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Roberto Vargas, MD, gynecologic oncologist at Cleveland Clinic, joins the Cancer Advances Podcast to discuss adding immunotherapy to chemotherapy for endometrial cancer. Listen as Dr. Vargas sheds light on recent studies demonstrating that adding checkpoint inhibitors to standard chemotherapy could notably lower the risk of cancer recurrence in patients with MMR-deficient or MSI-high tumors and the potential of genomic-based therapies for endometrial cancers.

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Adding Immunotherapy to Chemotherapy for Endometrial Cancer

Podcast Transcript

Dale Shepard, MD, PhD: Cancer Advances, a Cleveland Clinic podcast for medical professionals, exploring the latest innovative research and clinical advances in the field of oncology.

Thank you for joining us for another episode of Cancer Advances. I'm your host, Dr. Dale Shepard. She is a medical oncologist here at Cleveland Clinic directing the Taussig Early Cancer Therapeutics Program and co-directing the Cleveland Clinic Sarcoma Program. Today I'm very happy to be joined by Dr. Roberto Vargas, a gynecologic oncologist here at Cleveland Clinic and Associate Program Director for the Gynecologic Oncology Fellowship. He's here today to discuss adding immunotherapy to chemotherapy in the management of endometrial cancer. So, welcome.

Roberto Vargas, MD: Thank you for the invitation and for allowing me to join you today, Dr. Shepard. It's my pleasure.

Dale Shepard, MD, PhD: Absolutely. So give us a little idea, gave us a title sort of thing, what you do do here at the Cleveland Clinic.

Roberto Vargas, MD: So, as you mentioned, I'm a gynecologic oncologist and here at the clinic, that means that I'm responsible for not only the surgical management of gynecologic malignancies but also the administration of the majority of our chemotherapies before we send them over to you in the phase one, two trial team.

Dale Shepard, MD, PhD: Very good. Endometrial cancer. So just give us a little idea why are we specifically interested in newer therapies for endometrial cancer.

Roberto Vargas, MD: So, as you know, Dr. Shepard, we've made great advances in a lot of our disease sites, a lot of our cancers with novel therapies, and we've been able to improve mortality in all cancers but one. Endometrial cancer is the only cancer that over the last three decades we have been unable to move the bar. So we have a lot of ground to make up there and that's why there's such an interest in trying all these novel therapies and approaches to improve our patient outcomes.

Dale Shepard, MD, PhD: And we're going to talk about traditional chemotherapy and immunotherapies and how that might impact, but has there been one underlying reason why endometrial cancer specifically has been so tough?

Roberto Vargas, MD: I think there's more than one reason. I can give two main reasons for that statistic, and one is that the incidence of endometrial cancer continues to rise as opposed to ovarian cancer and cervical cancer where we've seen a decrease in the number of new cases. The incidence of endometrial cancer has actually outpaced predictions and that then coupled with the increase for unknown reasons, but the increase of the aggressive types of endometrial cancer. When you put those two together with a lack of new exciting therapies up until recently, we're just going to get ourselves in trouble in terms of patient outcomes and mortality.

Dale Shepard, MD, PhD: We’re going to talk about the newer things with immunotherapy, but right now what would be considered standard therapy for endometrial cancer?

Roberto Vargas, MD: So, the majority of our endometrial we're able to address surgically if they're early stage, and after that, sometimes we employ radiation or chemotherapy to try to prevent their cancer from coming back. The problem really is when those patients that cancer does come back, or those that do present with stage three, four advanced disease, those are the patients that we have to rely on more traditional chemotherapies, our carboplatin, and our Paclitaxel backbones.

Dale Shepard, MD, PhD: And when we think about that presentation, oftentimes earlier than what we think about with ovarian.

Roberto Vargas, MD: Yes, a lot of our patients are presenting with early-stage endometrial cancer because we do have a warning sign that postmenopausal bleeding or abnormal uterine bleeding that we don't have in our ovarian cancer patients.

Dale Shepard, MD, PhD: All right. So let's talk a little bit about, you mentioned traditional chemotherapy. Talk to me a little bit about the studies that have been done recently that have shown a benefit for addition of checkpoint inhibitors or immunotherapies.

Roberto Vargas, MD: Yeah. So there's been two recent phase-three randomized trial, NRG-GY018 and the RUBY trial. And both of those look to see if there's a benefit to the addition of PD-1 inhibitors, pembrolizumab specifically and the NRG-GY018 and do Dostarlimab in the RUBY trial when we add those to our carboplatin paclitaxel backbones. And they're given during their chemotherapy, but also then kept on as a maintenance therapy for two to three years.

Dale Shepard, MD, PhD: And so the populations that were studied in both studies, those had MSI-high disease primarily, or tell me a little bit about the patient selection.

Roberto Vargas, MD: That's a great question, Dr. Shepard. The studies included both patients that were MSI-high, MMR-deficient, and patients that were stable microsatellite and had proficient MMR status. So it included all recurrent or advanced stage in endometrial cancers. But then it's stratified based on that genomic marker that you mentioned. And the outcomes were different as we would expect.

Dale Shepard, MD, PhD: And so I guess before we talk maybe specifically about what those results have been, how much has immunotherapy been a player as single-agent pembrolizumab has an indication for any tumor that has MSI-high status? Has that really been incorporated much at this point into endometrial cancer?

Roberto Vargas, MD: It has. That's actually the grassroots where we started with the immunotherapy application. And endometrial cancer is the monotherapy and the recurrent, after having failed traditional chemotherapies and we have a patient with an MSI-high tumor, we would be able to trial that. And it was efficacious. And from that, then we built moving it to the first line as a recurrent pairing it with other biologic agents, and then now more recently with chemotherapy in the first-line setting.

Dale Shepard, MD, PhD: And then ballpark, what percentage of patients with endometrial cancer are MSI-high that could benefit from addition of an immunotherapy?

Roberto Vargas, MD: So ballpark, 25 to 30% of patients. So a quarter of our endometrial cancer cases are going to be MMR-deficient.

Dale Shepard, MD, PhD: So a lot higher than a lot of other tumors.

Roberto Vargas, MD: Yes.

Dale Shepard, MD, PhD: Okay, excellent. So going back to this addition to chemo, what were the primary findings

Roberto Vargas, MD: Consistent across both trials? And they had similar populations, like I mentioned, they were advanced stage or recurrent cancers, but their findings were that in those patients that had MMR-deficient tumors or MSI-high tumors, there was about a 70% reduction in their risk of recurrence during that study time period. And it was remarkable. And both studies showed the same relative risk reduction with the addition of the checkpoint to the chemotherapy and then keeping it on as a maintenance therapy.

Dale Shepard, MD, PhD: So pretty impressive response.

Roberto Vargas, MD: Yes. The results weren't as robust in those patients as we would expect that were MMR-proficient or did not have an MSI-high tumor. In those patients, they did still see a reduction in their risk of recurring. About 30% on average between both studies. So there seems to be some effect even in those tumors. And that builds onto why we think adding it to chemotherapy is going to be a valuable strategy. And that in certain patients, that chemotherapy with the immunotherapy may be enough to make up some ground in those tumors that are MMR-proficient.

Dale Shepard, MD, PhD: Which is, I guess from a trial design standpoint, it's good that everybody's included because you have single agent for people that already are MSI-high, you might think you can improve that, but I guess that's the nature of these combinations. You don't know if you can induce some sort of response. So I guess it was good that they enrolled that. Do we have any idea about duration of response? Was this durable in terms of response?

Roberto Vargas, MD: So that's a great question. I mean, we expect that there's going to be a large subset of patients, as with the immunotherapies in general, that we do have long-term responders that stay on the immunotherapy for many years. The studies, the RUBY trial kept patients on maintenance for up to three years, and the NRG GY018 kept them on maintenance for up to two years. But the reality is that there was 30% of patients that even within that two-year window, they had their disease recur even if they were MMR-deficient, even if they were supposed to be their responders. So there's still a subgroup even within those that we need to make up some ground that we're not even getting added benefit on topic of chemotherapy.

Dale Shepard, MD, PhD: And then the trial is still looking at an overall survival endpoint?

Roberto Vargas, MD: Yes. So the trial, the follow-up, these were early analyses that RUBY found both progression-free survival benefit, and also an survival benefit, most notably in the MMR-deficient tumors, which is likely what fed into the FDA approval of that drug. Pembrolizumab wasn't ... The trial wasn't ready to provide overall survival data. So we're still awaiting that. So hopefully in the next couple of years, we'll get more mature overall survival data and we'll be able to get a glimpse as to how many patients are able to fall in that long-term responder category.

Dale Shepard, MD, PhD: Or just to be annoying, I'll point out hopefully it's four or five years because that means it took longer to ...

Roberto Vargas, MD: Absolutely.

Dale Shepard, MD, PhD: So what sort of things are happening in endometrial cancer with other types of immunotherapy?

Roberto Vargas, MD: So I think the focus has turned into, like you alluded, improving the response to that immunotherapy backbone because if the immune system, even with the PD-1 inhibitors on board cannot see the cancer cell, it's not going to go after it. So trying to figure out are there biologic agents or specific chemotherapy combinations that are going to make that tumor hotter or no easier, whatever analogy you'd like to make, so that the immune system with the PD-1 inhibitor on board is able to go after that cancer. And that's really been a lot of the attention because like I mentioned, there's still going to be patients that their disease comes back. CarboTaxol wasn't enough with the immunotherapy to get them there. So is there something better that we can do for them?

Dale Shepard, MD, PhD: And I guess something better. I guess the question is better from an immunotherapy standpoint, but I guess also better from a chemotherapy standpoint. I mean, what's the, I guess big picture when you look at in terms of lines of therapy, you see a patient, where do we think this combination ultimately fits in compared to other immunotherapies, other chemotherapies? Is there a thought that maybe another chemo in combination with immunotherapy might be effective?

Roberto Vargas, MD: That's certainly a possibility. That's not something that I think right now is in a large phase-three randomized trial, but the carboplatin, paclitaxel, pembrolizumab or dostarlimab is going to move to the front line. And then second line, we're still using pembrolizumab, often paired with another drug lenvatinib. But after that, aside from a clinical trial, we are back to our traditional cytotoxic chemotherapies that really have 10, 12% response rates. So the numbers really aren't phenomenal. And that's I think the area that we need to really, really work on that we're going to improve the frontline responses. But those patients that fail, we're still stuck at therapies that are 20, 30 years old and have unacceptable response rates the way that I look at it. So we need to do a lot more work in that realm.

Dale Shepard, MD, PhD: And I guess the good thing is that I mean, our groups collaborate quite a bit from an early-phase trials perspective because it's good to see that a lot of those early-phase trials are including endometrial cancers as potential cohorts.

Roberto Vargas, MD: And we're very thankful and appreciative of your team in the early phase trial group because a lot of these endometrial cancers, if they don't have an MMR deficiency and a signal in that route, they may have another biologic pathway that we can target. And getting these early phase trials off the ground and finding active relevant biologic targets then opens the room to studying those with immunotherapy.

Dale Shepard, MD, PhD: So, what typically happens, of course, if you find something that works in first-line recurrent, first-line metastatic, the next thing to do is think about, well, maybe it works somewhere else in another stage of disease. So is there interest in looking at this in an adjuvant setting, interest in a neoadjuvant setting? What kind of interests are there for that kind of approach?

Roberto Vargas, MD: It's another fantastic question. And there are trials. There's another NRG-sponsored trial that looked at incorporating pembrolizumab into that adjuvant setting for early-stage patients, but that they were high risk for their disease to recur. And that trial is designed to assess whether or not pembrolizumab was effective as an additional adjuvant therapy component on top of radiation. So in that setting, they were getting radiation and pembrolizumab.

Dale Shepard, MD, PhD: When we think about patients and who gets treated and where they get treated, is this immunotherapy with chemotherapy something that's likely to be incorporated pretty quickly in academic centers, but also in community settings?

Roberto Vargas, MD: I'd like to think so, but that's in part to the experience that our providers have had with pembrolizumab and now with dostarlimab and other immunotherapies and other disease sites that there's going to be a little bit more comfort in knowing what to expect and what to look out for. And carboplatin Paclitaxel has been around many, many decades, so I'd like to think that the uptake is going to be rather rapid and large across the nation. And we are seeing patients from the community that are coming to see us for trials after already having received chemo and immunotherapy.

Dale Shepard, MD, PhD: Which is good. I mean, I guess as you alluded to, the toxicity profile is different. The way to manage is a little bit different. And on a medical oncology side where we don't get to do the surgery, all we do is that the systemic therapies, we're more used to using those drugs. And so this is kind of a totally new type of drug for people to incorporate. So it's good to hear that getting good uptake.

Roberto Vargas, MD: Yeah, it makes us optimistic that, again, in the next four, five, six years, that we will start to see that needle for overall survival in endometrial cancer start to shift back towards improvement. But we have to, I think, again, make some strides in what happens after chemo and immunotherapy, what do we have to offer them there.

Dale Shepard, MD, PhD: Makes sense. Just to shift gears slightly, in terms of types of therapies for endometrial cancer, how effective have genomic-based therapies been in terms of getting sequencing, finding targets within patients with endometrial cancer? Has that been a very significant player?

Roberto Vargas, MD: We are big proponents of molecular profiling to understand that genomic makeup of these endometrial cancers because there are times that we have drugs that are active that we can use dependent on those genomic signals. MMR deficiency was one of those clusters that was identified in the genomic profiling. But there are other tumors that let's say we find have an HER2 amplification, and now with the advent of the antibody drug conjugates, the ADCs and those coming onto the field, that's where I'm honestly most excited because as long as there is a signal, those antibodies can go after that signal. And then assuming that their payload that they're carrying is an active agent, we have seen some pretty remarkable responses in otherwise patients who we feel are out of options incorporating these ADCs.

So I do think that molecular profiling and understanding the genomic makeup is going to open the doors not only for enrollment in early-phase trials, but also using these antibody-drug conjugates.

Dale Shepard, MD, PhD: So what has been historically a difficult-to-treat type of tumor? Sounds like there's reason for optimism.

Roberto Vargas, MD: The rare and aggressive histo types that I mentioned in the beginning that are also on the rise in incidents are traditionally the ones that are harder to treat. Not only are they aggressive, but they are usually MMR-proficient. So we do not expect them to have a robust response to immunotherapy. And while there may be added value with chemotherapy, they're still at high risk for not really having a durable response to that therapy. And then afterwards, they also, when we start adding our drugs like lenvatinib to the pembrolizumab, which is often used in the second line, we don't really expect them to have a robust response.

So really these are the ones that HER2 specifically and the HER2 ADCs have come now to be very useful, assuming that there's a genomic marker there. And there's more trials incorporating these ADCs that we're opening here at the Cleveland Clinic using and looking at other targets. So we're really very excited for those drugs in this specific genomic cluster per se, that immunotherapy is not really active, but we also know is driving the majority of the mortality figures.

Dale Shepard, MD, PhD: Well, you have provided some great insight for us today. Appreciate you being with us.

Roberto Vargas, MD: Thank you for the invitation, and we'll look forward to seeing what happens in the next four to five years in endometrial cancer.

Dale Shepard, MD, PhD: And we'll have you back.

Roberto Vargas, MD: Perfect.

Dale Shepard, MD, PhD: To make a direct online referral to our Cancer Institute, complete our online cancer patient referral form by visiting clevelandclinic.org/cancerpatientreferrals. You will receive confirmation once the appointment is scheduled.

This concludes this episode of Cancer Advances. For more podcast episodes, visit our website, clevelandclinic.org/canceradvancespodcast. Subscribe on Apple Podcasts, Spotify, or wherever you listen to podcasts.

Thank you for listening. Please join us again soon.

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