Good afternoon and welcome to the symposium. This is a symposium that is sponsored by ESAI. I think this is going to be a great interactive session. We're going to talk about the changing paradigms in endometrial cancer, and I'm going to ask our esteemed panelists to predict the future and answer any questions that you might have. So I think we're going to have some fun. My name is Wendell Nauman. I'm from the United States. I'm a gynecologic oncologist. I'm the co-chair of the IGCS 360 education program, which is basically online now. You can visit the portal, and it's actually free to all. You don't even have to be a member. You have to register as a guest. And Floor Backus is my co-director of that. So we're going to need to interact with this program, so I'm going to ask for you to download the app, the IGCS 2022 app from the App Store. We're going to do some polling and some case presentations. I'm going to go over some of the data and ask to sort of use this as a springboard in terms of our discussion, and then we'll discuss the results of the polling questions, talk about the future trials and directions, and try to predict the future, as I mentioned. So this is all phone-driven. If you want to download the app, it takes a little bit. I think you can also do this directly from a browser. You navigate to this session within the app, and then you can either use the Resources tab from this session, or if you want to take a picture of this QR code, this will allow you to use the interactive polls. I'll leave that up for a second. And that's, I believe, a web-based app. So I want to thank my panelists, Keta Larusso, Jonathan Latiman, and Vicky Mocker here from both. And, Jonathan, I know you're from the U.K., not from the U.S. So from Italy and the U.K. All right. So our first polling question, where are you from? Asia, Africa, Australia, Europe, North America, non-U.S., South America, or U.S.? We're going to load the results. How long have you been in practice? Less than five years? Five to ten years? Ten to twenty years? Or greater than twenty years? I always regret these questions because now I'm in the last category. Alright, results. Good mix of experience here. I seem to be the minority. What is your specialty? Do you want oncology, medical oncology, pharmacist, advanced practitioner, nurse, student, or other? Alright, results. Practitioner. Oh, so what do you want, oncology is heavy, that's good. Do you have access to Linvatinib and Pembrolizumab? Yes? Yes, but very restricted or no? Very restricted. About twenty percent of us don't have access. So how would you manage somebody with a recurrent grade two, estrogen receptor negative, MMR proficient, endometrioid, endometrial cancer, who recurs fourteen months after adjuvant therapy with carboplatinum and paclitaxel? Would you use platinum based chemo? Would you use non-platinum based chemo? Would you use Linvatinib and Pembrolizumab, hormonal therapy, some other therapy like an aromatase inhibitor and an mTOR inhibitor, or would you use something else? Fourteen months after adjuvant therapy with platinum. I think that's why we're here, right? So a lot of support for chemo. Any thoughts on that? We'll talk about these results in a minute in terms of what you think. Alright, so the next question. A very similar patient, recurrent grade two, ER negative, MMR proficient, endometrioid, endometrial cancer, who recurs eight months after a complete response to paclitaxel and carboplatinum. Same answers. Platinum chemo, non-platinum chemo, Lenpem, hormonal, five or other. A little bit more for the hormonal therapy. So in light of chemotherapy, so this is sort of asking the question sort of directly, in light of keynote 775, do you use chemotherapy as second line, and assuming she's a good candidate for either, do you use chemo as second line almost always, because you don't have access to immunotherapy, almost always due to the toxicity of immunotherapy, only if the recurrence is, and this is when you use chemo, only if the recurrence is greater than 6 months from the platinum based chemotherapy, if the recurrence is greater than 12 months from the platinum based chemotherapy, or almost never. What is your starting dose if you use Linvatinib? Do you almost always start at 20 mg per day? Almost always start at 14 mg, but escalate if well tolerated? I individualize the dose on the patient. So less than 20 mg, you just pick a dose based on how you think they're going to respond, or other. This is assuming you use Linvatinib. Your app is working? No, it's not. It's good. Is there something we can do about the polling? I think it's working now. So about 25% start at 20. About 60% do something else, which I assume is they don't have access. Again, this is the same sort of question. If you start at less than 20, do you increase the dose? If you start at 20, almost always, most of the time, sometimes, almost never, if you start at less than 20. What's your greatest toxicity concern for the combination of these drugs in terms of your management of these patients? Hypertension, diarrhea, endocrine abnormalities, hypothyroidism, isthenia, or some other toxicity? What do you think is the greatest concern, greatest management problem? About what I would think. Do you manage your own hypertension? I almost always refer comfortable managing one drug if no change is required. Do you manage one drug but comfortable changing agents if you need to? You'd manage two drugs or maybe you would be comfortable managing three or more drugs to manage hypertension. So I think people are beginning to manage their own hypertension now, that's interesting. Are you comfortable managing hypothyroidism? No? Sometimes? Most of the time or always? All right, so I'm just going to go over the data briefly. You will note that one of our panelists is the first author on most of these papers, but she graciously let me present this data. So we started with a keynote 146, which is lenvatinib plus pembrolizumab in patients with recurrent endometrial cancer with one or two prior therapies with good performance status. The end point of this study was the overall response rate at 24 weeks. As you can see, the response rate was a very respectable 40% in this trial. This is the waterfall plot. You can see both the patients in red, microsatellite instability, or MMR-deficient patients responded fairly well, but also we saw a lot of responses in the MMR-proficient patients. I think what's interesting in the presentation was the types of cancer. You can see we had a lot of responses seen in the serous cancers in red there. Also in orange, clear cell cancers responded very well. So all four clear cell cancers met the definition for response. You can see the others in that waterfall plot. These were fairly dramatic responses as well. Even though serous ovarian cancer doesn't seem to respond quite as well to immunotherapy, it looks like serous endometrial cancer patients are pretty good candidates based on some of the data. I think what else is interesting, if you look at these data, if you look at the six-month response rate, the one-year response rate, and the two-year response rate, you can see that the patients that had these deep, ongoing responses that seemed to last quite a while. On the left is the progression-free survival, and on the right is the duration of response. You can see that the patients that had a good response tended to have a durable response. I think that's very interesting and something that we see in many of the immunotherapy trials. Of course, we have the 775 trial, which was Lenpiam compared to a physician's choice of doxorubicin or paclitaxel in patients with recurrent endometrial carcinoma with one or two prior chemotherapies. The trial was powered. It had a co-primary endpoint of PFS and OS. This trial was the pivotal phase three that led to full approval of this combination. If you look at these patients, about a quarter of these patients had serious carcinoma. We had only about 5% with clear cell. If you look, the vast majority of these were MMR-proficient patients, about 85%. What we saw was about a 40% reduction in terms of the progression. The hazard ratio was 0.6 for the immunotherapy arm as opposed to the chemotherapy arm. The PFS in this trial went from 3.8 to 6.6 months. There was a similar improvement in overall survival that was a statistic with a hazard ratio of 0.68. The overall survival went from 12 months to 17.4 months. I think the toxicities, we alluded to those in the polling questions. For the toxicities of lenvatinib and pembrolizumab, you can see in green, these are the ones that are different than what we're normally used to managing with maybe the exception of hypertension. I think we've gotten a little bit more comfortable with hypertension with our experience of bevacizumab, but the grade 3 hypertension was 38%. Hypothyroidism is common, it's over 50%, but grade 3 is rare, and of course the diarrhea, which is troublesome to both physicians and patients, and a concern because of the potential toxicity from the pembrolizumab. Increased appetite, nausea, vomiting, weight loss, worsening arthralgias, and proteinuria from the TKI. For the chemo, of course it was anemia, neutropenia, and alopecia. I was showing this, and I know the forest plot is a little bit small here, but what I was alluding to earlier about the non-endometrioid cancers, both seemed to do a little bit better with the combination. These were not broken out by subtype, but presumably the majority of the non-endometrioids are serous, and it looked like patients who had only had one prior chemotherapy did a little bit better. Again, this is the waterfall plot of chemotherapy on the left in orange versus the immunotherapy on the right. I'm going to put the panelist on the spot here. Can we pull up the polling results from that trial? What do you think about the audience choices in terms of use of IO therapy? I think a lot of this is lack of access. Patients greater than six months, 22% of people would use chemotherapy. Greater than 12 months, 14%, so it's a little unusual there. The break point is at six months. I can comment on this. Can you use the mic? Oh, the mic, yeah. Okay, great. So I think this is a very interesting split, and I think you're right. I think this does reflect somewhat just access, but also probably just this is a new regimen, and I think the points that I would make here in terms of chemotherapy versus this regimen is a few. Number one, I think we need to be cognizant of the fact that the data regarding platinum-based doublet chemotherapy really hails from retrospective studies. These are heterogeneous studies. They're small studies. How they define platinum-free interval is different from study to study. The whole concept of platinum-free interval, platinum sensitivity, optimal time to restart chemotherapy has never been prospectively assessed nor validated in endometrial cancer. Endometrial cancers, I would say, are not ovarian cancer. I think they warrant their own treatment paradigms. And so I think that we need to be thoughtful about this whole idea of platinum resistance versus sensitivity because, again, has not been prospectively assessed in endometrial cancers. The other point I'd make here is that we now have a randomized phase three clinical trial that compared a TKI plus IO regimen to what are considered standard options for chemotherapy. And across the board, we saw statistically significant higher response rates, PFS and OS. And so this is really a landmark development. So my general practice is to follow the data. And so I think the data is very clear. I would also say that endometrial cancer patients are not ovarian cancer patients in that they often have metabolic syndrome and are medically just more delicate and more feeble and may not go on to third or fourth line therapy. So my general approach, regardless of platinum-free interval, is to focus on patient factors that might push me to do one versus another therapy. But my general approach is to attempt to use this combination for my patients. I fully agree with you. If I can also add a comment, the strategy of platinum retreatment in endometrial cancer rises in the last years from the absence of alternatives. Because after platinum paclitaxel, we only have anthracycline. We only have potentially weekly paclitaxel in the more recent years. So in the absence of any alternative for our patient, we start reintroducing platinum. But in this moment, with an alternative which has reported to increase overall survival, we did not have any positive trial for overall survival in endometrial cancer in the last 20 years. I think it's an opportunity that we cannot preclude to our patient. Well, I never disagree with these ladies. It's part of it. But I mean, I think it's absolutely important that we remember that this is not ovarian cancer, that we don't draw conclusions that we make from ovarian cancer, which in themselves actually are subject to a lot of discussion now in the six-month, 12-month cutoff period in terms of whether or not platinum should be given. We know the results of chemotherapy trials in endometrial cancer are not good in terms of the median progression-free survival is poor. And as Vicky said, these women often do not tolerate the drugs well. They have other metabolic problems. They're often older patients than those with ovarian cancer. And so we're sort of pulling together all sorts of phase two data, making cross analogies with other diseases, and yet we have now excellent phase three randomized data showing not only progression-free survival benefits, but overall survival benefits. So I think if it wasn't for the fact that there's a restricted access to Pembro-Lembert, then I think more people would probably be switching to this combination earlier on. So do you think this is driven by the efficacy, perceived efficacy of chemotherapy or the perceived toxicity of the IO therapy? So I think that's an interesting question. And we don't like to do new things. Nobody likes change, right? So new toxicities that might be a little bit concerning to us. So what is your access in the UK or Italy in terms of these drugs? So we have restricted access. At the moment, it's going through NICE, which is our body that reviews data, licensed data, to see whether it's cost effective. And that takes some months to come through. And I think it's projected to come out in the first quarter of next year. So there is, at the moment, a restricted access program that we can use. We are waiting for the final reimbursability of the combo. In this moment, we can use it without restriction based on KNO1775 trial under a special condition that our government introduced. But we are waiting for the reimbursability. And we will see what the reimbursability is, broader indication of restricted to MSS. Yes. Does the site of recurrence have any bearing on the management, infield, or long, or whatever? So I think that, in general, no. I think if someone has metastatic disease that's close to major airways or we're worried about hemoptysis or bleeding, then I'd be mindful of that. Certainly, if someone has a recent bowel obstruction or is showing quasi-obstructive symptoms, then any VEGF therapy is more challenging. Certainly, patients with recent cardiovascular events or very, very weak health that are in hypertension, nephropathy, obvious issues that would make this combination potentially unsafe. Aside from those issues, those are the big things I think about. If I can add a comment, probably it's not the single disease which precludes the use of the combo. It's what we call a frail patient. It is true that for a frail, generally frail patient, this combo should be managed with more attention. And we need to be careful. We need to educate patients. But in my experience, it's always not a problem of a single comorbidities. Yes? How about timing of the parts? Somebody who recurs a year out versus somebody who recurs three years out? Actually, I was going to ask in terms of the, yes, along those lines, do you think people are more likely to go back to chemotherapy because it was used in the adjuvant setting as opposed to the treatment setting? And about the timing, is there a cutoff that you would say, wow, you know, they've really done well with chemo? Is there any cutoff? Vicki, I mean, you probably have the most experience of anybody with this combination, eh? Yeah, I mean, I think it goes to the point we made earlier, which is, you know, patient factors I think are important to consider when you're thinking about whether you're going to do chemotherapy or LENPEM. I think that, you know, in a patient that has extraordinarily indolent disease, low volume disease, and to Dr. LaRusso's point, maybe is a little bit more feeble, you know, one might consider alternative approaches like hormonal therapy or even, you know, chemotherapy. But I think, you know, by and large, I think when you have randomized phase three data that show an improvement in survival, I, you know, would tend to want to offer that therapy. And I think that then that saves chemotherapy for down the line if you need to use it. Oh, it's very difficult to answer your question, because for sure, after three years, we are all potentially in favor of range-reduced platinum. To be honest, this is the case. But we have not forget that when you look at the forest plot of the keynote 775 trial, patient to gain the higher benefit are patients who have received only one prior line of therapy. So we need to be careful, because it's quite evident that for this combo, the earlier the better. Sure, there were no patients recurring after three years in the trial, and the question you pose is very interesting. But in general, when you have a combo that increase overall survival, the earlier you use it, this is a common practice in oncology. If you have a strong combination, a strong drug, you tend to use it as early as possible. And we've seen that in other trials, too, that the immunotherapy earlier in the sequence is more effective. Absolutely. And for reasons that I don't quite understand why that would be, but it is. I support that. But I mean, just to come back to your particular question, you know, I think here we're dealing with a patient with slightly unusual biology with this very long recurrence-free interval. And so I think we also have to bear in mind that these are not curative treatments. And therefore, in someone who's had this very long interval, and all other things being equal, which is what we've said, then I think it would be quite reasonable to re-challenge that patient with chemotherapy, platinum-based chemotherapy. And then the next time, as there will likely be a next time, to use Lempkin. What do you think about hormone receptor positive? I took that off the table. Where does that fit in? Where does hormonal therapy fit into this paradigm? Well, I think for those sorts of patients, if she was ER positive, I certainly would use hormonal therapy as an interim there, yeah. Sure. And also next year probably we will have the results of LIP001 trial in advanced but not pre-treated patient that will compare this combo with carboplatin packet access. So probably we will have more information to answer your question. We're actually going to get into that. What about the what about the starting dose? I know there's a lot of controversy about this and I think some hesitation to start at the approved dose which is 20 milligrams per day. Any thoughts on that? Can we bring the poll up? So it looks like the majority of people who are using this use it at 20 but I think there's some hesitation there. Any thoughts on that? I mean I would just say I think that you know this combination has been fully vetted in each disease type where it's been evaluated not only in early phase clinical trials but also detailed pharmacokinetic studies that have been done to you know ensure efficacy but also to mitigate intolerance. And I think in this particular malignancy this is the dose that was tested and recommended as the phase two you know dose to be carried forward. And I think that you know that we should keep that in mind and certainly in other diseases such as differentiated thyroid cancer and in renal cell carcinoma now they are different diseases but it is intriguing that when lower than the recommended starting dose was evaluated compared to the recommended starting dose that the toxicity was not necessarily less but the efficacy did appear to suffer. And so I think it is important to keep you know these these findings in mind and really try to bolster supportive care, educate the patient, educate your team to try to mitigate toxicity, see patients back frequently in those first few weeks to ensure that you're catching things early. And I think that that can allow you to feel more comfortable at the recommended starting dose of 20 milligrams. Yeah I think that's I absolutely agree with that and I think you know there is a sort of fear factor amongst physicians. We're dealing with two new drugs that really we're not familiar with and a different pattern of side effects which some of which you came up in the poll earlier on I'm sure we'll come back to. So I think there is a there's a fear factor and therefore you know there's a sort of tendency well I play safe I'm gonna you know reduce the dose when really I think as Vicky says you know the evidence is for for that that higher dose to start with. And I think education is absolutely key and not only education of our patients but education of us and our colleagues about the management of toxicity and the early detection of toxicity because we've we've had experience with other TKIs in gynecological cancer but until Lenvatinib none of them have been licensed. They've been licensed in other diseases and we you know we borrow that learning from our colleagues in other diseases. But in our own experience in clinical trials for example we found when we started to use a drug called Siderinib which is a VEGF TKI in ovarian cancer in the first trial we did the icon six trial we got a lot of toxicity a lot of diarrhea fatigue a lot of patients dropping out you know patients coming into hospital and we're now reusing that drug at the same dose with a lab ribbon the trial called icon nine and we're seeing far fewer problems because the most of the investigators were those who investigated icon six or many of them were and have learned learned how to educate their patients the nurses know how to educate their patients and we've got that experience and so we see the far less toxicity so I think it's the same with Lempem we've got to really push that education amongst our colleagues across you know the whole healthcare community including nurses and pharmacists and so forth and of course our patients and then I think it will be more manageable. So we used to put patients in the ICU for paclitaxel. I cannot agree more I want also to add that we have a very interesting discussion with our pharmacologist in Italy and they reported that there is a biological reason for starting with the full dose because these are TKI and the immediate saturation of all the receptor produce the best response in terms of response rate and efficacy and then so it's much better to start at the full dose in order to completely saturate immediately the receptor and then according to the toxicity that patient eventually experience reduce the dose it's much better than the contrary. I think there's some hesitation just because of the the percentage of patients that come down on the dose but I mean this is the lesson we learned with the PARP inhibitors too. But despite that right the efficacy held so that's the point that I think it's sort of par for the course exactly to Keta's point to maintain that dose intensities for as long as you safely can and then realize that lowering the dose is part and parcel of you know the care but that the efficacy is maintained despite those dose reductions. I mean it's sort of a test of the farmer the the individual pharmacology I guess as well in terms of metabolism and absorption. Our next question yeah we do I think we've covered the the dosage here. I think some people will tell me that you know they don't want to start at the high dose because they don't want to get intolerance of the patient immediately and you know I get that I think there's some some hesitation there so. Toxicity can we have the polling result? So I obviously you know distressing to the patient and also to us is this diarrhea the concern that the patients may have colitis from the pembrolizumab this can be difficult to manage. Thoughts here in terms of your experience what works what doesn't work when do you get worried about colitis and how do you evaluate the patient? As Jonathan said the real problem is the patient the physician experience. We perform our learning curve in the management of hypertension with the pembrolizumab. So actually hypertension is not more a problem for us. It may be more tricky the management of diarrhea from my point of view because both the drug can have diarrhea as a side effect and sometimes it's not so easy to distinguish what of the two drug are in charge for this side effect and also because sometimes this problem is huge for a patient and probably diarrhea may be more tricky but at the end we have to remember that in my experience it's much more probably that diarrhea is related to TKI than to pembro and it's a typical the typical diarrhea of TKI is a very close time with respect to the drug administration. You stop the drug and in 48 hours diarrhea disappears. So it's very easy at the end to identify which of the drug is provided this symptom. When do you get worried about colitis? When it doesn't stop. After 48 hours. I agree with Dr. LaRusso it's pretty immediate right I mean you hold the drug and they really tend to improve and colitis you know generally again there are exceptions larger volume stool you know associated with cramping, tinnitus, bleeding, you know severe dehydration. Patients look toxic. The Lendema diarrhea tends to be more sputtering lower volume again close relation to the drug and often you know frequent during the initial days after you take that you know with the dosing but I think here too it's important to remember that we have subspecialty consultants you know that are there and they can guide us if we're not sure which agent is it is you know that's really important to keep in mind that you can phone a friend and ask for help with regards to really the common AEs that arise. And just from a practical perspective you know you've got a drug that you're giving daily and a drug that you're giving every every three weeks so you know if if this is occurring you know after you've seen the patient at home they phone in the simplest thing of you know the PEMBRA has been given the simplest thing is to hold the Lenvatinib for 48 hours and see what happens. If it doesn't get better then you you know you're worried that it actually might be the PEMBRA and you need to act on that. Do you give any treatment before you hold the drug? I mean you would you have them take Lamotil or Pepto-Bismol or what are your tricks there? You know unless the patient's toxic our general approach is to go ahead and prescribe something like Loperamide again very close follow-up you know follow up with them the next day you want to make sure this isn't colitis that you're missing and if there's not a pretty immediate improvement then you need to think about colitis. Any tricks for the Asthenia particularly these frail patients? I want to touch the problem of Asthenia but even more another problem which is correlated to Asthenia which was the weight loss. Weight loss with this drug is not a loss of fat mass but it is a loss of muscle mass. So what we do with our with our patient is try to prevent this side effect. We prescribe integration with proteins and we start quite immediately with the drug and we reduce this side effect so much. Yeah good point. Anything else? Yeah I mean I think nutrition consult is also helpful you know food diaries things of this nature they these are easy things that really can give you a nice picture as to what's really happening with the patient and small changes can make big differences. I think you know it says other IO toxicity I think we're all a little bit skeptical of the IOs but they're coming in every disease. I think it is important to know when the side effect is expected. Hypertension looking at the keynote 146 that Vicky you presented. Hypertension the median time to the insurgents of hypertension is two weeks. This means that for the first month, two months, three months I would say of treatment patients should be visited very frequently and the day in which patient receive chemo, the combo of pembro plus limbatinib, we used to prescribe hypertensive therapy and we report to the patient to measure and control pressure every day and if the limit overlap 140 or 90 they start treating with the drug. So we anticipate some side effect according to the time interval in which we expected the side effect. I agree. Can we have the next poll the hypertension poll? So I think it's it's interesting so people are beginning to get more comfortable treating hypertension. I've found that it's it's difficult to manage hypertension with a consultant because of the delay in getting people in. Any thoughts on that? I mean I think you're right I think we all have developed greater comfort managing hypertension. I think that you know some of this is our regional differences also differences between whether a medical oncologist is perhaps involved versus a surgical oncologist just in terms of you know prior experience with these drugs but it's heartening to see that you know folks are more comfortable managing blood pressure and we have a wide array you know array of blood pressure medicines that are safe and easy to administer and I we also prescribe prophylactic antihypertensives and give it to our patients. What do you give them to take home? You know we like the calcium channel blockers and the ACE inhibitors ARBs those really tend to work well. Many of them are kidney protective as well but we give clear instructions on when to call and really the instruction is if it goes above 140 over 90 even one time despite what the label says you know we really want them to call us so we can quickly up titrate because the blood pressure does increase steeply and very early. And even I mean this is translated to other other drugs so you know I used to not manage my own hypertension and I think that the complications and the side effects of bovacizumab were greater and now that we jump on it immediately I don't see that anymore. I think you know many of us are using niraparib and we've become accustomed to the the early monitoring for hypertension in niraparib so we've got the mechanisms in place within our clinics and that you know again boils down to education and the feedback of information so that you know we're monitoring blood pressure every week for the first eight weeks and patients on niraparib and so it's really translating that that that pathway to to patients on Lempem. Can I have the next poll? Yeah so hypothyroidism it looks like a lot of people are comfortable prescribing for this? This is quite surprising to me because this is the typical situation in which I refer the patient. We have a multidisciplinary board of specialists that works with us referral specialists and one of them is our endocrinologist so when I have any kind of problem with hypothyroidism we refer the patient. Yeah I mean I this is a common thing I think people are comfortable writing for I guess that's just one drug. Yeah it's also I mean you know you're picking you know you're measuring thyroid function regularly so you're watching you know particularly for hypothyroidism and CSH going up so you know you're you're up can be on it quite quickly and then I think it's just being comfortable with you know starting doses and I think then if if at that point if you're if the TSH isn't coming down and you know you just then might call the endocrinologist for support. I mean it varies and depends on what the local the local setup is but you're not dealing with an acute problem like acute hypertension or acute diarrhea in the same way because because you're monitoring thyroid function regularly. What do you think about this endometrioid versus non-endometrioid? Do you make much of this is that? Yes so actually the study did look at clear cell serous endometrioid subtypes and really the benefits seem to hold across the board with regards to PFS and OS so that was very encouraging to see these are small numbers obviously when it comes to the serous and clear cell patients but still you know very encouraging. Were you surprised that the serous cancers responded as well as they typically thought of as different? You know I think I would say that I was very encouraged to see that the serous cancers responded especially because it's such a recalcitrant subtype and really very difficult to manage. And you know there was a subgroup analysis of the GOG trial suggesting that p53 mute patient responded better to anti-angiogenic agent and now we have TKA inhibitor with anti-angiogenic agent but really when we look at the histology it was amazing to see the results in a clear cell tumor in terms of progression free and overall survival that the calves of clear cell were touching I have to say. What about any any thoughts on the MMR deficient tumors? Do you ever go to combination if they progress on single agent? Obviously off-label. Well I guess it's not necessarily. Anecdotally speaking yes I have done this in a couple of patients and and I have you know I've seen efficacy but clearly this would need to be prospectively evaluated on a larger scale. Is there any thought to doing that, maybe? Since you're in the driver's seat in terms of this research. I think it would be very intriguing to do this. I think it's gonna become a very relevant question very soon, given the leaps, you know, 001 studies about to report. So I think that this is a very important question to answer. There is NRGGY025 that is looking at the DMMR patients and I think in that trial, it's a randomized phase two trial of nivolumab versus nivolumab and it allows patients that have had prior IO therapy and targeted therapies, which I assume would include TKIs. But yes, this warrants, I think, dedicated studies. Vicky, you are absolutely right also because in the coming years, we will have a lot of data of immunotherapy in combination with chemo in the first line metastatic setting. So we need to know if there is a space for the reintroduction of pembrolin batinase in patient recurring after immunotherapy single agent. So this is an important and emerging question for the clinical practice in the coming year. Do you stop the immunotherapy at any point? If they have a complete response? In clinical practice? In this moment, no, because we can only use in second and third line setting and we tend to continue. And in the clinical trial, 84% of patients are still in response after two years of starting treatment. So I tend to continue. Same. In cervical cancer, the Checkmate 35A data, we stopped it two years and the patients continue to do well. So it's an interesting question. So just the future directions, I think, and we've alluded to this, these data. This is NRG 018, so it's chemo versus chemo plus pembrolizumab in previously untreated patients. It's stratified by MMR status, but the MMR status is not limited. The RUBY trial, which is looking at the PD-1 inhibitor drostolomib, a similar trial for this arm of the study. And we have the ATTEND study, which is looking at teslizumab, all in the frontline setting. So we're gonna have three now trials with PD-1s up front, so why that was such a relevant question. And as was alluded to earlier, the LEAP-001 trial or the EN9 trial, if you're in Europe, looking at the combination of linvatinib and pembrolizumab, so a chemo-free regimen versus chemotherapy in the frontline setting. So now we're gonna have to make all sorts of cross-trial comparisons and everything. And we've got a lot of data coming, right? So we have in the yellow the MMR-deficient trials for single-agent PD-1. We have in the blue the LEAP trial, which is linpem versus chemo. And then you can see all of the trials up front adding to a non-selected population, a checkpoint inhibitor plus chemotherapy. And then there are even some combinations now where we're going to use a checkpoint inhibitor plus a PART plus chemotherapy. So we're gonna have lots of interesting data coming out here. I won't go through the timeline here because many of these trials have actually been done now. And we're gonna have the others reporting out fairly soon, probably mid-next year for LEAP-001, is that right? Possibly, yeah, possibly. So anyway. And so I guess, you know, predict the future for me. Now, you don't have to disclose if you have inside information, but what do you think about single-agent PD-1 or PD-L1 agent checkpoint inhibitors with chemo and an unselected endometrial carcinoma? Is this gonna be a strikeout or is this gonna be a single or a double? What do you predict? Not in unselected. I think that the single-agent immunotherapy will substitute chemotherapy, but in MMRP population. Exactly as in colon cancer. You guys agree? You don't think these trials are gonna be positive? Well, no, I agree with that. But I mean, I think one of the difficult things is going to be to dissect out whether or not chemotherapy can be replaced by the checkpoint inhibitors because you see a lot of trials that may well come out positive, combining chemotherapy with checkpoint inhibitors, and then the LEAP-001 against chemotherapy. So if they're all positive, what message do you take away about whether you do or you don't? That's why I have you sitting here to make that prediction. So I would have thought that in cervical cancer, of course, with A26, even though single-agent PD-1 has about a 15% response rate in cervical carcinoma alone, certainly the A26 data was much more impressive than I would have predicted. And maybe there is some synergy between PD-1 checkpoint inhibitor and chemotherapy in some way that we don't quite understand. So I have hope that these are gonna be positive trials and move PD-1 to the front line. So it's gonna be, now your second-line treatment's gonna be a problem, and we had this a little bit in cervical cancer. So how do you think? I think it's gonna be very difficult. I mean, I think, as we also heard this morning, it's difficult to sort out whether there's a negative-positive interaction with chemotherapy, whether the effect is largely the post-chemotherapy effect. I mean, we see in cervical cancer, single-agent activity in recurrent cervical cancer with overall survival benefits. So I think it's gonna be very hard to unpick that. And also it's very difficult to compare cervical cancer and endometrial cancer. Immunotherapy single-agent in cervical cancer provide 1.5, 15% response rate. In MMRP population, endometrial cancer, we have 58% response rate. So the efficacy of the drug is completely different when used as single agent. In MMRD population, I think that in MSS population, the combo with the chemo may work. I think that it will be very difficult to provide the level one evidence for all the molecular biomarker we have, because this population are shorter and shorter. The number are smaller and smaller. I think we will stick in the future more and more on the suggestion that came by the forest plot, which are hypothesis-generating, but I think that we will discuss more and more about forest plot subgroup analysis. And it may come down to a menu of recommended options and where patient factors will become important along with molecular phenotype to help guide treatment at the end of the day, which will of course make second line therapy very challenging. Right, well, that was my next question. So what is, what do you think is second line therapy? I mean, how are we gonna navigate that since we don't have any data to guide our decision? And that's gonna be problematic, right? Thoughts? Well, I mean, I think suddenly clinical trials will become even more important in the second line setting. Certainly there are a number of antibody drug conjugates that I think may hold promise in endometrial cancer that I think would be exciting and potential contenders for that space. And then we have our standard palliative chemotherapy, hormonal therapy, but yeah. And as somebody who's interested in clinical trials, it's very hard to design clinical trials when you don't know what the results of these are gonna be because all of a sudden your design is not as good or clever as you thought it might have been. But I think it's a good way to start designing the new clinical trial allowing a patient to have received prior immunotherapy and stratify according. Agreed. I think so. So let's just say they're both positive. The future. What is the future here? What is, you know, let's say that they're both significantly positive. My personal point of view, it will depend on the magnitude of benefit, first of all, and then if the magnitude of benefit is the same, the toxicity profile will make the difference. Agreed. I absolutely agree with that. We're just gonna have to, we're gonna have to see not only the PFS data, but we're also gonna have to wait for a longer follow-up in the OS data. We're gonna have to wait for a longer follow-up in the OS data, which will help us make those decisions. Yeah, I think that's very important because the tail on those curves is significant. You saw the duration of response in 146 was just amazing. If you got a response, it just kept going. And, you know, that's been my clinical experience as well. What about predictive factors other than MMR? Are we gonna move beyond MMR in endometrial cancer? I mean, we're already going to these molecular classification, talking about, you know, all the TCGA data and, you know, how to classify endometrial cancer. What do you see here? I mean, I think TMB appears to be an important factor in endometrial cancer, regardless of microsatellite instability status, it seems, based on assessments with pembrolizumab and drostalumab. There's data emerging that the reason for microsatellite instability is important, whether you have a somatic or germline mutation versus whether you're MLH1 methylated, for example. The methylators seem to do less well. So I think this is definitely an area that warrants, again, prospective investigation to try to understand why that is. So I think it's important. So you brought an interesting point up on your TMB high patients. Do you treat them with single agent PD-1 or do you treat them with a combination in the recurrent setting? I mean, I do take into consideration, you know, patient factors, toxicity from prior therapy, and also disease burden, pace of disease, and really do both, but I tend to do more lenbatinib-pembrolizumab in the TMB high. Depends on how high sometimes, too, but that's my general approach. I mean, some of these Pol E patients will be, I've seen TMBs of over 100. That's right. So, yeah. Any other thoughts? Oh, I think it is a very interesting question, and also it's a real problem for the European people in the room because we have the possibility to use in MSI patient immunotherapy single agent or the combo. I tend to, to be honest, I tend to use the single agent for most part of my patient. For sure, we do not have a direct comparison between the single agent and the combo, and in a very bad indirect comparison, when I simply look at the response rate, the response rate is very similar, I have to say, in both the population. The data that Vicky mentioned are really interesting because of what is evident is that, also in clinical practice, what is evident is that MSI patient are not the same, and we have some patient that respond very well to single agent and some other that probably would benefit more from the combo. And the mutation of MMR or the methylation may be a predictor, even though I agree, we need prospective data. TMB may be an additional predictor. In the GARNETT trial, TMBI patient responded regardless MSI or MSS, and in the PEMBRO trial, TMBI patient responded better than TMB low. So these are additional biomarker that need to be addressed, but honestly, for in absence of a head-to-head comparison for MSI patient, I tend to use for most of them, single agent immunotherapy. Yeah, I agree with all that. I mean, I think the other is access to testing, which certainly in Europe is, in terms of routine testing, is not as easy as it perhaps is here in the USA. We certainly aren't able to routinely do TMB testing. But I think drilling down on MMR deficiency and it's just not saying it's all or none is really important, and I think that's an area where I think we could start to split out, if you like, patients who might do better than others. Any trials looking at this that you're aware of? Anybody? No. No. I think those are really good questions, and so hopefully people in the audience will take that. So I think we can open this up to any discussion or any questions. Any other thoughts on interesting agents that are coming down the line? Any other? You mentioned the PD-1, CTLA-4 combination. I think that's certainly interesting, and there's another, the digits or tigets, depending on how you say it, have had some, we've had some interest in those and some responses. Oh, yes, we have some data. Mainly the development of the combo is in cervical cancer, but we have several data that probably the combo of immunotherapy works better than single agent because we block two different pathway. But I, coming back to endometrial cancer, I fully agree with Vicky. I think that antibody drug conjugated are an emerging, very interesting class of agent. Personally, I think that ADC will play a well-defined rule after immunotherapy for cervical and endometrial cancer and after PARP for ovarian cancer. It's a very, very interesting concept to deliver high dose of chemo to a well-defined target. I think it's a very promising class of agent. With the bystander effect. With the bystander effect. And actually there's some in vitro data that suggests that these agents are probably immunostimulating as well. So I think it may be that they play nicely in the sandbox, and of course, I think that Dr. Fragote presented some of his data in cervical cancer with the combination of ADC and PD-1. Yes, and I think there's interest in developing such an approach in endometrial cancers, for example, as well. So yeah, lots of good things happening, but ADCs. Questions from the audience? I can't see back there, so. No? Well, I want to thank you guys for doing such a great job, and let me put you on the spot. So, I think this is a rapidly emerging field, and I'm, but I am excited that we're making progress in endometrial cancer, which it was ignored for so long. To have now new choices and new agents that are effective has been a great amount of progress made here. So, going from no agents approved in endometrial cancer other than Majestrol, to now we're actually debating about how we're gonna treat our patients in the future is a great thing, so. Well, I appreciate your attention. Thank you very much. Thank you. Thank you. Thank you.

endometrial cancer

changing paradigms

immunotherapy

lenvatinib

pembrolizumab

MMR-deficient tumors

MMR-proficient tumors

side effects

hypertension

clinical trials