expected, the most frequently reported toxicity, but less than 2% grade 3 and 4, and no impact in quality of life. So based on this data, we believe that this data supports pembro in combination with chemoradiation with the new standard treatment in this patient. Thank you so much for your attention. Thank you very much, Dominika. I will now invite Dr. Janice Balega from United Kingdom to speak about role of surgery in locally advanced cervical cancer. It's going to be my walk of shame. I never felt so alone as a surgeon, and I'm afraid for the surgeons here I've got some bad news to share. So what is locally advanced cervical cancer? It's a group of patients with a wide variety of cervical cancer. As you can see, bulky 1B2s, or now it's 1B3, up to the 4As when disease is obviously invading into the pelvic organs. This is a very, very difficult patient group to treat, but obviously we have to put this surgical issue into the context of the newly published and recently published chemotherapy results. So the ESGO guidance is very clear that this patient group needs to be treated with chemoradiotherapy or the sequence of these two modalities. So I think I've got more questions to bring to the audience than answers. I've got a few questions that should we downstage these large-volume cancers, mainly those with no invasion into the bladder and rectum, obviously. We haven't talked about the rare types of cancers. Adrenal carcinoma, not very well responding to chemoradiotherapy. How about clear cell carcinoma? It's a rare disease, but clearly not a chemo-responsive and definitely not a very radio-responsive disease. What about those cases who have disease left behind after radiotherapy or when the brachytherapy fails because of perforation or other reasons? And then the very big question of shall we surgically stage the patients, i.e. shall we remove the pariotic lymph nodes, and then shall we radiate these pariotic microscopic metastases in the era of immunotherapy and chemotherapy? And obviously it was one of my questions from a patient with stage 4B disease with complete response after immunotherapy, whether we should do a completion surgery or not. So let's go through piece by piece. According to ESGO guidance, neoadjuvant chemotherapy plus surgery should not be practiced outside clinical trials. And there is a good reason for this. The PUPTA trial was very clear about it was cranial cell carcinoma, and it was very clear that, unfortunately, the surgical arm did not benefit. In fact, it had an adverse outcome when compared with the standard treatment. So the overall survival was not conclusive, as the study was not powered accordingly. The other trial, which unfortunately has not been published, according to my best knowledge, but it was presented in the ASCO meeting, again did not show any benefit of the neoadjuvant kind of downgrading plus surgical approach. The next question is, what shall we do with patients with residual cancer after chemoradiotherapy, or those who did not receive brachytherapy? The salvage surgery, we know this. There is fairly good evidence, although not randomized evidence, that we should not offer patients kind of standard hysterectomy after radiotherapy. But in Birmingham, in the United Kingdom, we are proponents of salvage surgery in case of failed brachytherapy for those patients with persisting disease. We noted that patients with persisting disease do not do very well after salvage surgery, although the options are not many after this failed radiotherapy. So the next one, you know, we surgeons, we love removing things, and we thought, you know, let's do the pariotic lymph node surgical staging. It's such a beautiful operation. And possibly, you know, there is a theory that maybe radiotherapy to this region will help. But the evidence is not very strong on this. So unfortunately, randomized trials failed to demonstrate any benefit. In fact, the LIE trial from Taiwan showed a very bad impact of surgical staging. The POMEL, Christopher POMEL, and two main cancer centers in France, they compared the different practices. Again, it was the surgical staging arm showed adverse impact on the survival. And a third study, the Marni study from Germany, again showed no benefit on the group of patients. Notabene, five-year survival was better on the surgically staged patients on the 2B subgroup, but obviously it was a subgroup analysis. So my conclusions are that there isn't very strong evidence of supporting surgery in this setting. The second one is that we definitely need to put surgery into the context of these new trial data. And the third one, if we have to perform salvage surgery, these patients should be referred to expert centers with experience of operating on radiated patients. Thanks so much. Thank you, Dr. Baleka. And with this, we actually come to an end to the locally advanced cervical cancer talks. And we would like to have opened the floor to any Q&A. And while we are getting ready with our first question, maybe I can already start with Mary. Congratulations on very timely publication. So can I ask you, this is such an important trial, which is going to make so much difference. Isn't it unusual, and I'm going to touch on the statistics part of the study, that when sample size was reduced to 700 to 500 in the trial, I noticed in the manuscript that already the power was set between 70 to 80 for the trial design. Is that usual for a Phase III randomized trial? And when you had less number of events, how was it statistically adjusted? I think possibly you should be asking the statistician if he were here to answer the question. The numbers were adjusted when we looked at the overall numbers and the timing and the duration of the study. We had to look at that, which is why we had a sort of a sliding scale for our statistics, 70 to 85 percent power. And actually we needed 150-odd events for that higher level of power. So we did have that in our final analysis. So I don't think the change in the numbers compromised the statistics in any way. There's a very clear difference between both arms of the trial, a very clear difference in outcome between the standard and the standard with the induction chemotherapy. Thank you. Can we have questions from the floor for any of the five presentations? Okay, we have a question there. Thank you so much for your presentations. My name is Sally Agalo from Nairobi, Kenya. I'm here to represent so many women who have gone through cervical cancer, and I just have one concern. From cervical cancer, I also got colorectal cancer, and I'm living with an ostomy. So I run a support group for people who are living with ostomies, and lately I've been finding members who are joining are having fistulas, and mostly it's because of the chemoradiation side effect. I don't know if you have this experience, any client coming back to say that I'm having a fistula as a result of the treatment, and most of them are ending up with ostomies, and it's very depressing. Thank you. Alexander, do you want to address the question? Yeah. Oh, sorry. I think that's something where we need to be looking. It probably is a consequence of the radiotherapy planning technique, and this is when we're talking about looking at the doses to the organs at risk. We know when we start looking back at conventional radiotherapy, your hot spots are often on the bowel and bladder, and the same with brachytherapy with point-based. So in terms of going forward, I hope that, I mean, as you know, IGCS is doing work as well, looking at trying to work with centers to improve and take forward the radiotherapy approaches, and it may be something to look at, because if you're describing that amount of fistulation, certainly we don't see that anymore once we move to more advanced techniques. Certainly when I started, we used to see a lot more fistulation using conventional, so I'm sure that's the reason. Mary? I think the other factor, of course, is the stage of the disease, bulkier, bigger tumors with more extensive disease in the pelvis. Those are clearly going to be the patients that are at most risk, and we don't tend to see as many of those in our practice. Do you have another question? Yes. I'm Professor Sabira Khatun from Bangladesh. Regarding the surgery for the locally advanced cervical cancer cases, I had a research work comparison between the near-given chemotherapy and the concurrent chemotherapy in stage 1B3 cases, and I found that it's very effective in increasing the susceptibility of the cases. Now, my question to all of you, every time it is said that the result is not good by doing near-given chemotherapy followed by concurrent chemotherapy, that radical histectomy, the result is not good. Always it is said for a long time, but my question is that why you do not take the initiative to do a large number of cases and trial by the G-Seq, Gynecological Cancer Intergroup? Can you take the initiative to do a long-term clinical trial in this group of patients, stage 1B3 cases, near-given chemotherapy followed by radical surgery? Because you are doing trial by giving the induction chemotherapy followed by concurrent chemotherapy. Then my question, why you are not taking the initiative to give the near-given chemotherapy followed by radical histectomy by the G-Seq, Gynecological Cancer Intergroup? As far as I'm concerned, there is an ongoing trial on this. As you can see, the large volume, bulky, these 1B3s, had better survival under the surgical, sorry, the near-given arms. They would like to see on larger population, and I think there is a prospective randomized trial going on. I saw the publication of the trial proposal. So I guess, unfortunately, if I remember, it's going to take so many years to publish that, so you won't have the results tomorrow. We, the Asian people, there are many cervical cancer cases, and many of the patients come with this large volume tumor. So we are interested to be included in this type of clinical trial. This is a multinational trial, this one, which is running currently, indeed, yes. There is already, if I get your question right, there are already two randomized trials that have been published negative for this approach. So I don't think this question will again be visited. At least I don't see it being visited. Thank you. Do we have more questions in the audience? Until we don't have, maybe, Dominika, I can possibly ask you also a very provocative question, right, that now we know that from your study, even though we see that it works very well immunotherapy, but for stage 1B, early-stage node positive, it crosses unity. It's only for stage 3B and 4A it's working. And most of the countries will not have access to immunotherapy. That is also a reality. So what are your thoughts about keeping immunotherapy for reserve when patients metastasize, right, and it automatically selects? So what are your thoughts about that? Thank you so much. It's a very important point to answer for the same question. So regarding FIGO stage 1B, 2B, node positive, forest plot analysis should be interpreted with caution because our event-driven descriptive analysis. At the first interim analysis, we have only 25% progression events in FIGO stage 1B, 2B, node positive. And the other ratio was 0.91. At the second interim analysis, the progression events increases from 25% to 37%, and the other ratio decreases from 0.91 to 0.85. To me, this is a clear signal that the drug works also in this patient that are erroneously considered early-stage because these are the patients that, according to the new FIGO 2018 classification, at the FIGO stage 3C and the FIGO, recognize the importance as prognostic value of lymph nodal status, and that's the reason why they were upstaged. And this patient has 40 to 50% risk of recurrence. And now I come to your second question. Why not to spare immunotherapy for recurrence? It's a golden rule in oncologists. When you have a drug that works and increase overall survival in a potentially curative setting or in a metastatic setting, I have no doubt that I have to use the drug in a curative setting. When the patient recur, and this is the message of Keynote 826, in the best scenario, no contraindication to Bevacizumab and PD-L1 positive tumor, the median overall survival is 28 months. This means that 28 months is less than three years. And this is what we can offer to our patient at the time of recurrence. If I have something that prevent recurrence and can cure a larger number of patients, I will not expect recurrence to provide. I think the question was more because of lack of access. Of course, what you're saying is, of course, there are problems. But this is a problem that we will face also in Europe. CHMP of EMA confirmed the indication of FDA right now. I have to say, I was involved in the discussion. It was not no, it was not now. They are requesting to see longer follow-up overall survival data, and final overall survival we anticipate will be Q1 2025, so in few months, and potentially with this data, both the regulatory authorities will reconsider the indication. Thank you, and before we move on to next session, I think I have a question both for Alexandra and Mary. What is NHS doing after interlace? A lot of centers in the UK participated in the trial, and we did recruit three quarters of the patients. So several of the centers have already adopted the interlace protocol, some have not. So I think just like in the audience, I'm sure there are those that like the approach, and there are those that don't. But there don't seem to be any barriers to adopting it, because these are drugs that are already available. No, I agree. I think, I mean, there's probably a split of people who are still undecided, and also thinking which patients particularly would benefit from it. But in terms of barrier of delivery, it's a straightforward approach. It's not really delaying your radiotherapy significantly, and it's very feasible to implement. And Ms. Zambartini, I ask you, in the trial, and again, congratulations for the publication we read last night. In the trial, where it is supposed that everything is under control, not the sequencing, 22% of patient delayed the starting of chemoradiation more than seven days. Do you think this could be potentially an issue in the real practice, in the general world? We had the discussion yesterday about the new standard of care, clinical consensus, and it was evident, in particular in country where the access to radiotherapy is more struggling. This can be considered an alternative, and not to maintain the timing, which is the strange of the strategy. No, I mean, I'm very clear. We did not design interlace so that people who had problems with delivering radiotherapy could get around that. I mean, that's a whole different story and a different discussion. I think it is important to identify your radiotherapy places, your radiotherapy slots, before you start your patient on induction chemotherapy. You then have a six-week window to plan the radiotherapy so the patients are ready to start in week seven. Now, there may be some scheduling issues, or maybe the odd reason why that's not feasible, but that's what people should aim to do, because there's no point in saying we've now demonstrated that giving short-course chemotherapy is beneficial unless we do it according to the protocol. I think that's a very important message. Thank you, thank you so much. Unfortunately, we have to move to the second part of the meeting. Do you want to introduce? Yes. So it's my great pleasure to invite again our colleagues to present the second cases on the metastatic setting. Thank you so much. Thank you. I will present now the clinical case of a dear friend and colleague, Anissa Mumbru. She's from Kenya. She couldn't be here in person, so I will present her case. This is a metastatic cervical cancer case. It's a 42-year-old patient presented with a three-month history of foul-smelling vaginal discharge affecting her quality of work life. She reported lower abdominal pain, and she had developed vaginal spotting and post-coital bleeding for five months prior. She was treated severely in small clinics with other strategies, with pessaries and antifungal pills. As past medical family and social history, she has no social, no history of cervical cancer screening. She is an HIV uninfected. She had vaginal deliveries and no history of smoking or other risk factors. In the examination, she has a COG status zero with no palpable lymph nodes. She was pale. In pelvic exam, she had a suprapelvic tenderness and a bulky uterus, approximately 40 centimeters, and the vaginal examination showed a pungent, yellowish, watery discharge from gaining friable mass in the vagina involving cervix, both parametria, upper vaginal wall, and left pelvic side wall. The rectal mucosa was free. In investigation, she had anemia, and they performed a biopsy and confirmed the SCAMO cell carcinoma of the cervix with an HPV, the 18 positive, and the immunosubchemistry showed PD-L1 positivity with score more than one. This is the DC scan. The positive findings are the hypodense subcapsular and deep liver parenchymal masses. The largest one was 7.6 millimeters in segment two and five, and also a six centimeters bulky cervix tumor with parametrial involvement, left pelvic side wall involvement, and upper to mid-vaginal involvement, too. Also, they were found, there were pelvic paracaval and paraortic lymphadenopathy measuring 14 millimeters and 10 millimeters, approximately. She was staged as FIGO stage 4B, and the treatment was indicated in a multidisciplinary committee, too. She started with palliative chemotherapy, carboplatin, and paclitaxel. She tolerated well the treatment, needing one transfusion and a filgastrin rescue. She completed six cycles of chemotherapy on September 26, 2024. This is the post-treatment examination. She had a vaginal mass regression, but with persistent disease. And in the DC scan, they found oligometastatic persistence of the lesions, a subcentimeter diffuse hypodense hepatic lesion, and residual disease at the cervix, with no lymphadenopathies. So these are also some questions for debate. The role of radiotherapy in this metastatic setting, the induced response of radiotherapy in this scenario, and also the palliative indication. The management of residual tumor after good response to systemic therapy in high-income countries, but also in our settings in low- and middle-income countries. And if there is any comment about additional treatment options in this scenario, and another plan for follow-up. Thank you very much for your attention. Okay, thanks very much. So our next speaker is Dr. Ana Ocman from Spain, who's gonna give a trial update on the BEAT cervical cancer. Good afternoon, ladies and gentlemen. I would like to thank the scientific committee for inviting me to present an update. Indeed, you know, small new data in the BEAT-CC trial, the randomized phase three of first-line atezolizumab combined with the vasizumab and a platinum doublet for metastatic persistent or recurrent cervical cancer. Here, sorry. Oh, it's not moving? Okay, this is my disclosures. BEAT-CC is an open-label randomized phase three trial evaluating dual blockade of PD-L1 and BGF. Eligible patient had metastatic persistent or recurrent cervical cancer. They may have not received prior systemic anticancer therapy for the recurrent setting, ECOG-001. Those patients with a specific risk for fistula, namely those with bladder or rectal mucosal involvement, were excluded to reduce the vasizumab toxicity. Remarkably, we enrolled an all-comer population we didn't take into account the PD-L1 status. Stratification factor were prior concurrent chemoradiation, histology, ischemos versus adenocarcinoma, and chemotherapy backbone, either cisplatin or carboplatin. Patient were randomized in a one-to-one to a standard chemotherapy regimen established by the GOG-240, shown here in red, or the same regimen with the addition of atezolizumab. Patient received chemotherapy until progression disease and acceptable toxicity in combination with the biological therapy. However, those patients with achieved a complete response after at least six cycles of chemotherapy, they could stop chemotherapy and continue with biological therapy alone. The dual primary endpoint for the study were investigator-assessed PFS and ovarian survival. And I would like to stress that it was not a hierarchical analysis. We pre-specified in the protocol an inter-inovarial survival analysis at the time of the PFS analysis. Here, one of the primary endpoint, the dual primary endpoint PFS, the trial met its objective. The addition of atezolizumab to the combination of evasizumab and chemotherapy show it has a ratio 0.62 with a highly significant P value. It means they show a statistical significant 38% reduction in the risk of progression or death. The median PFS was 10.4 months for the standard arm compared with 13.6 months in the experimental arm with atezolizumab. The other primary endpoint, ovarian survival entering ovarian survival. I mean, the addition of atezolizumab to evasizumab chemotherapy show it has a ratio 0.68, representing a statistical significant 32% reduction in the risk of death. When we look at the median ovarian survival, it was 22.8 months for the standard arm comparing with 32.1 months for the atezolizumab arms. I'm sorry, it means an increase in 10 months ovarian survival. Indeed, when we look at the percentage of patients who were alive and two year, it was 61% for those patients receiving atezolizumab compared with 49 patients in the standard arm. Since in the BCC was an international trial, you know, we enrolled patients from Japan, so we thought that it was very interesting to look at the data in the Japanese population. We enrolled 56 patients from Japan, as you can see in the atezolizumab arm, you know, there was a superiority in terms of PFS with a hazard ratio 0.51. The median PFS was 15.8 months in the atezolizumab arm compared with 11 months in the vivacizumab arm. In terms of ovarian survival, also in the Japanese population, the addition of atezolizumab to a standard arm show a hazard ratio 0.53 with a median ovarian survival for the atezolizumab arm of 34 months compared with 31.6 months in the vivacizumab arm. Turning to safety, you know, the addition of atezolizumab in the intent to treat population, the addition of atezolizumab didn't seem to increase the adverse event as shown by the percentage of patients suffering from any adverse event, grade three or greater adverse events, aesis for vivacizumab, that it was almost the same in both arms, and the aesis for atezolizumab was 5% in term of grade three or greater. When we look at the Japanese population, it seemed that they suffered for a greater incidence of aesis related with vivacizumab, and the adverse event leading to treatment discontinuation was greater in the Japanese population compared with the intent to treat population. The other important point that we analyzed in the BCC that was presented by Laurent Gladiev this year in ESMO was long-term patient-reported outcome. I mean, this measure was analyzed at the week 19, and as you can see in the graph, there was no difference between treatment arms in the mean change from baseline in terms of quality of life. There was not either difference between treatment arms in time to deterioration or death in both arms. So, in conclusion, BCC confirmed the clinical benefit of combining immunosuppression inhibition with angiogenesis in recurrent metastatic cervical cancer. Adding atezolizumab to vivacizumab plus chemotherapy provide statistically significant and clinically meaningful improvement in PFS and overall survival in patient with recurrent metastatic cervical cancer. In the Japanese population, improvement across primary endpoint were consistent with the trial results in the intent to treat population. Adding atezolizumab to first-line vivacizumab chemotherapy didn't impair quality of life, and there are no new safety signal with atezolizumab in combination with vivacizumab plus platinum-based chemotherapy. So, atezolizumab combined with vivacizumab added to platinum-based chemotherapy should be considered a new first-line option for patient with recurrent metastatic cervical cancer. Thank you so much for your attention. Thank you, Anna. Now I would like to invite Dr. Rupali Arora to speak about PD-L1 testing, if it's reliable and useful. Good afternoon, everybody, and thank you for the organizers for the invite. As a pathologist, I feel a rare breed with Glenn and the others, just a handful of pathologists here in the audience. So, PD-L1 testing, is it reliable, and is it really useful? Just a little bit of background. I work at University College London Hospital, which is affiliated to a large referral tertiary sent immunohistochemistry lab. So, I do see a lot of referrals for PD-L1s, not just from London, UK, but also abroad. Background about PD-L1, we all know that these are immune checkpoint proteins, and they play a vital role in enabling the cancer cells to escape the immunity, proliferate, and progress. Inhibitors of these proteins can be used to reactivate the immune system to fight the cancer. Now, selection of patients for such therapy requires the demonstration of PD-L1 activity on the tumor cells. Considering the potential adverse events that we talked about, and the high cost of these inhibitors, there is a substantial need to identify selection of patients which are likely to benefit from this treatment. We all know the story started in cervix for the keynote A26 study. In this study, the subgroup analyzed a cohort of PD-L1, which had a score of more than one CPS, or CPS more than 10, showed an improved overall survival with PEMBRO. In the CPS less than one population, the difference in overall survival did not meet statistical significance. So, these results suggest that PD-L1 may be a valuable biomarker to predict the outcomes for patients with cervical cancer treated with PEMBRO. Now, how do you test for PD-L1? It can be tested as a PD-L1 protein levels in plasma by ELISA method. It could be by western blot. It could be by targeted NGS panels, or by immunohistochemistry. And of course, immunohistochemistry is widely available, is practical, and it's an economical approach as well. Now, across various tumors, there are various guidelines, various clones, and various cutoffs that are used. That is what makes PD-L1 so confusing. The PD-L1 FDA approved clone is the DACO clone 223C. But you'll see various clones have been used even in the gynecological cancer settings. Now, how is PD-L1 scored? There are two typical scoring methods for PD-L1. One is the total score, total positive score, and one is a combined positive score. The difference between the two is the total combined score looks at only the positive and negative tumor cells, whereas the combined positive score combines positive cells, which are tumor cells, and the immune cells as well. Now, both these methods had proved to be equally predictive of response to anti-PD-L1 therapy in lung and head and neck cancers, but that's not the case in cervix. So the CPS, the FDA approved scoring method in cervical cancer is CPS. You do need a minimal of 100 viable tumor cells to make the PD-L1 test adequate. So as a pathologist, I have to show you some path images. You do have the pink image is an HNE image, which shows you the squamous cell carcinoma and the inflammatory cells. The brown and gray is the immunohistochemistry for PD-L1, and you can see there is a lot of positivity around the tumor and the inflammatory cells, and that gives you a CPS score of 90. Here you have a poorly differentiated adenocarcinoma, and in the brown stain, you can see the stain is picked up only by the immune cells and the gland cells staining positive. Still, because this is a CPS score, the CPS score would be a 20. Now, the whole point is that there are lots of artifacts and pitfalls when you're assessing PD-L1. The tumor cells with complete or incomplete membrane staining are supposed to be positive, but there is a caveat. If it's an adenocarcinoma, the luminal staining is considered negative. Macrophages can resemble tumor cells on immunostain because they look larger cells, so you do need a comparative HNE slide to keep comparing which cells you're looking at. Nucleus staining can be seen, and of course, this is not to be counted because you're just counting membrane staining. And heterogeneity of PD-L1 expression is always present. Now, this does affect sampling, especially if you're dealing with a needle-core biopsies. Factors affecting the CPS, there will be intra- and inter-observer variability, biopsy sampling sites, that means primary versus metastatic size, how old the archival tissue that has been used for sampling, and tumor subtypes as well. There's a lot of variation between various laboratories, and of course, quality assurance is key here. There is intra-cellular pigments like melanin and hemocidin can complicate the interpretation. Platelets often take up PD-L1 staining as well, so when you have aggregates of platelet, they will give rise to a false sense of positivity. Bacteria and acellular debris can also show significant positivity. With regards to types of cancer, squamous cell carcinoma were most frequently positive for PD-L1, and they also contain more PD-L1-positive tumor-associated macrophages as compared to the adenocarcinomas. Within the different types, adenosistic and basaloid do not express usually PD-L1. The PD-L1, the HPV-negative mesonephric and the invasive stratified mucin-producing carcinomas do show high expression levels. Usually, PD-L1 expression is strongly associated with HPV status in the cervix. And the more poorly differentiated carcinoma, the less likely it is to express PD-L1. PD-L1 also has different patterns. It has a diffuse pattern and a marginal pattern, and the survival is associated with that. Survival significantly poor in squamous cell carcinomas where the pattern of staining is diffuse as opposed to marginal. When I mean marginal, it's the margin of the tumor with interface with the stroma. Survival was significantly worse in adenocarcinoma patients with PD-L1-positivity tumor-associated macrophages compared with adenocarcinoma without the PD-L1-positive tumor-associated macrophages. So there is a difference in the pattern and the survival. PD-L1 expression may be related to worse prognosis, but again, the results are variable if you read different papers. Some patients with PD-L1-negative primary tumors do respond to anti-PD-L1 treatment. Now, this may be because of the discordant PD-L1 tumor staining between the primary and the metastatic tumors. Some patients develop resistance to immune checkpoint therapy, and again, of course, this is going to cause hindrance to the further applications. New adjuvant chemotherapy and radiotherapy may enhance the PD-L1 expression in the tumor cells, and based on the currently available studies, PD-L1 expression has a low positive predictive value in relation to immune therapy response. You can get false negative PD-L1 tests when you're using archival samples, which may have caused some degradation. If it's a small tumor size, we talked about heterogeneous staining, and also tumors can have, if the biopsies don't include the invasive end of it, where you actually do have the T cells present, so those will not be included in your PD-L1 expression. Significant differences are noted in PD-L1 expression among various trials. Now, why is that? That might be because the selection of specimens is quite variable, whether the trials were using the specimens at the initial diagnosis or it is used after treatment. Some of the trials have used blood, some of the trials have used tumor specimens, and of course, there are various antibody clones which might be used in these trials as well. Now, what about PD-L1 with other gynecological cancers? Vulval, in vulval SCCs, PD-L1 expression is present in neoplastic cells, and this is more in HPV-independent rather than HPV-dependent tumors. What about PD-L1 in immune cells in vulval? This is said to be equal between HPV-independent and HPV-independent tumors. Endometrial carcinomas, there's a higher prevalence in MMR-deficient cancers, and there was no survival difference between the PD-L1 expression in the different tumor subtypes in ovary and the survival. What about in cytology? Of course, all the trials and the FDA have not talked about cytology material. They've all talked about a paraffin-fixed tissue, and hence, although you can perform PD-L1 in cytology, this is still not approved, so in settings where you can't access a biopsy, yes, you can refer to cytology, but with a caveat that these have not been validated. How do you improve, then, the reliability of PD-L1 testing? Get the most recent biopsy from the metastatic site, ensure that it's adequate tissue fixation, use controls, use an H&E section alongside the immunostain, and of course, standardized kits have to be used rather than the homegrown kits which laboratories can use, because frankly, they're quite cheap. What are the upcoming biomarkers that can hold your hand with the PD-L1? It's usually the high-burden and the PD-L1 MMR expression, and so to conclude, is it reliable? Yes, but with a lot of caveats. Is it useful? Yes, with a lot of caveats, and currently, there is no uniform and standardized scoring system for PD-L1 across all malignancies. Thank you. Thank you. Thank you very much, Dr. Arora. I'd now like to welcome my colleague and friend, Dr. Keishi Fujiwara, who's gonna come and discuss tezotamab and metastatic cervical cancer. Thank you very much. Thank you, Alex. So, I'm gonna talk about the tezotamab-vidotin study results. So, this is my disclosure. So, the tezotamab-vidotin is an investigational antibody drug conjugate, ADC, directed to the TISH factors, and INOVA-TV301 is a global, randomized, open-label phase three trials in the TV versus chemotherapy in patients with a two-line or third-line, second-line or third-line recurrent or metastatic cervical cancer. So, this is a summary of the key eligibility criteria, and the criteria has already mentioned in the previous lines. So, the treatment will be randomized to either TV or the physician's choice chemotherapy, including those five chemotherapy agents. So, the primary endpoint is overall survival, and the key secondary endpoints included PFS and safety. So, the baseline patient characteristics are well-balanced between two arms. So, this is the overall survival, which is the primary endpoint result. As you can see, the hazard ratio is 0.70, and the statistically significant P-value is 0.0038. So, when you look at the one-year overall survival rate, the TV arm shows the almost 50%, and the chemotherapy arm shows the almost 35%. And the progression-free survival and objective response rate is shown here. So, both PFS and the overall response rate is better in the TV arms. And this is the key subgroup analysis for the OLS and PFS, and as you can see, almost all, except for the prior or no prior vivacism of here, no prior vivacism of here, is rather than this, all the subgroup analysis shows the result is in favor of the TV arm, TV patients. And if you look at the most common treatment-related adverse events, the TV arm shows the conjunctivitis, peripheral neuropathy, or alopecia and epistaxis, which is related to the TV, and also shows the anemia or neutropenia was shown, demonstrated in the chemotherapy arm. So, the overall incidence is about the same, but the characteristics of the adverse events is very, very different between two arms. So, in conclusion, TV showed statistically significant and clinically meaningful improvement in OLS compared to the chemotherapy, and consistent benefit in the PFS, and confirmed ORR were also observed. And the safety profile of the TV was manageable and tolerable and consistent with the previous experience. So, based on these results, TV should be considered as a potential new standard of care for patients who have progressed after the first-line chemotherapy. I forgot to tell you, but the P, prior, the immunological checkpoints in-vitro didn't affect the efficacy of the TV. Well, I really thank for the patients and families and the investigators. Thanks so much. Thank you very much, Casey. We'd like to invite people for questions. Please don't hesitate to stand up. In the meantime, while you're walking towards the microphone, I have a question. Anna? Very practical question. Women with HIV are at an increased risk for cervical cancer. Where access permits, what would you recommend for a patient with metastatic cervical cancer who happens to be HIV-positive, maybe is on retroviral therapy and controlled? What would your advice be to clinicians? You said with mitral riser? Just HIV-positive metastatic cervical cancer. Honestly, I think that the therapy that has shown better outcome is the combination of chemotherapy plus pevacizumab plus immunocheckpoint inhibitor. In the BCC trial, the use of pevacizumab was mandatory because we built the therapy on the standard and that it was chemotherapy plus pevacizumab based on the GOG-240. So in addition, when you look at the outcome from the keynote 826 in the subgroup analysis according to the use of pevacizumab, there's clear effect of pevacizumab in outcome. So as long as the patients don't have any contraindication to use of pevacizumab, I think pevacizumab should be incorporated. So summary, chemo plus VET plus IO therapy. Thank you very much, Ana. I guess my question was more in an HIV-positive patient. HIV? HIV. Ah, I didn't take you, sorry. So unfortunately, that is a case we have, some of our patients with cervical cancer are also HIV-positive. Yeah, yeah, yeah, I got it. What would be your recommendation? I got it. Would it be okay to give an immune checkup? I mean, the most important point is that the patient has the HIV under control. If the patient is receiving the triplet therapy for HIV and the viral load is under-recommended in terms of the triplet therapy efficacy, I think those patients should receive exactly the same therapy that other patients suffering from cervical cancer. I mean, we cannot jeopardize the outcome of those patients because they are suffering from HIV. And I think that's really important. Sorry, Alex, that I didn't get that. Thank you, Ana, because I think that's really important because they were often excluded from trials, but data from other tumor types have shown that you can do that. Could I ask a question to Rapali? It's just about the staining, the PD-L1 staining. So, you know, we're told that the DACO-223C is the one that's FDA licensed, but do we need to actually use that antibody because most of the laboratories won't have it? And, or can we use other antibodies? I've heard some people saying you can use any validated antibody. Have you any thoughts on this? Well, you can send it to UCLA, Glenn, because we do have the antibody. But no, we're sticking with 223 clone because that's the only antibody that is FDA approved. There are, the reason why there are differences in the clinical trials and the studies, I feel, is because of the different clones being used. And, you know, people choose to have just positivity because they want to treat the patients. And I feel it shouldn't be the case and you should have validated studies and approved clones to be used. I know in lung they use different clones, but for the cervix settings, I know in the vulva they've used two clones, which are getting approved. So, yeah, it might be in different gyne cancer settings. Thank you very much. We have a question from the audience, and I think I even recognize who's asking the question. Thank you, go ahead. So I'm Asima. I just want to ask a question regarding IO and any one of you could answer. And we talk about HIV, but do you know what happens with tuberculosis or somebody on antitubercular drugs? Is it a problem with IO? That's number one. And then the other question is, you know, like you say, the 15 cycles of maintenance, right? Do you have any plans to think about that maybe there are some patients who may be eligible for a reduced duration of IO? So, thank you. I'll take the second question. I think that's an excellent question. We don't know the duration. And given the cost and potential toxicities, I think it'd be really worthwhile investigating reduced durations in a clinical trial. It's being done in other tumor types like lung cancer. And I think that that would be worthwhile for our patients. It might improve access to these immune checkpoint inhibitors in areas that have more scarce resources. So I would be very favorable for that kind of a study. Yes, Athena, for sure. I think you are talking about locally advanced, not exactly metastatic, because the 15 cycle were for locally advanced. When we designed the trial, we were completely blinded about the possible duration. We choose the 15 cycle because literature data suggested that 80% of recurrence occurred during the first two years. And we simply want to protect the patient during the maximum risk future trial. Keynote 18 is the beginning of a new era and future trial will explore better. But this is a good opportunity also to underline that this is a preventable disease. We spend all the sessions celebrating the new overall survival data in locally advanced, in metastatic, but this is a preventable disease. I think that we have to implement, particularly in low and middle income country, preventable strategies with primary and secondary tumor. We do not need to wait that the tumor occur and the cure in a locally advanced setting when we can prevent it. Can I just add to the first part? One was for the question on tuberculars. So normally not all patients with HIV would be on antitubercular drugs. Not the HIV, I'm just saying if a patient has tuberculosis and is on ATT, is that a contraindication for IO? I don't think we will be able to answer that question. And for the second part for duration of immunotherapy, the next studies that are being designed now in locally advanced setting, they have limited duration of one year for IO. Thank you. Thank you. Thank you, and we have another question. Thank you for your presentations, they are excellent. I have a question about PD-L1 evaluation. What would be the recommendation to make the sampling from the metastatic nodule from the primary tumor? And the second question is, sometimes it's relatively complicated to evaluate the PD-L1. Would artificial intelligence would be useful in that setting or help our pathologists to improve in their reading? All right, thank you. So the answer to the first question is, like I said in the talk, if you take a biopsy from a metastatic site, that is the preferred site of biopsy because a tumor does show heterogeneous staining. The studies show that the primary versus the mets have different staining patterns of PD-L1. So the fresher the biopsy, the better it is. Between different metastatic sites, if you've got multiple metastatic sites, it's preferable to sample all metastatic sites if your first metastatic site is negative and you want to give the treatment. The second question was about AI in PD-L1. Yes, of course, I mean, we haven't got AI as yet, but of course, with any interpretation, having so many difficulties as PD-L1, AI will hopefully solve all of them as we hope for everything else, so yeah. Thank you. Thank you, we have another question from the floor. Yeah, hi, good evening. My name is Sudip Gupta from India. I am discussing the A18 trial tomorrow, but because of the duration question, let me make a comment. In locally advanced breast cancer, triple negative breast cancer, the maximum period of risk for recurrence is two to three years after surgery, and one year of pembrolizumab was found reasonably good in that setting, and my second comment is that it is very difficult to redo the trials again. Perhaps there was an opportunity to include a third arm in the A18 trial with one year of pembrolizumab. I don't think, I would like to have another keynote A18, but I don't think we will do, but other trials that are coming are exploring different durations, so. Okay, we'll take a last question because then, unfortunately, we're over time. Thank you all. I'm Graziela Damolim from Sao Paulo, Brazil, and my question is for patients that had metastatic cervical cancer and had platinum bevacizumab and IO and have a recurrence. Should we go to Tizotumab with Odin, but if it's a HER2, 3+, positive patient, we only have a phase two trial, but we have the phase three trial with Tizotumab with Odin. What is your opinion about it? Okay, Key, it's to you. Well, if you can use experimentally, you can choose either one. However, if the TB is an only choice of the insurance coverage or the reimbursement, well, the first choice will be the TB. Did I answer to your question? Okay, I think the overall response with Tdxd was so high in the phase two trial, we don't have the confirmatory results in the phase three, so that's why I'm really in doubt what should I offer before. Yeah, that's a good question. We really need a confirmatory trial results for everything, yeah, I agree. Thank you very much, and we greatly appreciate the questions, and I'm just so sorry to say that we've gone over time, and so we are now obliged to close this session, but feel free to come up and talk to the speakers. Alex, one important message, okay. We have not answered to the question of the first case yet, so what are we gonna do for the patients in Kenya, right? So we have to think about the palliative care for those areas, so that is, the IGCS is working very hard now, so please join the palliative care, the program, to the IGCS is doing. Thank you so much. Can you just do, we start with that session, but there is a lot of role of radiation, which we could not.

cervical cancer

locally advanced

metastatic

chemoradiation

image-guided brachytherapy

intensity-modulated radiotherapy

INTeRLACE trial

pembrolizumab

neoadjuvant chemotherapy

atezolizumab

PD-L1 testing

Tisotumab vedotin