Let's begin today's webinar. Welcome all. I'm Flora Backus. I'm a gynecologic oncologist and professor in the Division of Gynecologic Oncology at The Ohio State University and James Cancer Center in Columbus, Ohio. I'm honored to be one of the co-chairs of the IGCS Education Advances and Updates Workgroup and excited for our webinar today titled Multidisciplinary Approach to Treating Advanced Endometrial Cancer, which is in part sponsored by ECI. IGCS is committed to providing meaningful education opportunities through a unique year-round educational engagement program. This platform provides the level of strategic engagement and exposure needed to educate and inform gynecologic oncology professionals on current and future treatments to optimize patient care. Before we get started, I want to mention a few housekeeping items. Please know that a recording of this webinar will be available on the IGCS Education 360 Learning Portal within one business day. We encourage you to submit questions via the Q&A feature at the bottom of your screen and we will do our best to answer and address as many questions as possible. Now it's my honor to welcome our faculty. We have a pharmacist, Amber Kahn, from The Ohio State University and James Cancer Center in the United States. Dr. Ketela Russo, she's an associate professor and gynecologic oncologist in Rome, Italy. I will leave it up to her nurse also to properly pronounce her institution. Her nurse, Marta Muscatelli, also from the same institution in Rome, Italy. I'm really excited to have this panel here and thank you for joining us today and providing your insight and approach for treating advanced endometrial cancer. Before we get started, I do want to mention that Dr. LaRusso had a clinical emergency come up this morning or this time, I guess, afternoon in Italy. She'll be joining slightly late, but we will get started and she's going to make it as soon as she can. Before we get started with our panel discussion, I first want to share some important data. In the Zoom chat, you will find a link to the article Optimizing the Use of Levatinib in Combination with Pembrolizumab in Patients with Advanced Endometrial Carcinoma. We highly recommend this as a resource with additional information and it was co-authored by our panelist, Dr. LaRusso. Let's go ahead and review a couple data before we dive into our discussion. Why are we having this discussion today? Levatinib and Pembrolizumab saw endometrial cancer approvals. This was in July 2021. The FDA approved this combination for patients with advanced endometrial cancer that was not MSI-high or mismatch repair deficient who had progression following prior systemic therapy in any setting. Around the same time in November 2021, the European Commission approved Pembrolizumab in combination with Levatinib for advanced or recurrent endometrial cancer, but regardless of mismatch repair status or MSI status, also who had progression on or following prior treatment with a platinum-containing regimen. What data do we have to support this regimen? First, there was a single-agent study that showed exciting data, but of course there's a confirmation needed in a comparative study. This was study 309 or Keynote 775. Here on this slide, we see the design. For this study, patients had to have advanced metastatic recurrent endometrial cancer. They had to have disease that was measurable and one prior platinum-based chemotherapy regimen. ECOG status, performance status zero to one, and they had to have tissue that was available for mismatch repair deficiency testing. They were then stratified by mismatch repair proficient or deficient and further stratified by region where they were, ECOG status or performance status, and the history of prior radiation. These patients were randomized one-to-one to Levatinib starting dose at 20 milligrams per day and Pembrolizumab, 200 milligrams IV every three weeks. This was compared to either Doxorubicin, 60 milligrams per meter square IV every three weeks, or Paclitaxel, 80 milligrams per meter square on a weekly basis, three weeks on and one week off. Patients were treated until either progression or unacceptable toxicity, and the primary endpoints for this study were progression-free survival by blinded independent central review and overall survival. Secondary endpoints were objective response rates, quality of life, which is also very important, pharmacokinetics, safety, and also was a key exploratory endpoint, which was duration of response. Here are the most important outcomes and really earth-shattering for many of us that have been treating recurrent endometrial cancer, and before it is approval, there really was not much approved. We were using either hormonal therapy with progesterone therapy, which was one of the few approved agents, or maybe Doxorubicin. Here's what we see in the mismatch repair population, the proficient mismatch repair population on the left, and on the right, on the left, we see the median progression-free survival, which was 6.6 months with the combination of Atenepimbralizumab versus 3.8 months with chemotherapy, and the median overall survival also, which is really important to realize that now we see an important overall survival difference here of five months, which we hadn't really been able to show in recurrent endometrial cancer. As you see below these graphs also, the objective response rate in the mismatch repair proficient group was 30 versus 15 percent, and in the mismatch repair deficient group, 40 percent versus 12 percent, and look at these duration of response. It's 9.2 versus 5.7 months in the proficient group, and not reached versus 4.1 months in the mismatch repair deficient group. This was the reason, of course, for confirming the approval, but with new regimens, as we started to use this regimen based on this exciting data, we're also starting to see some very different patterns of adverse events. I circled some of those adverse events here. A couple key differences. We see that overall, any adverse event is fairly similar between the Levatinipimbralizumab combination and chemotherapy, but I highlighted these differences. Hypertension, much more common on Levatinipimbralizumab, and one of the main adverse events that we'll see happening in our patients, and very uncommon with chemotherapy. Similarly, over half of the patients will develop hypothyroidism, so this is something new that we have to learn also to manage again. Diarrhea was much more common, also some grade three, but overall, the majority are grade one to two, with some still in the grade three area. Weight decrease, somewhat of a unique side effect also. Decreased appetite and fatigue, certainly, but also that weight decrease that you see here, and 10% of patients actually developed a weight decrease of grade three or more. Arthralgias were much more common, not so much on the severe grade three or greater, but any kind of arthralgias were much more common than compared to chemotherapy, as was proteinuria. Of course, these proteinuria hypertension were things that we were familiar with other anti-VAGF targeting therapies, such as bevacizumab, a monoclonal antibody. The other side effects are relatively similar between the chemotherapy and the Levatinipimbralizumab group. As we see these differences in side effects, we also need to think about how we counsel our patients, educate our patients, and guide our patients, and manage these toxicities. There is a lot to learn for our team of providers. Other things that are quite unique, and rather than the myelosuppression that we see with chemotherapy, we see these different side effects that we just saw on the previous slide, but there's also a timeline associated with it. You can see here, for example, in the column on the left, you see the type of side effects. Then immediately next to it, we see the incidence of that, but also how many times Levatinipimbralizumab, or maybe both, required a dose interruption or dose discontinuation. We see here that for many of these side effects with incidences, you can see, but also Levatinipimbralizumab was dose interrupted somewhere between usually 2 and 15 percent. Then a dose reduction was needed for many of these patients. Even for fatigue, for example, 24 percent of the patients required a dose reduction. These are manageable side effects. We can also see subsequently that the number of patients that actually had to discontinue Levatinip for an adverse event was very low, somewhere between 0 and 1 percent. If you manage these properly with counseling, good education, symptom control, and dose interruptions or dose reductions, we can avoid patients to have to stop this very active regimen. Looking at Pembrolizumab, similarly, there were some dose interruptions also noted, but very rarely Pembrolizumab had to be discontinued. The other interesting thing that we can see from this graph is that there's this kind of timeline. The bar graphs see a median time to first onset. You can see in this graph that the error bars extend all the way from right in the beginning within even the first week, 0 to 1 weeks, but then you see the number of times listed. Hypertension, for example, arrives, can start very early within the first week of taking Levatinip with a median time to first onset of 2.1 weeks. We really have to start thinking about these patients and educate these patients right before starting this treatment because they could certainly become very overwhelmed if they start their first cycle and develop all of these side effects at once if they weren't prepared for that. That's what the goal of our discussion is today. With that, I would love to get some input from our nurse and our pharmacy here and our panel who do a lot of the help us with this preparation work. Marta, let's start with you. When the patient is scheduled to start on Levatinip Pembrolizumab, how do you educate these patients and prepare them to get started? Marta, I think, are you frozen? You're still muted though. Marta, you're still muted. Amber, why don't we start with you while Marta makes sure that she's on muted. Amber, you help us with a lot of these patients also. Can you go over what you do for these patients? Typically, I talk to the patients about each drug individually. Usually, we start with lenbatinib and some of the common toxicities, and then I go into some of the less common toxicities, and then I start with the pembrolizumab adverse events. For lenbatinib, the first thing I usually mention is hypertension. As you mentioned, it can start fairly quickly after initiating the lenbatinib. In terms of the study, any grade of hypertension was in 64% of patients, so it's fairly common that they could have this adverse reaction. Hypertension, diarrhea is the next one I usually mention to patients because lenbatinib can cause a diarrhea as well as it could be a potential IO toxicity. Nausea and vomiting is usually the next toxicity that I'll mention to patients because in the studies, approximately 49% of patients had any grade of nausea. Grade three was in about 3% of patients, but it's still something that I definitely counsel the patients about. Mucositis is usually the next one that I tell patients about, and I ask them to call us early because we have options for symptom management of mucositis as well as for obviously nausea and vomiting. I usually go through rash next, fatigue, and then I talk about impaired wound healing. And if they are ever scheduled for any type of procedure, that's something that we need to know about because we usually hold lenbatinib prior to surgery. So if it's a smaller surgery or elective, we usually hold it for a week before surgery, and then if it's a major surgery, that's usually about two weeks before we restart lenbatinib. There's other toxicities also that are less common, but I do mention them because it's important for patients to know these toxicities are possible so they know when to call us essentially. So thromboembolic events is something we go through. The possibility of GI perforations, the VEGF inhibitor, and rarely, but I do mention the reversible posterior leukoencephalopathy syndrome. So if they have visual disturbances, neurologic disturbances, those are things, nuance of headache, lethargy, seizure. I mean, those are important things that we need phone calls about. A rare side effect, but it is possible with lenbatinib is osteonecrosis of the jaw. So I do mention that because sometimes our patients are on other medications such as bisphosphonates or denosumab can also have that side effect of osteonecrosis. So really being cognizant if they're going to have any sort of invasive dental procedures can cause cardiac dysfunction as well as rarely can cause hypocalcemia. We're usually monitoring for these electrolyte abnormalities, but I do mention them to the patients, mostly so they know when they should pick up the phone to call our clinic. Great. Yeah, that's great. And I think, Marta, I think you use some forms also or some education materials. And how do you, what do you use and what have you found helpful? Are you talking with me? Can you hear me now? We can hear you. Yes, this is great. Thank you. I'm sorry. So from the beginning, we welcome our patients with a quick and simple recap after their medical interview with the doctor. We explain again that their therapy involves 30 minutes intravenous every 21 days in an easy way and a daily table always at the same time or less. And we always specify that the fasting is not required because our patients love to eat. So first of all, they always want to know if they can eat or not. So we specify that the fasting is not required. We don't use anything, actually, because some of our patients maybe are older than 50, 60 years. So we prefer to explain to them in an easy way what they have to do in the later months. So we talk with them in an easy way and we don't use anything, actually, brochure, we don't, we have anything. We only have to, we have prepared a daily diary written by us, me and my colleagues, that we can use with the recorder, the daily recorders of the blood pressure. And we provide them this small diary, only this one. Great. And I see that Dr. LaRusso has been able to join us also. This is very exciting. Good morning. I'm so sorry for the delay. I was visiting, you know, we do also this. You're a real active doctor. So yes, we all know how that goes. But we'll start right with you then. We went over these slides already. And so one of the questions in the chat also is, if a patient is 80 years old, do we put her on this combination? And I think the follow-up question to that would be, what doses would you start on? Would you like to address that? Sure. My pleasure. So first of all, we all know that the anagraphical age is not the only criteria we take in consideration when we choose a treatment for our patient. It's much more important what we call the biological age. I mean, you can be an 80-year-old woman, but you can be very performing without comorbidities. And you can be a 65-year-old woman with a lot of comorbidities. So age is not the only criteria we consider. What we consider also is the caregiver of the patient. Because for sure, this patient should be able to move to the hospital every three weeks, but should be able to take pills every day at home, to call someone who has any kind of side effects. So these are the aspects that we take more in consideration, not only the treatment by itself. As for the dose floor, you know, this is a very, very difficult question because the trial used the full dose of 20 milligrams and 66 percent of patients reduced dose and 33 percent of them discontinued treatment because of toxicity. So the most easy question is why not to start at a lower dose? I have a very long conversation with our pharmacologist. Here we have a pharmacist that can better than me address this question. But what they answer, and honestly, they convinced me, what the answer is that these are TKI inhibitors. It is of utmost importance to proceed with the full starting dose in order to immediately saturate all the receptors and leaving the therapeutic dose in tissue. Because this translates in a shorter and higher tumor shrinkage. And then according to the toxicity, the patient experience, you can reduce and adapt the dose. But it is of utmost importance to start at the full dose. And we have also we have a lot of preclinical data suggesting that the starting dose correspond and translate in a better tumor shrinkage. But we have also some clinical data in thyroid cancer suggesting that the starting dose may play a role in the tumor shrinkage and the overall response rate of the tumor. So we start at the full dose and then we adapt according to the toxicity. That's yes, absolutely very important to realize that. Amber, for you, are there any medications or other things that we do need to do a dose reduction for? So typically, the drug interactions that you really think about with Limbatinib are usually QT prolonging medications, the ones that have drug interactions with Limbatinib. And so the big classes of drugs that come to mind are antiarrhythmics, psychiatric medications, including antidepressants or antipsychotics, certain antimalarial drugs or certain antibiotics, like certain fluoroquinolones and certain antiemetics can be an issue. So in general, when you think about drug interactions with Limbatinib, there's approximately 250 actual drug interactions. Approximately 60 of them are actually considered major. But again, these are mostly QT prolonging potential of the drug, which is then amplified when it's given concurrently with Limbatinib. So in terms of antiemetics, Olanzapine or Haloperidol or Ondansetron can have the risk of increased QT prolongation when administered with Limbatinib. And so the recommendation is to really monitor the EKG periodically when these agents are given concurrently. So in our practice, yes. Yeah, and it's not that we have to dose reduce for this, but just monitor closely that we're not getting QT prolongation, correct? Right, right, right. We don't have to preemptively dose reduce Limbatinib at all for that. Typically in our practice, we reserve Ondansetron as more of a second line. So when we start patients on this regimen, the antiemetic that we send is really Prochlorperazine or Compazine, because it doesn't have as much of the QT prolonging issue. Another option is Promethazine or Phenergan, but it does have the side effect of drowsiness, which we know Limbatinib can also cause fatigue. So it's something to consider. Another option that we try to avoid for antiemetics is Metoclopramide, because that can sometimes have a side effect of diarrhea, and Limbatinib itself can also have diarrhea as a side effect. So that's something that we think about in the back of our heads. But in terms of major drug interactions, when I looked at the list, I pulled out the drugs that sort of we see most commonly in our practice. So antiarrhythmic things like Amiodarone, Procainamide, Sotolol, that should flag if a patient is on that. Antidepressant like Citalopram or Escitalopram would be an issue with Limbatinib. Certain anti-malaria drugs like I mentioned, Chloroquine, Hydroxychloroquine. Certain antibiotics like Moxifloxacin, and pain medication like Methadone. So these are drugs that have interactions, but you don't necessarily need to dose reduce a Limbatinib. You just need to monitor the EKGs more closely. And so if a patient is on one of these drugs that has like a major drug interaction, you really need to sort of assess what the patient's baseline QTc is. And then how long is the patient going to be on that second agent? Potentially if it's a short-term antibiotic and their baseline QTc is fine, then you can proceed. But if it's something where they're on like an antiarrhythmic and they've been on that for years and their QTc is somewhat prolonged, and you know that they're going to be on both agents for a sustained period of time, that is something where you need to think about like a risk versus benefit and perhaps reaching out to our cardiology colleagues. Perfect. Yeah, I think really important to prepare. And I'd love to go over some of these common side effects that we see. And what are, Marta or Dr. Larisso, what kind of tips and tricks do you have for some of these common side effects that you see? Which is probably the most, which one is the most important one or the most common one that patients complain about or maybe even the most difficult to manage that you have some good advice for? Well, the question is very difficult, you know, because the point of view between a physician and the patient is sometimes very different. Physicians are more scared by, consider, more impacting side effects like hypothyroidism or diarrhea or hypertension. Patients are more scared about diarrhea, which is quite common, and fatigue. This is in my experience, but Marta can confirm because they are very close to the patient. Our nurses perform a very good job. They are very close in the management of the patient, but the fatigue is what the patient suffers more. And unfortunately, we have a strong, we have no strong weapon against fatigue. What we provide, what we suggest to our patient is a protein intake before starting treatment in order to avoid the decreased weight, which is particularly a decrease in the muscle weight, not in the fat weight. And the other thing is to move. Physical activity, at least 30 minutes every day of physical activity is what we continuously suggest to our patient. But again, I want to underline that when we start using this drug, we were lucky, Flor, you know, we do it in clinical trial. When we start using a drug in a clinical trial, the protocol guides you in any single stop the dose, reduce the dose and whatever. When this drug moves in clinical practice, it's of utmost importance that clinicians perform the learning curve in the management of side effects. But even more important, that patients are educated. They should not be afraid, but they are not afraid if we very carefully explain before starting treatment what can happen. And the most important thing is how carefully these patients are followed. This table is very clear. Most part of our side effects occur during the first 10 weeks of treatment. This is a key point. Patients should be carefully followed mainly during the first 10 weeks of treatment. And sometimes we see the patient every single week. And when patient is unable to move to the hospital, Marta calls them every single week. This is absolutely important because only in this way we can anticipate any kind of side effect. And we can immediately stop treatment, reduce dose, restart treatment, prescribe antidote. Only in this way, the tumor is under control. The quality of life of patient is not impaired. Yes, and I think that's a great point that you make, that it's really a team approach here. You see the patient, but also your nursing staff is and Marta is calling the patients to see how they're doing. And specifically, a lot of these side effects I think we have to ask for. Also, not just wait for the patient to tell us because then we can't intervene or they may not realize that we can do something else. Absolutely, absolutely. And sometimes the physician cannot follow very carefully. This is the reason why we need a team. We need a multi, a multi-person team. And our nurses are the key person in this strategy. Go ahead. I agree. I think we spend a lot of time counseling the patients to tell them what these possible side effects are, but also that a majority of them are actually manageable. So we have supportive care measures that we can provide. But we just need the phone call to talk it through, to make sure that it's truly one drug versus the other drug. We need to tease out which medication it could be that's causing the adverse reaction. And then we can go from there, holding, dose reducing, or initiating all sorts of supportive care measures that we have at our, you know, in our armatarium. Yeah. And Dr. Larissa, I'd like to ask you, like, for example, for hypertension and hypothyroidism, we're always used to like just dose reduce, but these are also some side effects that likelier just need some additional medications to manage it before we start dose reduction, dose reductions, and potentially have the patient on too low of an effective dose. Sure. Sure. Consider that the median time to occurrence of hypertension is two weeks looking at this table. This means that the day one of cycle one, you have to explain the patient to measure blood pressure every single day and report the value on a diary. And the diary should be communicated every week when patients come to the visit. The second point is that we prescribe antiperspensive therapy day one, cycle one, so that if patients experience side effects, she has to take the pills in the house. So she's not should be afraid. She simply have to take a pill. So this is an immediate, immediate reaction that and if patient is not afraid, everything is OK. But this is important, hypothyroidism. We evaluate thyroid hormones every, every cycle. If patients experience hypothyroidism, no problem at all. We work in a multidisciplinary team. We are not able to manage by ourselves this side effect, but we are not alone. We work in a multidisciplinary team with our endocrinologist who prescribe substitutive hormonal therapy. If patients have a grade one, she does not need to discontinue Lendima. She introduced the Teroxin, the hormonal therapy, and she continued Lendima. But for sure, you need to discover the hypothyroidism as grade one, and you cannot do it if you forget to prescribe every single cycle the thyroid hormones. This occurs looking at this table. You know, after week six, from the third cycle on forward, we change the monitoring. We repeat the hormonal treatment every cycle, but in the first two or three cycles, we follow the patient very carefully. Yeah, I think that is great. Marta, what is a common side effect that patients tell you that they may not be telling their doctor? Marta, you are on mute. Usually patients, thank you. Call us for arterial hypertension and weakness, asthenia. But from the beginning for us, for me and my colleagues, the very important point is to educate our patients to self-monitoring their symptomatology, because we teach them to recognize very early their symptoms. So about, for example, fembrolizumab, such as joint pain, weakness, skin rashes, colitis, for example, or about Lendima, we recommend to monitor side effects such as increasing blood pressure. And they use the journal we suggest them, or for example, weakness or asthenia. So that's it for hypertension and asthenia. We suggest them to do exercise, but also we suggest them to rest when they need. So they have to do what they feel best for them in that particular day, how they can feel. Dr. Larusso, do you tell your patients whether to, if they develop diarrhea, are they supposed to call? Do you give them a prescription beforehand? Or how do you deal with this that are very common side effects? Flor, thank you for this question. This question is absolutely important because we are talking about the combination. And the diarrhea may be a side effect, both of Lenva, but also of Pembro. So it's how to distinguish what is the drug involved in diarrhea. For sure, there are some signals if the diarrhea is in combination with blood and mucus, it's more probably that it is a colitis linked to Pembro, for instance. But there is a very easy, easy test. The diarrhea linked to Lenvima stop 24 to 48 hours after Lenvima discontinuation. So the first thing to do when patient call you and tell you, I have a grade two diarrhea, more than six stools every day, you have to stop Lenvima immediately and start immediately hydration and antidiarrhoic agent. If the diarrhea does not stop 24 to 48 hours after discontinuation of TKI inhibitor, then you have to explore if this is related to a colitis. So in that case, abdominal X-ray, colonoscopy, and more important, add corticosteroids. The first thing to do in terms of symptomatic approach is to add corticosteroids, usually one milligram per kilo is enough, but you can increase in case you do not obtain benefit while starting the workup for colitis. Great. And we're getting kind of to the end of our webinar here. Are there any other side effects that you want to highlight or mention or any tips or tricks or any questions that anybody has about any of these? And you can put your questions into Q&A at the bottom also. I think the one toxicity we didn't talk about too much was proteinuria, which we monitor for. So we do urine protein monitoring each cycle. We usually check a UPC-R, like the UPC ratio, and that roughly gives us an estimation of what the 24-hour urine protein excretion is. But we usually check that every three weeks or each cycle. And we typically hold the lenbatinib when the UPC-R is greater than or equal to two, and then we'll follow it with a 24-hour urine. And if that comes back elevated greater than two at that point, we'll usually try and get our nephrology colleagues involved. Yeah, absolutely. As we see that protein starting to increase in the urine, even if it starts going over one gram for 24 hours, getting the nephrology colleagues involved to help with adjusting medications and really tight blood pressure control is very important. And so usually if they have proteinuria like greater than or UPC-R greater than one gram and they have evidence of hypertension, usually if we're starting at the hypertensive, it's an ACE inhibitor that we'll try to add at that point if they have evidence of proteinuria because of the RAS blockade. So that can help reduce proteinuria as well as manage the blood pressure. Amber, this is exactly what our cardiologists suggest to start with the ACA inhibitor because this gives you both a dual benefit on hypertension and proteinuria. This is exactly what they suggest. Yes, we learned that from our nephrology colleagues here. Certainly a lot of multidisciplinary learning evolved as we managed a lot of these very different side effects than we're used to with myelosuppression. Yes, for, I think the other thing maybe to mention for the rashes, ointments, so Dr. Loris, do you want to mention anything for rash or stomatitis? We are proactive for stomatitis. All our patients are educated to have mount lubrication and hygienic strategies before the stomatitis occurs in order to reduce the incidence. But when the stomatitis occurs, according to the grade, they are treated with antimicotic and local treatment or systemic treatment. Stomatitis may be a problem in the measure it precludes the possibility for the patient to eat and drink. In that situation, we hospitalize the patient and treat it accordingly. Fortunately, I have to say, in our experience, it's not so frequent, a grade 3 or 4 stomatitis, but this is an aspect that should be monitored. But we start collutorium and something like that before starting treatment. And we educate patients to have hygienic strategies for the mount every single day. Flor, I want to add, because in this moment, the education is fully in the hands of clinicians and nurses, which play a major role. But we are preparing some divulgative material in Italy for our patients. And we will be more than happy to share, if required, with other colleagues, in which we try to translate all these advices that will be reported in order to give some explicative and educative material to the patient. But we are doing the same with a different language, also for the colleagues. And in the coming months, we will implement this instrument in our clinical practice. Fantastic. Yeah, that will be really great. And we're already over time a little bit. Really important, I think, in that we really learn to manage these toxicities. And there's two questions. Amber, I think you can see the Q&A. Also, you may want to answer one of those, especially the second one about the antiemetics that you talked about, if you want to type the answer there. But important that we manage this. We see this regimen can have an overall survival benefit, very effective across all tumor and all histologic types. So we and our patients should not be afraid to use the regimen, but help manage the toxicities that can be associated with that. Dr. LaRusso, do you have any other closing comments? Yes, I was answering to the second question and Amber to the fourth. So I have to say that it's important to remember that for more than 20 years, we consider endometrial cancer as easy to treat disease because it was diagnosed at stage 1, 2 in more than 80 percent of cases. And this creates a decentralization of treatment and also less investment in treatment and clinical research. What's the consequence of this environment? Endometrial cancer is the only, the only gynecological malignancy with an increase in incidence and mortality. So probably it's not so easy to manage as we consider for several years. For the first time in 20 years, we have a new combination of Pembrolin and Vatinib, which increases overall survival, not only progression-free survival by medium four to five months, which is good, but overall survival, seven months median increase in overall survival. It's something that we never saw and it's not possible. It never happened that our patient does not receive a combination which increases overall survival because we as a clinician are unable to manage the side effect of the combination. These side effects are new for us. We are GYM oncologists. We have no other TKI inhibitor approved in any other gynecological cancer. So these side effects are quite new. I'm quite sure that actually today we are probably, we will be more clever in managing side effects that at the time of KNOT 775, which was our first experience. But if we ameliorated, all people can ameliorate and we need to manage, to perform our learning course and manage the side effects. Our patients should be treated with the best we have. And this is an effort that we as a clinician have to do. Also because Flor, you know, this year we will have the results of LIP001 trial that is a trial comparing this combo with carboplatin-paclitaxel. So if the trial is positive, we will not use chemo in first line. That's an opportunity for our patients. This is an additional reason why we have to learn how to manage this combo. Absolutely. Thank you so much for those comments. And thank you, Dr. Khan, Dr. LaRusso and Marta, again, for your time, your insight, your expertise. And thank you to Isai also for supporting this webinar. If you're interested in additional resources on advanced endometrial cancer treatments, we recommend these three other webinars, which were recorded in 2022. And these recordings may be found on the IGCS Education 360 Learning Portal. Again, we also recommend you read the article, Optimizing the Use of Limbatinib in Combination with Pembrolizumab in Patients with Advanced Endometrial Carcinoma, which is another great research on this topic. And that link can be found in the Zoom chat. Thank you all for attending. And thank you again to our panelists and them sharing their knowledge. The recording of today's session will be available in the IGCS Education 360 Learning Portal within one day. We wish you continued health and safety. Thank you so much and have a great day. Thank you.

Multidisciplinary Approach

Treating Advanced Endometrial Cancer

Lenbatinib

Pembrolizumab

Combination Therapy

Progression-free Survival

Overall Survival

Objective Response Rates