Perfect. Hi, everybody. So again, my name is Leslie Andriani, and I'm a GYN oncologist in Connecticut in the United States. Today we're going to talk about unresectable endometrial cancer. And so kind of our agenda for today is listed here. We'll go over some definitions, presentation and workup, the role of radiation, and then kind of subsequent lines of therapy, when to consider surgery in these patients and future directions. Today we won't follow adjuvant therapy following surgery. And also I will briefly touch on some evolving targeted agents, but there are so many in this space that it would be hard to cover them all in depth. And then we're also not going to talk about sarcoma. This will be just focused on endometrial epithelial pathology. So I have no disclosures. A lot of what I'll talk about is based on my experience in the US and we only have 15 minutes. So this will be the tip of the iceberg for a lot of the studies that I'll show you. And I'm happy to share my slides where you can go kind of more in-depth to the studies. So what is unrespectable endometrial cancer? It can present in two different ways. It can be somebody who presents and has never received therapy and is not amenable to surgery due to either their disease distribution or their comorbidities. And then also can be considered somebody who has recurrent disease. And oftentimes in clinical trials, patients who are quote unquote advanced or current are often lumped together in your demographics tables. So for our fellows, feel free to shout out when you're seeing somebody who you think might have unrespectable endometrial cancer, what kind of symptoms might they have? Walter, those of you in the room, okay. This patient will present with a fixed pelvic mass in most cases. That is what would always probably stop you from going in or the performance test is too poor. That you cannot take out. You know, she has comorbidities that prevent. What are the symptoms that they present, symptoms? The symptoms usually is palpational bleeding, palpational disease, I think. Absolutely, and they might present non-specifically similar to an advanced ovarian patient. So in addition to bleeding, they might have hematuria, GI symptoms, pain, leg swelling, as your patient today had, weight loss, anorexia, or even chest pain or shortness of breath due to disease burden or a DVT-PE. So your workup for these patients, you definitely want complete imaging. So if available to you, a CT of the chest, abdomen, and pelvis. If you can't get that, at least a chest X-ray to look for distant disease. And if available to you, you can get a PET scan. Or if you're thinking about surgical resectability at some point and available to you, you can get an MRI. Things that you want to be looking at are your routine labs, like a CBC, hepatic panel, and basic metabolic panel to look for liver and kidney function and coagulation issues. And then a CA-125 for many of these cases can be helpful. And then you definitely want a biopsy. So you want a histologic diagnosis. And then things that can help guide your treatment are mismatch repair, which can be done either by IHC or by PCR for microsatellite instability. Remember, IHC looks at the proteins being present, but it doesn't talk about their function. So if you're still concerned, doing a PCR tells you, are the proteins functional as somebody in a microsatellite unstable? You can also do HER2 testing by IHC and then subsequently by fish if needed. You can do hormone receptors and then if available, next-generation sequencing. So unrespectable endometrial cancer or metastatic endometrial cancer presents for 10 to 15% of our patients presenting with endometrial cancer. These patients do account for many of our endometrial cancer-related deaths. For patients with stage four disease at time of diagnosis, their five-year overall survival ranges between 12 and 48%. And then patients who do have recurrent disease, their five-year survival is about 20 to 25%. So when you're working up your patient and you suspect extra uterine disease and they're not suitable for surgery, you wanna think about, does this patient have local regional disease where you may combine radiation and systemic therapy or is it distantly distributed and you're gonna go primarily with systemic therapy? So I am not a radiation oncologist and very much appreciate our colleagues within radiation oncology. And the systemic treatments that I'm gonna be talking about, their combination with radiation is an ever-evolving question on how they interact with each other. But in these distant recurrent unrespectable patients, who should get radiation? It can help at the primary site if they're having pain or bleeding. It can help distantly, again, with pain and other symptoms. Or if somebody has local regional disease, it can be helpful if a patient is not a surgical candidate. If they're getting radiation, kind of the question of when to get it, should it be before chemo? Should it be after chemo? And if they get it, what type? All really requires a multidisciplinary conversation. But for patients with unrespectable distant metastatic disease, systemic therapy is the way to go. And most of the times you're talking with this patient saying that this is palliative in nature, though there are lots of exciting therapies in this space. And hopefully we will be having different conversations in the years to come with these patients. So for these patients when they have primary, distantly metastatic disease, you're gonna have a carboplatin-paclitaxel backbone. And then you'll see on the right for some different tumors, you're gonna add something else to it. And how did we get there? So the history of our standard of care for advanced endometrial cancer comes from a series of studies. And I just highlighted a few. So first was GOG-177, which compared doxorubicin and cisplatin versus doxorubicin and followed by paclitaxel. And they found with the paclitaxel, there was improved progression-free and overall survival. That then led to GOG-209, where carbotaxel was found to not be inferior to TAP or cisplatin, doxorubicin and paclitaxel, but quality of life data did favor carboplatin-paclitaxel. And that's why we moved forward with using that in this space. And then in 2023, very excitedly, GY-018 and the RUBY trial were presented. And addition of immunotherapy to this carboplatin-paclitaxel backbone was found to be incredibly beneficial. Separately, I just wanted to highlight the history for uterine carcinosarcoma is slightly different and needs to be discussed because often these patients are not included in advanced endometrial trials. And so this usually start, this started with an ifosfamide backbone with cisplatin and then later paclitaxel. And then we had GOG-261, which compared ifosfamide and paclitaxel with carbotaxel. And we found that there was a statistically significant difference in progression-free survival with carboplatin and paclitaxel, but not overall survival. And given the overall good tolerability of this regimen, the carboplatin and paclitaxel became frontline for uterine carcinosarcoma. So the two big studies to know about for the addition of immunotherapy to the carboplatin-paclitaxel backbone are GY-018 and the RUBY trial part one. Both studies included patients with measurable stage three and stage four A disease, non-measurable stage four B disease and recurrent disease. So there was no inclusion criteria, which is important to know. So for patients on GY-018, they had a treatment-free interval if it was recurrent of 12 months, whereas in the RUBY trial, it was only six months. And carcinosarcoma was only included in the RUBY trial, not in GY-018. GY-018 gave carboplatin-paclitaxel with PEMBRO followed by a PEMBRO-lizumab maintenance, whereas RUBY gave Dostarlimab instead of PEMBRO-lizumab maintenance. GY-018 commented that only about 10% of their cohort had no prior surgery, and the RUBY trial did not list this in their demographics page. But they did say that about 50% of their participants had primary stage four disease and about 50% were treated in the recurrent setting. So they did break down their findings by MMR status. Initially for GY-018, the PFS benefit was not reached. That's how beneficial it was. And then you did see some benefit for the MMR-proficient. Due to this data, PEMBRO-lizumab became approved for MMR-proficient and deficient advanced endometrial cancer. You can see similar progression-free survival benefits for the patients on the RUBY part one, and this was also approved in the U.S. and in Europe for primary advanced stage regardless of MMR status. The next advanced stage cancer to talk about is a cancer that expresses HER2, and this is found in about 25 to 30% of copy number high or serous-like endometrial cancers and about 13% of carcinosarcomas. How do you know if your tumor is HER2 positive? It's done by IHC on a scale. And if a patient comes back equivocal or two plus, this is then confirmed by PHISH. There was a randomized phase two trial that compared carbotaxel with carbotaxel plus trastuzumab for advanced primary and recurrent endometrial cancers that expressed HER2, and this found that there was a progression-free survival benefit. Notably, there was not an overall survival benefit because there was lots of crossover. And so that's just something to note. Recently, there have been some studies exploring carbotaxel plus immunotherapy plus APARP, and this was found to be beneficial in all groups, so all comers, MMR-proficient, and deficient. However, this may be an area of interest for our MMR-proficient cohorts, which didn't have as much of a benefit with just immunotherapy. So this is an evolving area of research and something that may be approved in the coming years. So if somebody has been treated with carbotaxel or other regimens, you wanna move into your next lines of therapy and kind of the organization of how we're using these drugs is also underway. But as of now, if somebody has had carboplatin and paclitaxel and they haven't had immunotherapy, you're gonna treat them with immunotherapy. So if they're MMR-deficient, you can use pembrolizumab or dostarlimab based off of the Keynote 158 study and Garnet for dostarlimab. We found that patients with MMR deficiency had a response rate of 48%, a progression-free survival of over a year at 13 months, and 14% of patients had a complete response. So this led to approval of pembrolizumab in the second line as a single agent. Dostarlimab similarly had a great overall response and also was approved. For availability, you can also consider drivalumab and avilumab, but I'm not gonna cover that today. If your patient is MMR-proficient, you're gonna combine pembrolizumab with linvatinib, which is a multiple tyrosine kinase inhibitor that's oral. This was studied in a randomized phase three study against physician-choice chemotherapy of doxorubicin or paclitaxel, and all patients had received prior platinum therapy. In this study, patients with MMR proficiency had an overall survival benefit of about five months compared to standard chemotherapy, and also a couple months progression-free survival benefit. So for these patients, the FDA and European organizations did approve this for this cohort. Notably, in this study, there were patients who were MMR-deficient. They weren't specifically studied, but their overall response was similar to that of pembrolizumab or another immunotherapy alone, and given the added toxicity of the dual agents, you go with single agent for MMR-deficient, even though they were included in this trial. For patients who are HER2-positive and are presenting after previously having carboplatin and paclitaxel, this is a new study, a new drug, trastuzumab durextacan. This is also an infusion and has been gaining popularity since the publication of the DESTINY-2 trial. Endometrial patients were included and had an overall response rate of 57%, and that was even more profound for patients who had a higher intensity of staining for HER2, at almost 85% for those patients. Median progression-free survival on TDXT was 11 months. Other things to consider are hormonal therapy, and how does this work? As a fellow, I always had to think extra hard about how does hormonal therapy really work? A lot of this tumor growth is done by, it's mediated by estrogen. And so if you're using hormonal therapy, oftentimes this is an anti-estrogen therapy and a pro-progesterone therapy because progesterone inhibits growth and carcinogenesis. So you want to feed the inhibiting nature of progesterone. Who would really benefit from hormonal therapy? Patients who have low-grade disease, possibly a small tumor burden, indolent tumor growth, and possibly hormone receptor positivity. This is not standardly reported in studies. It is generally more beneficial in patients who express hormone receptors, but the specific cutoffs are not standardly used throughout the world. Also, it's better to have a more recent biopsy to assess the hormone receptors. Lots of different hormonal therapies have been evaluated in prospective and retrospective studies and not one has been found to be superior to others. And so I listed many of them here. Again, predictors of response are a well-differentiated tumor, hormone receptor positivity, a long disease-free interval, and possibly the location of disease, particularly lung metastases. And then different cutoffs are being evaluated prospectively. So maybe in years to come, we'll be able to better choose patients who should get hormonal therapy. Overall, the outcomes are pretty good in these later line therapies with response rates of 20 to 40%. And hormonal therapy is generally well-tolerated by patients compared to cytotoxic therapies. So if your patient has gone through carbotaxol, possibly the addition of bevacizumab, possibly the use of immunotherapy or a targeted agent later line includes mostly single agent chemotherapies. If you are going to re-challenge somebody with a platinum, you think along the lines of how you do with ovarian cancer. So patients are more likely to respond if they had a longer treatment-free interval from their last platinum of being over six months. Just a word on neoadjuvant chemotherapy. In the interest of time, there's lack of prospective data. Generally, primary debulking is favored if feasible, but retrospective data has shown that patients can benefit from neoadjuvant chemotherapy, but again, the studies are biased in that most of them are retrospective in nature. One study did show that patients who had neoadjuvant chemotherapy and then did ultimately undergo their debulking surgery had similar overall survival to those who had primary debulking. So if you're doing the neoadjuvant and they actually get their surgery, they do very well like patients who get primary debulkings. Additionally, there was a recent study done in the United States looking at the utilization of palliative hysterectomy, and this was patients who had chemotherapy with or without a hysterectomy, and this did find a survival benefit. Notably, most of the patients in this study had their hysterectomy before chemotherapy, so this was unrelated to neoadjuvant chemotherapy. They did find, however, patients with brain metastases did not benefit from a palliative hysterectomy, and patients who had lymar sarcoma did not benefit from a palliative hysterectomy. So kind of where are we going in the future? It's likely treatment by the TCGA, and as we're at 11 o'clock, fellows, if you could just shout out the four molecular subtypes for the TCGA, and then we'll conclude. So we- So copy number I, copy number law. We already talked about one with regards to immunotherapy. Yeah, normal and poly mutations. Exactly, awesome job. So this is probably where we're going in the future. We already touched on MMR-deficient patients, and poly has a great prognosis, but areas where we think we could really help in the P53 or copy number high is use of immunotherapy, which a sub-analysis of RUBY-1 found a benefit in P53. Bevacizumab has been found to be particularly helpful in patients with P53 abnormal. Similar to ovarian cancer, PARP can be helpful, and then HER2 has been found to be helpful. And then in our NSMP or copy number low group, the targeted agents shown here have been found to be helpful and are under investigation. So I know that was a lot, but I just wanted to see if there are any questions.

unresectable endometrial cancer

systemic therapy

immunotherapy

HER2-positive

clinical trials

molecular subtypes