DR LOVE: Subsequent to this recording, on August 1, 2024, the FDA expanded the approval of dostarlimab in combination with carboplatin and paclitaxel followed by single-agent dostarlimab from patients with dMMR/MSI-high endometrial tumors to include all patients with primary advanced or recurrent endometrial cancer, representing a new treatment option for those patients with MMR-proficient/microsatellite-stable disease in addition to those strategies presented in this program by Dr Secord.

Front-line management of ovarian cancer

DR LOVE: Welcome to Oncology Today, Management of Ovarian and Endometrial Cancer. This is medical oncologist Dr Neil Love.

This program is a follow-up to a live activity we conducted during the ASCO meeting in early June in Chicago. I met with Dr Angeles Secord from the Duke Cancer Institute in Durham, North Carolina, who moderated the meeting in Chicago. I wanted to follow up with Dr Secord on many of the issues discussed in the meeting, and to begin, particularly because of her recent presidency of the Society of Gynecologic Oncology, I was curious what attracted her to this field.

DR SECORD: One of the things I loved and really brought me into this specialty was not just the surgical aspects, but the medical aspects and taking care of patients throughout the course of their disease. You really develop such a strong bond. You’re with them at the very beginning, at the time of their diagnosis, through their surgeries and then help develop their treatment plans and continue to see them throughout. So I hope that that doesn’t change. I think GYN oncologists will determine what’s the best practice approach for them. And some may opt to do surgery only. Some may opt to do surgery and delivering of antineoplastic chemotherapy. And then there may be some that decide during their career that they would prefer to do more of the direction of antineoplastic therapy. So the fabulous thing is it’s a huge specialty. We all get along great. We have a wonderful relationship with our medical oncology colleagues, our radiation oncologists, our pathologists and all the additional healthcare providers that are involved, pharmacists, APPs, nurses. GYN oncology is a very, very special, unique space. And I’m just happy that so many people want to be involved to help our patients.

DR LOVE: Let’s kind of get into some of the major issues that we were talking about. As you recall, for this meeting, we were just focused on ovarian cancer and endometrial cancer. And then at the end, we discussed the use of HER2-targeted therapy in gynecologic cancers in general.

So let’s start out talking about something that’s been a big issue now, obviously, for quite a few years which is up-front management of ovarian cancer. And there are a number of issues that I’m hearing talked about more and more in clinical meetings. And one is, as this has evolved over the last few years, one key question, of course, that’s always been out there but maybe is even more relevant now that PARP inhibitors are on board is when bev should be used. And people have a lot of different formulas for how they think about it. Sometimes, people don’t use bev neoadjuvantly, but will use bev after surgery. What’s your approach to the decision about using bev? And maybe even backtracking into neoadjuvant therapy to start with.

DR SECORD: Right. Wow, this is a loaded question and so controversial. We do not use a lot of bevacizumab at our center. If I’m going to utilize it, I’m going to more strongly consider it for somebody who has Stage IV disease. We do so much more neoadjuvant chemotherapy at this point that if you even take somebody to the OR and you’re considering primary debulking surgery, if you look in and you can’t get them completely debulked, after we do that laparoscopy, we’re going to abort the surgery and move toward a neoadjuvant approach. So I think some of the classical parameters that we discussed before about patients who have sub-optimally debulked Stage III disease are no longer really relevant in this era. So it'll be for individuals who have Stage IV disease, pleural effusion or significant ascites that I would consider bevacizumab. But often, I find that there may be contraindications like specifically, bowel involvement. Either on imaging or symptomatically, they have concerns for a bowel obstruction. Or on exam, they might have big, bulky disease involving the rectosigmoid. So we’re just not huge bevacizumab users in the front-line setting in part because the long-term data hasn’t shown increased cure rates. However, I think there is some value in terms of controlling disease and improved progression-free survival. And it’s a discussion with the patient regarding these options.

I love the PARP inhibitor question here because for me, and I think several of my partners, we really utilize HRD test and BRCA1 or 2 testing to distinguish whether or not we’ll utilize a PARP inhibitor. And I’m still not fully convinced that a PARP inhibitor plus bevacizumab is going to be better than a PARP inhibitor only in those patients. I know there’s some provocative data in terms of comparing different components of studies to each other, but I think that can be challenging because even when you do that, you don’t know if there’s complete homogeneity between these studies and there could be differences in the patients that you’re not fully capturing.

DR LOVE: I’ve got to say, as a medical oncologist, it’s only been in the last year that I actually even heard about the KELIM score. So I don’t know if there are other oncologists who maybe haven’t. But could you kind of review what that is? And I have heard people say they integrate that into the decision about whether to use bev. If the patient is not having a good response, for example, they may think about it. But can you explain what it is and do you even look at it yourself?

DR SECORD: Well I think the data is very provocative here. But to my knowledge, it’s mostly all retrospective or ancillary. And it utilizes the CA-125 to determine if you’re going to direct patients who have a favorable KELIM score to receive bevacizumab or not. I would love to see this be utilized in a pragmatic clinical trial because I think it’s a really easy test to do and it may be helpful to direct therapy for those patients most likely to benefit from the addition of this drug.

DR LOVE: It kind of reminds me in prostate cancer, they look at how quickly the PSA drops and then they sometimes will intensify therapy after that. But let’s get into the key issue for the last few years which is when to use a PARP inhibitor, which PARP inhibitor and for how long. And one of the things is, and you sort of alluded to this, that as time has gone on since we’ve seen these studies and even in the studies themselves, it always seems to kind of be 2 branches. One is BRCA, HRD. And the other is either completely wild-type or not much of an indication of benefit. And within BRCA, you have some people who respond better. But 2 pretty big differences in terms of PARP inhibitors.

Let’s start with the wild-type situation which has gone back and forth over the years. We have some data in approval for niraparib. But in patients who have completely wild-type, LOH not high, how do you think through maintenance therapy?

DR SECORD: So I’ll just start by saying I believe that PARP inhibitor maintenance therapy should be discussed with all patients who have newly diagnosed ovarian cancer after chemotherapy whether or not I strongly recommend it based on their biomarker. And I know some people feel very strongly that there’s not a biomarker that really can be utilized to direct therapy. But I disagree with that because I think there’s differences of magnitude of benefit. So to address the question that you asked in those patients who are HRD negative and don’t have a BRCA1 or 2 mutation, I do review the results with those patients. I offer, the 1 PARP inhibitor that’s available in that setting is niraparib. And I discuss the side effects of the medication with them. And after reviewing the potential benefits in terms of disease control and the side effects of the medication, I work with the patient to decide what’s best for them. I do have some patients that feel really strongly that they want to be on a PARP inhibitor. And then I also have had some patients that feel like they’re done with chemotherapy, they just need a little bit of a break. And it’s probably around 50/50.

DR LOVE: Would you offer a patient like that anything else, for example, bev?

DR SECORD: Yeah. Those patients, I discuss bevacizumab options with all my patients. And it’s the same sort of situation. It’s like whether or not they want to utilize the drug and then continue on maintenance. I think part of the, you know, when you’re doing a lot of neoadjuvant chemotherapy, we didn’t really get into this, but if you’re going to utilize it, when do you utilize it? I like to stop it before the cycle right before their surgery. And then I won’t start it back up the cycle right after their surgery unless there’s a long delay before their treatment. I’ll usually start it up the cycle after that. So I think bevacizumab is an option for these patients as well. But I don’t, in that setting, I don’t combine the bevacizumab with a PARP inhibitor. And we’ll have data on that soon, hopefully, with the FIRST trial.

DR LOVE: I’m just kind of curious. When patients hear these alternatives of niraparib, bev or observation, what do they — any sort of trends to what you hear them doing?

DR SECORD: It is really variable on their preference. I’m really fortunate I work with some wonderful colleagues. And one of my colleagues, Dr Laura Havrilesky, did a lot of work on patient preferences. And it really amazes me how, what patients decide. Maybe really different than what you assume. And it’s really important to get their perspective. And sometimes, their perspective is based on what is going on with their family. Do they have a grandchild they’re expecting to see or somebody who is going to graduate or get married? Those are going to make differences in what they decide to do.

DR LOVE: I kind of wonder too what their perspective is on the benefit, whether they really hear what’s being said to them about, for example, this situation where you don’t really see a huge — you’re saying you could manage these people without treating them and you’d be okay. So obviously, the benefit is not that great. I really wonder, sure, people want to do everything they can, but I kind of wonder whether or not they’re kind of getting deals that maybe are not really in their favor in some cases.

DR SECORD: Sometimes, it’s really hard. I try very hard not to just talk about median progression free survival time, but also go back to — and I don’t say hazard ratios. That’s really confusing for patients. But I may say 30, 50% reduction of disease. Every once in a while, you can show them a survival curve. Sometimes, patients, that won’t work for them. But I have some patients that are really into medicine and I have some patients that are in medical fields as well, and they want that type of granularity. So I really base that discussion on what the patient wants.

DR LOVE: Yeah. I’ve been very curious about healthcare professionals, particularly physicians, who get cancers and how — because, to me, they should be able to understand this better. And I would wonder how they would process it. I can look at it myself, but of course, not being in the situation, I don’t know how it feels to have a — to me, this situation looks like pretty borderline benefit, frankly.

DR SECORD: Yeah. I think I would agree with you in patients who are homologous recombination deficient negative. It’s so confusing, right?

DR LOVE: Right.

DR SECORD: To say HRD negative. And I know that some of my colleagues will disagree with me. I just feel like we haven’t identified the right therapy that’s truly going to give them a significant benefit compared to the side effects yet. And we need to keep trying. I think we’re on the cusp of finding it, but we’re not quite there.

DR LOVE: Absolutely.

DR SECORD: However, you have these, you know, I know you’re going to get into other questions for me about different patient groups. And I think that’s how I discuss that. And what recommendation I give is very different.

DR LOVE: Right. And that is, of course, what I was about to, the next thing I was going to ask you about, these people, for example BRCA patients. There, I don’t think there’s any question whether you’re going to give a PARP inhibitor. But there, the question is which one and for how long? I’m kind of curious how you think that through.

DR SECORD: Yeah.

DR LOVE: And also, of course, whether you’re going to add bev to it too. I guess we should add that.

DR SECORD: So with olaparib and niraparib, there’s some distinguishers between these drugs. I think the biggest ones are, how long are you going to continue the therapy? For olaparib, it’s 2 years. Niraparib is 3 years. Although I have to say even with patients on niraparib, I would love a reason to stop even earlier at 2 years because I do start to worry that maybe that’s when the AML and MDS rates start to increase. And then the other big thing is how frequently they take the medication. Some patients really like the idea of taking it once a day. And in order to avoid nausea, they’ll take niraparib at night. But then, that may make them have more insomnia issues. And then with olaparib, it’s twice-a-day dosing. But it has less bone marrow toxicity, specifically on platelets. So after you review the medication with them, talk about the side effects, the other thing I find a lot of my patients do is they get in these chatrooms and they’re talking to other people probably around the world, maybe not the whole world and probably outside of the US, about what is their experience and which medication they would recommend. So often, people will come and just say this is the one I want. And I’ll say yes. And I think I try to be really fair about my approach in terms of talking about both the drugs that are available and not favoring one over the other.

And then the question about adding bevacizumab is really more based for olaparib. For patients who have newly diagnosed advanced disease who are treated with chemotherapy and have been on bevacizumab with their concurrent therapy, if they’re HRD positive, I will offer them olaparib.

DR LOVE: So I’m curious. For niraparib, we’ve had the weight and platelet, weights and plates approach to dosing now for the last few years to try to avoid extremes, particularly with thrombocytopenia. I’ve heard a couple of cases where they applied that and they still ended up having thrombocytopenia. I’m kind of curious what your experience is. Do you find that when you apply that, you pretty much stay out of trouble?

DR SECORD: Oh, that’s been my experience. I think it’s, you know, it’s not 100% you’re going to stay out of trouble, but I think it’s a lot better than when you don’t utilize that. We participated in the QUADRA study with niraparib, and we put on a lot of patients at our site. So I got very comfortable. We also had the NOVA study on as well. But I got very comfortable with niraparib and learned right away not to mess with this. When you start to see the counts go down, you just hold therapy. And I don’t mess with trying to maintain the same dose. Often, I will dose reduce. For me, it’s more about maintaining patient on drug. And even if the dose is lower, I think as long as you don’t have frequent interruptions, you’re still going to get that benefit.

DR LOVE: I have that discussion a lot with people in breast cancer. Of course, they’ve used long-term maintenance therapy, adjuvant therapy for a long time. And one of the things there, and I think you kind of alluded to, that you hear there because, you know, a lot of these oral agents may have significant side effects. So in terms of how you keep a patient adherent or how you encourage adherence. And one of the things, at least in breast cancer and I think you alluded to, is dose reduction. And they have the strategy they just want to keep the patient on the therapy. And that’s their primary issue. Do you kind of approach it the same way where you’ll dose reduce if people are having problems, not just with counts but with subjective tolerability issues?

DR SECORD: Yeah, absolutely. Part of this is they have no symptoms from their cancer when you’re doing a maintenance therapy. They have no symptoms from their cancer. The symptoms that they get are from the drugs that you’re using. So you want to really maximize their quality-of-life. So if they’re having side effects or issues with tolerability, I will often do a dose interruption, especially if it’s for nausea or fatigue, do a dose interruption, come back at the same dose but maybe try some better mitigation strategies. If that still doesn’t work, then dose interrupt and dose reduce. And I’ve found that to be very effective.

DR LOVE: What about the issue of sort of the immediate tolerability issues you see with PARP inhibitors, I think you can see it with all of them, in terms of GI issues, nausea, vomiting? Do you use preemptive medications? What do you observe? Do you think people get tolerant with time? And is this a long-term problem or more that you see it in the beginning?

DR SECORD: Well, I think that we’re much better now at mitigation strategies, so antinausea therapy 30 minutes before, eat some food 30 minutes before you take the medication. As I mentioned, some of my patients have really advocated for taking niraparib at night so that, I think, they’re sleeping when they’d have most of the GI symptoms. That may be one mitigation strategy.

The other thing too, I think that patients get used to maybe feeling some mild nausea and it doesn’t bother them so much. And what I often will hear is once they’re off the drugs, oh my gosh, I feel so much better, you know? So they didn’t really realize that they were having some of those side effects. But needless to say, when you look at some of the data that’s been done in terms of assessing quality-of-life with Q-TWiST, so time without intervening symptoms or toxicity, these drugs, even if they have some side effects, it’s still worth it in terms of the survival outcomes even after you account for those symptoms they may be experiencing. And there’s been several studies that have demonstrated that for all of the PARP inhibitors.

DR LOVE: Another issue, I hear this talked about with olaparib. I’m curious if you also see it with the other agents including niraparib, which is anemia, and how you handle that. Do you transfuse patients? Do you dose reduce? Do you stop? Do you switch? How bad of a problem is it? And do you see it with all the PARP inhibitors or just olaparib?

DR SECORD: You see it with all the PARP inhibitors. So I think the biggest thing is to be on the initial studies, you had to have a hemoglobin of a certain level. And then once a drug gets approved, people may treat despite the patient being anemic with hemoglobin levels less than 9 or 10. And so one of the things that I’ve learned is really give the patients time to recover, at least 4 weeks. And if their counts are still low, even give them a little bit more time before you start them on the PARP inhibitor. So hopefully, you don’t propagate that problem. And if patients have anemia, work it up. Get iron studies, folate and B12 because they may have a correctable cause of anemia that’s not due to the PARP inhibitor alone. And once you treat that, they’re going to feel a lot better. I’ve had very few patients that I’ve had to provide intermittent transfusions to for anemia. But I’m sure there’s some situations out there that are like that.

Management of relapsed/refractory ovarian cancer

DR LOVE: So another issue that we talked about in the meeting is the management of relapsed/refractory disease, including the use of newer agents that are coming on board. But I’m curious. We’ve been talking about PARP inhibitors. Obviously, we had this huge issue with the FDA and PARP inhibitors in the relapse setting. We went through that in the meeting. I think people are familiar with it. But just bottom line right now, what are the situations where you are using PARP inhibitors in the relapsed setting?

DR SECORD: Very uncommon. Most patients are seeing a PARP inhibitor in the front-line setting. In the relapsed setting, I might have a few patients that have been long-term survivors and have a platinum sensitive recurrence. So they may have not received platinum before and they’re HRD positive or BRCA1 or 2 mutation carriers or somatic mutation. Those patients, I would offer a PARP inhibitor to. And it’s really, there are some patients you’re going to encounter that they would much prefer to have a PARP inhibitor rather than chemotherapy. Those are challenging conversations because some of the overall survival data has been pretty concerning, and their ability to tolerate carboplatin. So I’ve moved away from that, but it’s something that would be worthwhile to discuss with patients. You just have to share the concerning data with them.

DR LOVE: And, of course, related to that is the duration of treatment. Theoretically, in metastatic disease, you would think indefinite but I imagine that that gets tempered by how the patient is doing, et cetera, et cetera. How do you approach duration in the situation where, as you said, they’ve never had a PARP inhibitor, they’re BRCA and platinum sensitive?

DR SECORD: So even in that situation now where the initial studies were maintenance until — therapy until progression, I have backed off on that and I’m trying to stop at 2 years. And that’s not a magic number. It’s just kind of based on what they did with SOLO-1 and then some of the data from the rucaparib trials that showed an increase in MDS and AML after that 2-year mark.

There is a trial that’s been designed proposing assessing olaparib at 1 year versus 2 years. And I’m really hopeful that that trial will move forward. It’s really a pragmatic trial design.

DR LOVE: One versus 2 years.

DR SECORD: Yeah.

DR LOVE: That’s interesting.

DR SECORD: So if you can get that same magnitude of benefit in terms of survival outcomes without that long of therapy or potentially if you reduce the time of therapy, you reduce those side effects that we’ve mentioned, that would be really beneficial to patients.

DR LOVE: Yeah, that’d be interesting. I guess the other thing is whether you can — everywhere in solid tumors now, people are looking at cell free DNA. You have pretty good biomarkers. Prostate has a great biomarker with PSA. But theoretically, you know, you see in colon and a lot of other tumors, they’re really using that to take care of patients. Do you see that day coming to ovarian cancer where in these situations, you could look at their MRD maybe?

DR SECORD: I hope so. I’m really intrigued by those tests. We just need to do more studies to figure out what is the role in making treatment decisions.

Management of microsatellite instability-high/mismatch repair-deficient endometrial cancer

DR LOVE: Let’s talk a little bit about endometrial cancer. And again, we’re just sort of chatting here today of some of the things that I think people would be interested in hearing about. I did notice you were on a paper from the SGO looking at biomarker assessment in endometrial cancer. And, of course, biomarkers are obviously all over oncology, but particularly endometrial cancer. Can you just sort of review your vision of the basic subtypes of endometrial cancer and how you think differently about it?

DR SECORD: Oh gosh. So great question there. I think we’ve gone from this point of view where we saw endometrial cancers as these histologic subtypes to these different molecular subtypes based on the TCGA study, which a lot of individuals will utilize the ProMisE algorithm which is a very simplistic view of 4 different types, the POLE mutant hypermutated type, deficient MMR or otherwise known as high microsatellite instability, and then you have your copy number low and your copy number high, which is really characterized by the presence of p53 mutation or not. And I actually think it is even much more complicated than that. Within those different subgroups, we probably have different splinter subgroups. And so within the context of other types of biomarkers, you have the ER/PR-positive cancers which are probably more under that copy number low or no molecular specific pattern. And then you have these HER2-positive cancers now that we have therapy for that target. And so this number of biomarkers is just going to continue to expand. And I think it’s even going to get more complicated because now, we have these antibody drug conjugates. Yeah, you can probably make your whole career out of just 1 of these cancers at this point.

DR LOVE: I spent an hour and a half recording a program just about HER2 assessment the other day, just to give you an idea, with a pathologist.

DR SECORD: Yeah. Yeah, it’s so complicated.

DR LOVE: Anyhow. Well it’s complicated, but then I started hearing something that sounded like a lot less complicated but I’m not sure exactly how valid it is, which is something you just mentioned which is p53. I don’t know exactly how flushed out these things are. But what I’ve been hearing, for example, is like, let me see if I’ve got this right, p53 mutant responds like really well like MSI-high, and that p53 wild-type maybe looks like it’s going to respond to selinexor. I don’t know. Do I have that right?

DR SECORD: You have that right. Yeah, p53 mutant, immunotherapy appears to make a difference. That’s based on the translational ancillary study in the RUBY trial that Dr Mirza presented. Beautiful graphs there. I love them. And then the p53 wild-type data that Dr Vicky Makker presented just recently at ASCO showing again the long-term follow-up data for these individuals with p53 wild-type, whether or not they were pMMR or dMMR, appear to have some benefit. So it’s really truly an exciting time where you get a direct therapy based on someone’s tumor type.

DR LOVE: But again, when you say benefit in the wild-type, you’re talking about selinexor?

DR SECORD: Yeah, selinexor.

DR LOVE: Okay.

DR SECORD: As the maintenance therapy.

DR LOVE: That’s what I’ve been hearing.

DR SECORD: Yeah. And that’s being evaluated in the XPORT trial.

DR LOVE: Alright. So let’s kind of get into some of the issues that come up here. And to me, it’s easier to go through MSI-high and MS stable kind of sequentially. So let’s start out with MSI-high. And it’s so interesting, you go to colon, MSI-high, upper GI. Some people add chemo. Some people don’t. So you guys are kind of in the chemo plus IO stage, as far as I can tell, for that. Can you just sort of summarize how you think through MSI in metastatic disease first line?

DR SECORD: Oh my gosh. So we just had tumor board this morning. And I was like, oh this is getting so complicated because since we met at ASCO for the meeting there, there’s been 2 approvals, right? One by the FDA for pembrolizumab for both dMMR and pMMR, and then in Europe for the EU, there was a recommendation to approve durva for MSI-high and then a recommendation to approve durva and olaparib for patients who have the pMMR cancers. So just in the space of a few weeks, the landscape has already changed. So I’ll follow along with your questions here though and then maybe we can discuss a little bit more about how the biomarker direction has gotten a little bit more complex with the FDA approval.

So my preferred first-line therapy for MSI-high disease in endometrial cancer is chemotherapy combined with immunotherapy followed by immunotherapy maintenance. And I’m not going to tell you which one. Hopefully, you don’t ask me. And then my approach is not any different in a younger patient.

DR LOVE: How about an older patient with a lot of comorbidities and not very aggressive disease?

DR SECORD: So when you say not aggressive, do you mean it wasn’t measurable?

DR LOVE: Well I guess what I’m questioning is, what I’m really questioning, any situation where, you know, this gets back to starting out with de-escalated therapy, any situation where you would just give an IO? Which is what they do in colon cancer.

DR SECORD: Yeah. So intriguing there. And we have 2 studies that are ongoing right now assessing that, one of them being C93. But I really feel like I need to wait for that study before I just go ahead and do an IO only rather than doing a combination. I, fortunately, have not come up in that situation yet. Now watch, it’s probably going to happen to me in the next few weeks. But I do know that there’s been reports of it in the literature from some of — and some of our colleagues have done this. But the biggest comorbidity that is challenging in the IO space is if they have an immunologic disease like rheumatoid arthritis. And I find that, and maybe it’s just the South. When we were trying to get patients on the study, we would screen a ton of patients and they couldn’t go on because there were seen to be so many types of immune-related diseases here whether it was rheumatoid arthritis or Sjogren’s or you name it. We’d always find some sort of thing.

DR LOVE: GI.

DR SECORD: Yeah, colitis.

DR LOVE: I hear a lot of — oncologists tell me a lot of people come in with GI. They don’t know whether they have, you know, what kind of colitis they might have.

DR SECORD: Recently, I’ve worked with rheumatologists who’ve said if the patient’s disease is well under control and they have Stage IV endometrial cancer and this is really going to help them, then go ahead and treat, and we will see what happens with their symptoms. So I have done that very carefully and always with a rheumatologist working with me.

DR LOVE: You alluded to the choice of IO. And I’m just kind of curious what your experience is with the 2 agents that are out there right now, and either clinically or from what you read in the literature, if you can distinguish them at all.

DR SECORD: Yeah. There have been some reports that perhaps an anti-PD1 approach is better than a PD-L1 antibody. I think in endometrial cancer, we have not had a head-to-head comparison at this point in time. There has been a head-to-head comparison in lung cancer.

DR LOVE: That sounds interesting. But getting more back to practical questions. I imagine that you’ve seen patients that had prolonged responses who were MSI-high. I’m curious in patients who are doing really well, at what point, if any, do you stop treatment?

DR SECORD: So for the metastatic setting, stopping at 3 years for the patients that were on the RUBY trial. And so currently, since the approvals, I don’t have anybody who is at 3 years yet off trial. And the patients who came off are, they had a CR which is really awesome. And then obviously, we had some patients progress. If somebody is on treatment for it because they have recurrent disease, there’s been cases where I’ve had to stop treatment because of side effects. And the patients have continued to do well with very prolonged responses. So I don’t think we know the right amount of time to be treating people at this point. And if somebody has a long-term sustained CR and they’ve been treated for 2 to 3 years, I would start talking to them about coming off. I have no data to support that right now.

DR LOVE: Any comments on patients with POLE mutations? I feel like nobody has even ever seen it. Have you ever seen it?

DR SECORD: It’s incredibly rare. We have a database, the Endometrial Cancer Consortium, that’s 23 sites right now and over 3,000 patients. And in our database for patients with advanced disease, it was at 1 to 2%. I really think it varies based perhaps on race. We have a different proportion of black patients in that study that I just mentioned. Over 25% of our patients are black. So this is why it’s so important to include diverse patient populations in trials.

DR LOVE: And for those patients, I know there’s a question of whether they even need to be treated even if they have metastatic disease. But if you had a patient like that with metastatic disease, would you use an IO alone?

DR SECORD: I would probably, at this point in time, use chemotherapy with IO. I don’t feel that confident to use just one or the other. I think also, not all the POLE mutations act the same.

DR LOVE: Oh, that’s interesting.

DR SECORD: So there may be differences in tumor biology based on the type of POLE mutation the patient has.

Management of microsatellite stable/mismatch repair-proficient endometrial cancer

DR LOVE: Let’s talk a little bit about MS-stable disease which, of course, is a real challenge. And I want to focus on the metastatic setting. How do you generally approach these patients in the first line and also in the second line? And what role does lenvatinib/pembro have in your practice nowadays?

DR SECORD: Wow, loaded questions here. So there was just the approval of pembrolizumab for patients who have proficient MMR advanced metastatic endometrial cancer. And so for patients who have measurable evaluable disease based on GY018, I’m definitely going to talk to all my patients about it. I would definitely offer that option for patients. I think that that was the only study out of all of them that was really designed to answer the question of the benefit of pembrolizumab or IO therapy in these cohorts separately, the deficient MMR and the proficient MMR group. I don’t think the other studies are adequately designed in that way to address that question specifically. So I think these results are very interesting. Where I struggle though is the B21 study was negative. And so patients who were treated in the adjuvant setting, we don’t know the results of that trial yet. I don’t know if there’s going to be a benefit for those patients or not. So if they have pMMR disease and it’s a single node, sentinel lymph node, resected and they have no additional disease on imaging, I don’t think I can recommend immunotherapy in that situation for those patients. I’m really looking forward to hearing the B21 study results.

DR LOVE: So any situations where you would use lenvatinib/pembro in a patient who, for example, had IO/chemo first line? Either MSI-high or stable.

DR SECORD: Well, there was a report that came out regarding the use of lenvatinib in that situation, and they did have some evidence of clinical activity, but it hasn’t been studied in a larger setting. It is actually something we’re studying in the real-world setting for investigators who choose to add lenvatinib to the immunotherapy for patients who are progressing. And I don’t have any early signals regarding activity yet, but stay tuned. We may have more data next year. I have put these patients on clinical trials where if they received a prior immunotherapy on one of the, like we had RUBY trial open, so we had patients on that study. If they progressed, then we had another study that we put those patients on. And it was a combination immunotherapy and biomarker-directed approach. And I have to say, I didn’t see a lot of activity there. So we have a lot of work to do in this space. Combatting or overcoming immunotherapy resistance is going to be very important.

DR LOVE: And I take it that you in general would rather use an IO first-line in these patients than wait until second-line to give them lenvatinib/pembro. And I guess the question would be in the long run, do you think they’re better off holding it for second-line so they can get lenvatinib/pembro or starting out with IO first line?

DR SECORD: For the proficient MMR patients?

DR LOVE: Yeah, yeah.

DR SECORD: Yeah. Well in the adjuvant setting only. We know the B21 study is negative. So I wouldn’t treat those patients with IO with chemotherapy. But if they recurred, then I would use pem/len in that situation. But you have so many other options now too, right? You have HER2-directed therapy if they have HER2 positive disease. And that’s a big gap. We don’t understand all the overlapping expression for these different biomarkers yet.

DR LOVE: And we’ll get to that in a second. But anything you want to say about how you get people through lenvatinib/pembrolizumab? What preventative strategies? How you follow them and prevent issues from developing?

DR SECORD: Yeah. So I was really fortunate to be — we had a few patients on the study and learned a lot from that experience. I think it’s always really helpful to have clinical trials open to get some experience with the drug in that setting. It’s a very controlled setting. So one of the first things I do is talk to patients about the side effects, specifically diarrhea. That’s one of the challenges with pem/len is determining, is the diarrhea due to the immunotherapy component or the lenvatinib component? And advise them regarding starting a BRAT diet, bananas, rice, apples, toast, using loperamide. And if their symptoms don’t improve, need to call us. Even if it’s going into the weekend or in the weekend, just call because we want to make sure that we’re not missing an immune-related colitis. And talking to patients about the possibility of having a rash and thyroid-related issues. Most common is hypothyroidism, but you can also have hyperthyroidism initially and then it becomes hypo. So the other one is the blood pressure. Blood pressure rise can be really rapid with lenvatinib, similar to all the other TKIs in this class. And so advising them about monitoring their blood pressure closely, when to contact us and give them a prescription for, typically I utilize lisinopril so that they have it if they need to fill it. And they can start taking low-dose, 5 mg with recommendations to contact you. Because inevitably, their pressure starts to go up 4:30 pm on a Friday. So trying to scramble and get a prescription all that late is more challenging than if they just have it.

DR LOVE: We were talking earlier about selinexor, particularly in people with p53 wild-type. I’m curious whether you’ve actually used the drug. It’s actually approved in myeloma and lymphoma. They kind of went through some hoops trying to figure out how to use it so that the patient could tolerate it. Have you used it on a trial? And any thoughts about whether you see this coming into practice and how much of a challenge it’ll be?

DR SECORD: I have not used it yet. We have XPORT open and we’re actively screening patients. I want to use this drug because I’m really excited about those long-term results. My understanding though is that the initial levels that they had were really quite toxic. And in the real-world setting, talking to some of the medical oncologists that have utilized it, it sounds like they’ve gone down on the dose substantially to avoid toxicity. I would not utilize selinexor outside of the trial under any circumstances right now. I think that trial needs to be done.

DR LOVE: Yeah. You’re right though. That’s what we’ve seen in myeloma. Reduced dose, also going once a week, combining it with other stuff. And I hear that it’s pretty well-tolerated. So we’ll see. Of course, the key thing here is whether or not we’re actually going to see the efficacy play out.

I wanted to ask you another question kind of getting back to ovarian as well as endometrial. So in ovarian, you have the issue of whether IOs are going to play a role in any way. It has been looked at. But in endometrial, we also have the issue of whether PARP is going to have a role. And we have the DUO studies kind of looking at those. And I also saw that you had a paper about looking at trying to differentiate advanced endometrial cancer from ovarian cancer which, as a medical oncologist, I’m looking at that thinking, wow, there’s a pretty big difference there. So I’m just kind of curious if you want to maybe talk a little bit about sort of how you think through these issues.

DR SECORD: Are you referring to Dr Berchuck’s paper on the endometrial cancer and ovarian cancer and endometrial biopsies?

DR LOVE: Yes, exactly.

DR SECORD: Is that the one? Yeah.

DR LOVE: Yeah.

DR SECORD: Yeah. So that was something that really intrigued him I think for a while, and especially when it became apparent that we were no longer in an era of chemotherapy with paclitaxel and carboplatin only and that these patients need to be treated differently cycle 1, right? So he started advocating that for all the patients that came on with advanced metastatic disease, in terms of their tumor profiling, also have an endometrial biopsy, and identified over time, I think, it was about 30-some cases or so that were actually advanced endometrial cancers. And so in our practice if a patient has a uterus and you’re able to get an endometrial biopsy easily, then that’s what we started doing.

DR SECORD: I think it’s going to be a small number overall, but the difference in how you’re going to treat them is so striking with immune therapy being beneficial for a patient who has endometrial cancer versus not for a patient with ovarian cancer.

DR LOVE: Well, also, as I was mentioning, it seems like there’s some evidence that PARP inhibitors, specifically olaparib, actually benefit endometrial cancer. And I’m not sure if they’ve clarified, because you can see people with “endometrial cancer” who are BRCA. I don’t know if, I guess that’s endometrial cancer for BRCA patients. I assume they would respond to PARP inhibitors. But is that why you see benefit from PARP in these trials of endometrial?

DR SECORD: Oh my gosh, I don’t think we fully understand that yet. What is really exciting though is just I think within the last 7 days or 8 days, what we talked a little bit about in Europe, that there was a recommendation to consider olaparib and durvalumab for patients who have pMMR. So that’s patients who have pMMR advanced endometrial cancer, similar to the patient population that was DUO-E, gets treated with chemotherapy and durvalumab, and then subsequently gets maintenance durvalumab and olaparib. And the biomarker data has been presented. And what’s really fascinating in this area right now is, how can we best identify those patients that are going to benefit? And BRCA mutations may have something to do with it. However, one thing that’s also really tricky here is that if you have patients who have the high TMB tumors or the POLE ultra mutated, how many of those patients are going to have BRCA mutations that aren’t the driver of their disease? That it’s just this hypermutated cancer. And actually, they’re rare. So I don’t know how much that’s going to make a big difference or not. And then we don’t know what’s going to happen with the RUBY trial with the niraparib addition to dostarlimab. So this is going to get even more complicated.

DR LOVE: How often do you have a patient with metastatic endometrial cancer who is BRCA positive? Do you ever see that? How common is it?

DR SECORD: Yeah, we do see it. It’s not very common. I don’t know what the percentage is off the top of my head.

DR LOVE: It seems like it’d be tempting to think about a PARP inhibitor, at least in that situation.

Targeted therapy for gynecologic cancers

DR LOVE: Let’s finish out talking about HER2, which really sort of blasted into the scene recently with this pan-tumor approval for IHC 3+ that sort of really rocked oncology from the beginning to the end. And in the middle of that were a bunch of patients with gynecologic cancers that have been reported, I think, over the last year that had objective response. The oncologists get all excited about it because they’ve seen T-DXd in breast cancer and they see the duration of response that you see there. And now, even in HER2-low, they see this in breast cancer. So they — you have 40 patients and half of them respond, they’re ready to go. But I’m curious how you view all this going on and the big changes going on. What’s your take?

DR SECORD: Oh, I’m just really excited to see that we have more and more tools in our toolbox to treat patients with these cancers. We have moved to asking for HER2 IHC on our patients who have advanced or recurrent gynecologic cancers to determine if they are candidates for T-DXd. The response rates are higher than almost anything we’ve seen in this recurrent setting given the number of lines of prior therapy. So when you look at ADCs, I’m really excited about the T-DXd. I’m also really excited about mirvetuximab. So in ovary, we have some more options because mirvetuximab is available for patients who are FR alpha-high. Some of these other cancers like endometrial cancer and cervical cancer, there’s not as many options. And we do see patients that have HER2 2+ and 3+. So there’s a difference there too, right? The NCCN guidelines allow for 2+ and 3+ with recommendations for this therapy. And then the FDA approved it as a biomarker-agnostic indication for patients who have 3+ HER2 staining.

DR LOVE: And in breast cancer, if you’re 2+, then they look at FISH. And if it’s overexpressed, they call it HER2-positive. And if it’s not, they call it HER2-low. But outside of breast cancer, it doesn’t look like they quite got there yet. But I’ve got a feeling it’s going to move in that direction. We’ll see.

DR LOVE: In lung cancer, they routinely use it first-line for HER2 mutated, not overexpressed. And that wasn’t even addressed in the approval. And, of course, the other thing about T-DXd that is definitely on everybody’s mind, starting with breast cancer, is the potential for interstitial lung disease. And it’s really interesting, again, to see other specialties now trying to sift through that. They’re talking to the breast cancer people. They have their whole way of doing it. What’s the message that’s come through to you? The breast cancer people are doing imaging as frequently as they can of the chest looking for asymptomatic ILD. If they have symptomatic ILD, they stop it. But when I get outside of breast cancer, I’m not so sure what people are going to do. And you probably haven’t used T-DXd, but what are you thinking?

DR SECORD: Yeah, I’ve utilized it. The most important thing I think is having a really high alert sense for when you need to be worried about ILD. So it’s not just symptomatic patients, but it’s also if you start to see evidence of it on imaging. Because we do typically get imaging every 2 to 3 cycles. So even off protocol, get imaging every 3 cycles. And if you see something there that’s concerning for ILD, halt therapy even if your patient is asymptomatic. For patients who are symptomatic, sometimes our patients have mild shortness of breath, and it can be really hard to tease out. But if they notice a change in their shortness of breath, and you may have to elicit this history, they may not be forthcoming, then hold therapy, get PFTs, DLCO, and get a pulmonary consult. That’s been really helpful for me. I was really happy, you know, when we did the course together in Chicago where people were very forthright about their experiences and shared some stories where they had a patient die on this therapy. But in part, it was, I don’t think the extent of disease was recognized. And just having that really low threshold to act and hold therapy if you have any concerns.

DR LOVE: The last thing I was going to ask you about is one of the papers that was presented at ASCO who focused on endometrial cancer and obesity trends. And I also noticed, I think, that you were on a paper looking at high-fat diet and obesity.

DR SECORD: Oh.

DR LOVE: With Dr Bauman. I don’t know how involved you were with that. But any thoughts in general about diet, exercise, not so much in whether you develop gynecologic cancer, but sort of once you have it, whether or not it affects the progression of the disease?

DR SECORD: Yeah. So this is a study, this was my idea. So I am so lucky I work with Dr Vicky Bae-Jump on some studies, and she’s developed all these really awesome animal models to look at diet and obesity. And my interest for a long time has been about angiogenic genes and the tumor microenvironment. And so I was able to work with her on this project and our goal was really identifying if there’s differential expression of certain angiogenic genes based on type of diet and obesity. So just because you, you know, and they don’t always go together. You can feed an animal a high-fat diet, these animals are bigger but it may not be within the definition of obesity, but they’re certainly larger. But the concern here is high-fat diet and obesity leading to inflammation, and how they can propagate disease and make disease more aggressive. So the mice that Dr Bae-Jump worked with that were fed the high-fat had larger cancers. And what we were very interested to see was if there was differences in the angiogenic gene expression. We did find some differences, and these are just candidate genes for further exploration to really dive at that underlying molecular biology of what’s driving these cancers. There’s the obesity paradox with endometrial cancer. And the obesity paradox is that most of the obesity-related endometrial cancers, they tend to be well-differentiated, so those patients do well. But then there tends to be worse survival outcomes for patients who are obese when you account for those differences. So you have to be very careful that you do the correct statistical analysis to account for the confounding variables. So I know that’s long-winded. You can tell this is a passion of mine. But we need to really strive to reduce the incidence of endometrial cancer, and we have issues with trying to reduce the obesity rates and make sure that we’re all eating healthier diets.

DR LOVE: So our audience is probably tired of me bringing this up. But since you’re so interested in this, I have to tell you about it. Ruben Mesa. He’s a myelofibrosis person. And I was doing a program with him where they looked at these 2 new drugs to see whether or not it would relieve the symptoms of myelofibrosis in these people who were already on ruxolitinib. And there were 2 new drugs that completely flopped. But then I saw he had done a paper on a randomized study, randomized study of the Mediterranean diet. Do you know what the Mediterranean diet is?

DR SECORD: Oh. Yeah.

DR LOVE: Same thing, low fat, plant. Same thing that you were just talking about. But anyhow. They saw a difference in myelofibrosis symptoms on that diet.

DR SECORD: Wow.

DR LOVE: So I know it’s not pure science or whatever, but they think it’s, they call it the “anti-inflammatory diet.” And it kind of sounds like fat in general is maybe, I guess, does fat cause an inflammatory response?

DR SECORD: Yeah, there’s increased inflammation in the tumor microenvironment and actually throughout. And Dr Bae-Jump’s work has been incredible in terms of identifying different pathways that could be important in this, like p53 may be involved in insulin growth factor pathways as well.