Dr. Tewari:
Welcome to Navigating the Immunotherapy Landscape in Advanced and Recurrent Endometrial Cancer, an ASCO Post Roundtable. I'm Dr. Krishnansu Tewari. I'm a gynecologic oncologist and Professor at the University of California, Irvine. Joining me today are two of my colleagues. Let's start with Dr. Bujnak.
Dr. Bujnak:
Hi. My name's Alyssa Bujnak. I'm an Assistant Professor in Gynecologic Oncology at the University of Chicago. Thanks for having me.
Dr. Tewari:
Welcome. Dr. Cloven?
Dr. Cloven:
Hi. I'm Dr. Noelle Cloven. I'm a gynecologic oncologist with Texas Oncology in Fort Worth.
Dr. Tewari:
All right, so that's fantastic. We've got the West Coast covered, we’ve got the deep south, and we’ve got the Midwest. I was reviewing both of your CVs, and I was astonished to realize that all three of us did our residency training in obstetrics and gynecology at UC Irvine, and we also completed fellowship training at UC Irvine in Gynecologic Oncology. Then, I guess we've dispersed around the country, so let's go ahead and present a case. This is case 2. Our patient is a 66-year-old African-American woman. She's had one child, and she presents with postmenopausal vaginal bleeding for about 3 weeks. Her BMI is 28. She has hypertension, insulin-dependent diabetes, asthma, no prior surgeries.
Her family history is negative for endometrial, ovarian, breast, and colorectal cancer. On a review of systems, she's had ongoing vaginal bleeding, resulting in a significant drop of her hemoglobin, down to 6 g/dL. She's required 2 units of packed red blood cells, and she's reporting moderate back pain. On examination, there's blood in the vagina. Her cervix is not expanded, but the uterus is kind of large. It's about 11 cm, above the normal limit. No palpable adnexal masses. You can see she underwent endometrial biopsy, showed a grade 3 endometrioid adenocarcinoma, and just to confirm that there were no adnexal masses and get a better look at what's going on in the uterus, an ultrasound was performed. As you can see here, there appears to be a lesion that's invading the myometrium pretty deeply.
Because of the extent and size of that tumor, she underwent further imaging studies. You can see an MRI, here on the left. It confirms that there's deep myometrial invasion, but you can see a fat plane between the bladder and the rectum, so there's no extra uterine spread, at least no direct extension. But on the PET scan, over on the right, we can see some aortal cable and mesenteric adenopathy. This patient, she's pretty sick, bleeding continuously. Her oncologist decided to proceed with surgery because, in most cases, or in some cases you may want to consider a neoadjuvant approach. Dr. Cloven, what would you do with this patient?
Dr. Cloven:
Yeah. I think the bleeding really does indicate that if the uterus is able to be removed, I think that should happen. If not, it's just going to cause problems to the patient as she starts treatment. Now, there is an option. We already know the patient has metastatic disease based on her imaging. If you want to do neoadjuvant chemotherapy, I think that's reasonable as long as the bleeding is controlled. One question I have for you guys is, I wouldn't normally get an MRI. That's not part of my general workup for endometrial cancer. I suppose, in this case, maybe it was to see if it was re-sectable or maybe there was something on physical exam to suggest that there was disease in the parametrium or extending, invading other local organs. That's just a question. I'm curious.
Dr. Tewari:
Yeah. Dr. Bujnak?
Dr. Bujnak:
Yeah, that's what I would do. Basically, in that exact scenario, if you're trying to see if it's resectable, if there's any bladder extension, rectal extension, parametrial involvement, just seeing if you can get the uterus out.
Dr. Tewari:
Yeah, this is a real case. I think, with the ultrasounds showing such a significant mass, there was some concern whether this was a little more advanced, and so I think, in terms of resectability, I agree with you, Dr. Cloven. I normally don't get MRIs, but if I'm thinking about a surgical approach, I may do that. This patient undergoes a palliative operation, basically. To your point, she has metastatic disease, and I would typically give a patient like this neoadjuvant chemotherapy upfront, especially with irritable adenopathy and mesenteric adenopathy, but because of the bleeding, the hemoglobin down to 6, the 2 units of packed red cells, she undergoes a robotic hysterectomy. Her T-score was 2. She's a great candidate, and undergoes bilateral pelvic lymphadenectomy and excision of aorta cable and mesenteric nodal metastases. Her surgical pathology is consistent with the FIGO stage IV grade 3 mismatch repair–proficient endometrioid adenocarcinoma. On her postsurgical PET scan, she does have residual and measurable aortic cable nodal disease.
Dr. Bujnak, how would you counsel this patient when she comes back to see you? I mean, I'm assuming her bleeding's at least stopped now that you've taken her uterus out.
Dr. Bujnak:
I would counsel her that, a few weeks after surgery, probably about 4 weeks after, that she would be a candidate and would likely benefit from chemotherapy, carboplatin, paclitaxel, plus immunotherapy, and then followed by maintenance immunotherapy. And you can choose dostarlimab or pembrolizumab in this scenario. Either one is FDA approved in this clinical scenario.
Dr. Tewari:
Dr. Cloven, when you look at the GY018 NRG study with pembrolizumab and the RUBY trial with dostarlimab, how do you see those studies? Are they complementary studies? Are they competing studies? How do you choose which immunotherapy agent you're going to use for your patients or a patient like this? In this case, what would you do for her?
Dr. Cloven:
Yeah. To be honest, if you look at the data from the trials, they’re so similar. I think you could use either one. And I try not to play favorites with one drug vs the other. I think they're both very active agents. If you look at the PFS, the hazard ratios, and all the data from the trial, it's very similar. There were a couple of differences in the eligibility criteria for the trials. Both trials did allow all comers; both mismatch repair–deficient and –proficient were allowed. Both trials allowed advanced, stage IV cancer or stage III with measurable disease, but the RUBY trial allowed patients carcinosarcomas, as well as those with high-risk subtypes that had positive lymph nodes only, so without measurable disease. So there are some differences. I think you really go either way with this patient, as far as standard approaches.
Dr. Tewari:
I tend to agree also. I see the trials as helping each other. With NRG GY018, we had two very distinct cohorts, the mismatch repair–proficient and mismatch repair–deficient cohorts, and as we know, the patients with mismatch repair–deficient tumors respond better. In fact, the hazard ratio for progression or death in GY018 was 0.3 for the mismatch repair–deficient patients. This patient's much more high-risk by virtue of a few things. She's mismatch repair–proficient, she's also got unresectable stage IV disease, and she still has disease in the abdomen.
I agree we could go either way. I definitely do want to highlight the RUBY study, because it was powered for survival, and we have a hazard ratio of death of 0.69 for all comers in the RUBY study. And so, to your point, we could go either way with either agent, but I think they're complementary, and I talked to the patient about both of them. They're both anti–PD-1 inhibitors. Another thing I wanted to ask you about, Dr. Cloven, is this patient seems like she'd also be eligible for a front-line trial, such as TroFuse-033. Can you tell us a little bit about that study?
Dr. Cloven:
I'd love to. That's my passion, clinical trials. This is what we're looking at now. Obviously there was a huge benefit in the mismatch repair–deficient patients with immunotherapy, combined with carboplatin and paclitaxel. There was still a benefit in mismatch repair–proficient patients, but the benefit was less, so we're trying to see if maybe we can build on that with some other trials. There is an ongoing trial right now that I'm very excited about, TroFuse-033, which is looking at an antibody-drug conjugate. It's called sacituzumab tirumotecan, and it is directed against the TROP2 antigen and has a TOPO-1 payload.
The way the trial is designed is that patients are eligible if they have stage III measurable disease, stage IV, or recurrent endometrial cancer, and they're mismatch repair–proficient—so she would be eligible. The trial design starts off with carboplatin, paclitaxel, and pembrolizumab, and then the patients are randomized in the maintenance phase, with half of the patients receiving pembrolizumab alone and the other half receiving pembrolizumab with sacituzumab tirumotecan. What I really like about this trial is, for patients who unfortunately progress during their front-line therapy, they're allowed to continue on the trial and get the sacituzumab tirumotecan, so it's an excellent option. I think that there's more work to do in the mismatch repair–proficient patients, so this is a good thing to think about for our patients.
Dr. Tewari:
That's wonderful. Dr. Bujnak, this is my question for you, and this is something many of us struggle with. So far, we've talked about she can get chemotherapy, plus a checkpoint inhibitor according to the RUBY study or GY018, or she could be eligible to be screened for the TroFuse-033 study, but because she's mismatch repair–proficient, and we do know, from very good data, that checkpoint inhibitors don't have as robust response in the mismatch repair–proficient patients, I've heard thoughts about not treating patients with a checkpoint inhibitor upfront. Just for example, give them chemotherapy, and save the checkpoint inhibitor for when they relapse, at which point the mismatch repair–proficient patients can be given pembrolizumab plus lenvatinib, according to the KEYNOTE-775 study, which did show a survival benefit in the recurrent setting. What are your thoughts about that?
Dr. Bujnak:
Well, we've talked about this for other cancers and other therapies as well, and I've heard of this same kind of concept of saving the therapy. At least I personally don't totally agree with that method. I would give the patient the therapies that we have, that we know have some survival benefit. We know it has some degree of survival benefit for this patient population, so I would give that to the patient upfront.
Dr. Tewari:
Yeah. I tend to agree also. Dr. Cloven, what are your thoughts about that? Have you heard some talk on the street that maybe the mismatch repair–proficient, newly diagnosed patients save the immunotherapy for when they relapse and then add lenvatinib to it?
Dr. Cloven:
Yeah. I don't think it's unreasonable to do that, but I agree with both you and Alyssa that I don't like the concept of saving the therapy. I would rather try to give my best effort upfront, because that's when I think you have the best chance at getting a long disease-free interval. The other thing that I guess I would want to point out is that we're moving into where we are treating patients with endometrial cancer more based on their molecular profile, so there is also a study that has completed now, but hasn't reported the EXPORT trial that's looking at patients with advanced endometrial cancer. You have a response to chemotherapy, who are p53 wild-type using selinexor, which is an oral agent for maintenance, and that's another promising avenue. I think that might be something. We don't know what the results of the trial are going to be, but that might be something to think about in the future for this patient as well.
Dr. Tewari:
Wonderful, and I think we'll be talking a little bit more about p53 as we move on in this program, but the key clinical takeaways that I'd like to leave our viewers with, for this case, are that platinum and taxane-based chemotherapy, plus dostarlimab or pembrolizumab, followed by maintenance to dostarlimab or pembrolizumab, improved survival in mismatch repair–proficient endometrial cancer. So, very similar to our first clinical takeaway with the mismatch repair–deficient, it also improves outcomes in the mismatch repair–proficient population, although maybe not as robust. Again, just to not confuse anyone, if you give a specific checkpoint with the chemotherapy, that's the one you should be using as a maintenance therapy. There's a rationale to use anti–PD-1 treatment in first-line therapy, because we have a strong survival benefit according to RUBY. Although there is a survival benefit in the recurrence setting with KEYNOTE-775, I agree with Dr. Bujnak that, if we don't use our best therapies upfront, when the patient recurs, we may never be able to catch up.
So, I'm an advocate of using immunotherapy upfront as well, just like the two of you. Clinical trials are something to consider, and TroFuse-33 would be a perfect clinical trial to screen this patient on. Again, counsel for endocrinopathies and autoimmune disease. If she does go on to TROPUSE-33 or a study like that, looking at a TROP inhibitor, we do want to counsel patients on stomatitis, which is one of the adverse effects of antibody drug conjugates targeting the TROP2 protein. Then, of course, do a whole panel of testing for all of the different things we talked about, tumor mutational burden, mismatch repair stats, which we already got, but also POL-E, P53, HER2, even folate receptor. We'll talk about some of this later. That brings us to the end of this case. Please see other segments for further discussion about the latest research in endometrial cancer or visit the ascopost.com.
