Dr. Tewari:
Well, welcome to Navigating the Immunotherapy Landscape in Advanced and Recurrent Endometrial Cancer, an ASCO Post Roundtable. I'm Krishnansu Tewari. I'm a gynecologic oncologist at the University of California Irvine, and joining me today are two of my colleagues. Dr. Cloven, do you want to introduce yourself?
Dr. Cloven:
Hi, everybody. My name is Dr. Noelle Cloven. I'm also a gynecologic oncologist with Texas Oncology in Fort Worth. And I'm the Executive Chair for the GYN Research Committee for Sarah Cannon Research Institute.
Dr. Tewari:
Dr. Bujnak.
Dr. Bujnak:
Hi, everyone. My name's Alyssa Bujnak. I'm an Assistant Professor in Gynecologic Oncology at the University of Chicago and I treat patients with gynecologic malignancies, including endometrial cancer and also participate in our clinical trials program here.
Dr. Tewari:
Wonderful. So, it looks like we've got California, we got the West Coast, we got the deep south in Texas, and we got the Midwest, so we've covered a lot of the country this way. What was interesting, I was looking through everyone's CVs, it seems like all three of us did our residencies and fellowships in gynecologic oncology at UC Irvine, and then I guess we dispersed. So all right. Welcome and I'm really excited to review these three cases and have some great discussion.
For our first case, we'll turn our attention to a 58-year-old Hispanic patient. She's had three children. She's been having postmenopausal vaginal bleeding for about 6 months. You can see her medical history is noteworthy for well-controlled hypertension, non–insulin-independent diabetes. Her BMI is 31. Surgical history, she had a laparoscopic cholecystectomy, three prior Caesarean sections done through a Pfannenstiel incision. You can see her family history is noteworthy for colorectal cancer. And in addition to the vaginal bleeding, on review of systems, she does report mild diffuse abdominal discomfort and some constipation. On physical examination, her uterus is pretty normal size, mid-position, and mobile, and there are no adnexal masses. Dr. Bujnak, can I ask you how you'd evaluate this patient?
Dr. Bujnak:
She needs endometrial sampling, so I would try to do that in clinic, or you can also do that under anesthesia. And then based on that result, I would decide if I needed more imaging based on the biopsy pathology.
Dr. Tewari:
All right. That sounds reasonable. You can see her ultrasound here. She has some abnormally thickened endometrium. Her endometrial lining is 13 mm, which is abnormal for someone her age. And the endometrial biopsy you recommended does show a FIGO grade 2 endometrioid adenocarcinoma. In terms of surgery, which is what I would assume most of us would consider, her T score is 5. CT scan of the chest, abdomen, pelvis is negative for metastases or local regional spread. She does have some medical problems, so she did undergo preoperative medical clearance. She underwent a pelvic exam under anesthesia as well as cervical injection of indocyanine green dye and underwent robotic surgery with sentinel lymph node mapping. The surgical pathology returned with a FIGO Stage IIIC1 grade 2 mismatched repair–deficient endometrioid adenocarcinoma. One of her sentinel lymph nodes was positive. Dr. Cloven, how would you counsel this patient when she returns to the office regarding adjuvant therapy?
Dr. Cloven:
Well, we generally do a panel of immunohistochemistries on the pathology. So, of course we test the mismatched repair proteins, but we also test for p53 mutations, HER2, ER, PR. And for me, I just do that on everybody now. I would want that information first. Also, what's noteworthy to me, just thinking back to her initial history and her family history in particular, is that she has the family history of colorectal cancer. With that and also having the mismatch repair deficiency, I would want to be talking to her a little bit about genetics. All that aside, as far as management, first I would go over everything with her as far as the surgery that was done, what we took out. We discuss the stage, we discuss the molecular profile, and then I would give her options for treatment. And I'm probably talking too much and I want to give someone else a chance to say something, but Alyssa.
Dr. Tewari:
No, that was perfect. I think that's real life. That's what happens in the office all the time. Dr. Bujnak, how would you counsel this patient? Anything to add to what Dr. Cloven shared?
Dr. Bujnak:
Well, I agree with everything. I think I would counsel her towards adjuvant treatment with chemotherapy and immunotherapy with a checkpoint inhibitor, followed by checkpoint inhibitor maintenance.
Dr. Tewari:
Right. And so I think that's reasonable also. How does the mismatch repair deficiency play into whether to use chemotherapy plus immunotherapy or not? She's mismatch repair–deficient.
Dr. Bujnak:
Well, a patient like this, I'm assuming after her surgery, she doesn't have any measurable disease. And that's typically the clinical scenario we're in with patients like this: we do their hysterectomy, their sentinel lymph nodes, and then they come back as stage IIIC1. And the question is if you should give these patients immunotherapy or not, because in the registration trials, most of these patients in this category were not included because they had to have measurable disease. More recently though, the NCCN did basically set approval for patients that are mismatch repair–deficient specifically if they're IIIC without measurable disease. So I think this patient falls into that category. So that's how I would think about that since she is mismatch repair–deficient.
Dr. Tewari:
Yeah, I think that's a really important point. And Dr. Cloven, I'd like to get your thoughts on that because it seems like we have three different sets of guidelines, if you will. So the clinical trial, for example, if we were going to give this patient chemotherapy plus pembrolizumab, clinical trial NRG-GY018 that Dr. Bujnak cited for advanced newly diagnosed patients, they had to have measurable disease to go on the study. But the FDA approved chemotherapy with pembrolizumab for everybody. There was really no stipulation about having measurable disease. And then the February 2026 updated NCCN guidelines for endometrial cancer said that patients who have advanced stage disease who do not fit the eligibility criteria for NRG-GY018, if they are mismatch repair–deficient, they should be offered chemotherapy plus pembrolizumab. How do you harmonize all these different regulatory bodies, the clinical trial that led to the approval, the FDA label, and then finally the NCCN?
Dr. Cloven:
Well, I think it's common. So you mentioned the GY018 trial. So there was also the RUBY trial, which was dostarlimab with carboplatinum and paclitaxel that showed very similar benefits and hazard ratio for the mismatch repair–deficient patients. So that would be another option for treatment. And I think it's pretty common when things get approved, we do tend to extrapolate some to patients that are close to meet the eligibility criteria for a clinical trial. Clinical trial eligibility is very, very strict as it has to be. It has to be rigorous. But when you think about reality in clinical medicine and how we practice, you have to think about this patient with mismatch repair deficiency who stands to benefit from the addition of immunotherapy. As you know, these are the patients that will benefit the most. So I agree. I would give chemotherapy, carboplatin and paclitaxel with immunotherapy to this patient. And then I would also counsel her about maintenance therapy if she has a good response to treatment.
Dr. Tewari:
All right. Really, I like that. Let's continue with this case. So the patient undergoes imaging after surgery and there's no measurable disease, but as both of you have pointed out, because she has mismatch repair deficiency, chemotherapy plus pembrolizumab, followed by maintenance pembrolizumab is reasonable, and that's what she gets. Dr. Bujnak, how do you counsel patients regarding potential side effects they may experience getting checkpoint inhibitors? And how do you monitor these patients?
Dr. Bujnak:
Well, I essentially explain to them that the way that the treatment is working is helping the immune system define cancer cells and be more active. But because of that, it can also cause the immune system to attack basically normal cells, normal organs. So it can essentially have any type of effect on any organ system and cause inflammation of any organ system. But having said that, most patients tolerate it very well. The most common organs that are affected are the skin and the thyroid, and sometimes less commonly, but the colon and lungs we also have to consider. So those are things I talk with patients about. This happens in about 20% of patients, the thyroid and actually higher see rash more commonly in patients. So I definitely tell them about those side effects. And then I just let them know that we're going to be monitoring for effects of the medication through laboratory tests.
With each cycle of the immunotherapy, they'll have a CMP, they'll have a CBC, they'll have their thyroid function test. We'll get a baseline cortisol level just to make sure that there's no adrenal dysfunction from the start of treatment and then will monitor that subsequently a few times during therapy. Those are the main things I'm considering during treatment.
Dr. Tewari:
Dr. Cloven, anything else you'd add?
Dr. Cloven:
Yeah, not really much to add to that. I agree. The thing that I see most commonly is the thyroid, but I counsel patients that anything can happen, like she said. If there's anything that's unusual for you and it's persisting and you're concerned about it, please let us know. But I would say we monitor the thyroid tests specifically at each cycle. Maybe I'll get a cortisol on some of the other labs initially, but I don't do that every time unless there's any symptoms to indicate more testing.
Dr. Tewari:
I typically do the same thing. I'll get a baseline cortisol and then test it every 5 to 6 weeks for the first 6 months and make sure the patient isn't at risk for Addison's disease.
The patient does develop some hypothyroidism that's easily corrected with thyroid replacement. At 36 months follow-up, her CT showed a 2-cm left lower lobe pulmonary lesion and a 1.5-cm mesenteric mass. Biopsy was performed and it established recurrent disease. Dr. Bujnak, how would you manage this patient who is now relapsing 3 years after diagnosis? Maintenance pembrolizumab is about a 2-year maintenance treatment, so this is basically a year after completing maintenance therapy.
Dr. Bujnak:
It's difficult. This is a situation we're in now a lot, with a lot of patients coming back with a recurrence. And our options are really limited because immunotherapy used to be an option in the second line and now it's up in the upfront treatment profile for these patients. Some people consider whether we should be challenging these patients with checkpoint inhibitors—and at least to my knowledge, there's not any strong data right now to support that. I don't know if you all have any other comments about that. But really, other than additional chemotherapy or a clinical trial, there are not that many great options for these patients at this point.
Dr. Tewari:
What do you think, Dr. Cloven? Even though it's 36 months follow-up, it's not really that she's had a 36-month interval between disease, because she probably got pembrolizumab for 2 years as a maintenance and then relapsed 12 months after that. What are your thoughts on rechallenging with checkpoint vs doing something else? Dr. Bujnak mentioned a clinical trial that patients could be screened for, and maybe you can share with us your thoughts on that as well.
Dr. Cloven:
Yeah, there's a lot to unpack. I don't think any of us really know how patients will respond to rechallenge with immunotherapy.. It's tempting because it's so well tolerated and she's mismatch repair–deficient, so I think that is a reasonable option. I really think for this patient, the best choice would be a clinical trial. And the other thing is that I would want to probably have a full molecular panel on this patient. So looking for other markers, does this patient have any other targets that we could look at? There's a lot of trials now that are directed at specific things, so that would be something I'd want to know for sure. So I would want to send for molecular testing. Most of the trials, so if you look at the trials for recurrent endometrial cancer, there were two trials that recently completed TroFuse-005 and then the ASCENT endometrial trial.
This was for patients with recurrent endometrial cancer with one to three prior lines of therapy using antibody-drug conjugate. Both of these were directed at the TROP2 antigen. So currently we have a trial that's underway RAINFOL-03 and this is a trial looking at an antibody-drug conjugate called rinatabart sesutecan. And this is an ADC that's directed against the folate receptor. No folate expression is required for entry into the trial, but this is basically targeted against the folate receptor. It has a topoisomerase I payload and it's given intravenously every 3 weeks. This patient would not qualify for the trial because it does require if it's been more than 12 months since you've had carboplatinum and paclitaxel that you're retreated. That's just something particular about this trial. So she would have to have that first. But the trial is a very good one. The drug is very active.
The phase II studies have shown very robust response rates up to 50% and also durable responses. The main toxicity is myelosuppression, but I really think a clinical trial would be something that this patient should seriously consider at this point.
Dr. Tewari:
Yeah. So possibly it's been 3 years since chemo, so rechallenge her with carboplatin, paclitaxel. And if she progresses, maybe she could be screened for one of these studies like RAINFOL-3.
So to summarize, the key clinical takeaways for our first case is platinum and taxane-based chemotherapy plus pembrolizumab or dostarlimab followed by maintenance pembrolizumab or dostarlimab improves progression-free survival in mismatch repair–deficient endometrial cancer. And as per the NCCN, if you have a newly diagnosed patient with no measurable disease that's mismatch repair–deficient, pembrolizumab should be offered to these patients together with chemotherapy, counsel carefully on endocrinopathies and autoimmune diseases.
You can see we want to test thyroid function, cortisol surveillance, genetic counseling. To your point, Dr. Cloven, with her family history, she could be at risk for lynch, test a whole panel of different biomarkers that could reveal other important targets and then consider a clinical trial. So I think that was a great case and I think all of us learned a lot from each other and hopefully our audience will feel the same way. This brings us to the end of the case. Please see the other segments for further discussion about the latest research in endometrial cancer or visit ascopost.com.
