Introduction

DR LOVE: Good morning, everyone. I’m Neil Love from Research To Practice, and welcome to “What I Tell My Patients,” as this morning we’re going to be talking about the management of endometrial cancer. This is the second of 10 programs we’re doing here at the ONS meeting. We’re really thrilled to be here. This is our 16^th year here today.

We have a great faculty today. As we do for all of these programs we have 2 physicians and 2 nurse practitioners, Drs Dave O’Malley and Shannon Westin here on the stage with us and also Ms Katie Lyle and Ms Jennifer Filipi, the nurses who will be discussing endometrial cancer here today.

As always we’re going to be emphasizing new developments, and there’s a lot going on in endometrial cancer. The Society of Gynecologic Oncology meetings were recently held and even more came out there, which we want to talk about today.

And for all of these meetings we will be talking about non-FDA-approved uses of agents at times. Please refer to the package inserts for all of the agents.

For everyone here in the room all of the slides you’re going to see today are on the iPad. Also there’s a survey for you to take there, and if you have any questions or cases to run by us you can do that as well. Welcome to everybody tuning in on Zoom. Maybe people are still lying in bed, but we’re welcome to have you here. And all the same functions are available in the chat room, as well, including a premeeting and postmeeting survey, which if you take you’ll get a lot more out of the meeting today.

We are recording all 10 of the meetings. We’ll let you know in a couple weeks when everything’s ready to go for your colleagues who weren’t able to make it here. And here are the programs that we’re doing here at the ONS meeting, and we like to think that we’re going to try to take things beyond these specific cancers and also talk about some general themes in oncology nursing, including a bunch of cases that we’re going to talk about today from the faculty, and one of the themes there is why was it different to take care of this patient than another patient with the same oncology situation but a different person, different attitude, et cetera.

And to try to enhance this year’s meeting, as we mentioned last night in our first meeting on breast cancer, we interviewed 8 nurses/nurse practitioners that we’ve worked with in previous ONS meetings who for various reasons were not going to participate this year, and we’re going to show excerpts of that. But if you go back — when you go back to your rooms or at any time if you go to researchtopractice.com/ONS2024clips we have 84 short videos from these 8 nurses there. We’re just going to show 2 of these today, but there’s much more from these people on the web if you’re interested.

So we’re going to focus now on endometrial cancer, and we’ll talk initially about the biology of it, and the big story with endometrial cancer is immunotherapy and also a lot of controversy and new developments as it relates to particularly the use of checkpoint inhibitor immunotherapy. We’ll also talk about some new, exciting developments, targeted treatments also, in the management of endometrial cancer.

But we just want to start out and just get in our mind the whole concept of taking care of patients. This is actually Kimberly Spickes, who happens to be a gynecologic oncology nurse, and she made some comments. Just to kind of get started, maybe Jenny you can comment on this, really what it’s like to walk into the room of a patient newly diagnosed with endometrial cancer, newly diagnosed with any cancer, what are some of the things that we think about as we go into the room. Here’s Ms Spickes.

MS SPICKES: I know that probably the biggest thing to remember is that patients are very anxious. They are anxious about their diagnosis. They’re anxious about the unknown. They have no idea what to expect. So I tend to start by saying, I know you’re scared, but it’s going to be okay. We’re here for you during your whole process. And just to kind of relieve a little bit of that anxiety. And also, it’s going to take multiple conversations of the same thing for them to really hear what you’re saying because they are so anxious. Their family members are anxious.

I really try to tell them everything to expect, good, bad and ugly. But one of the things I will say is nothing about cancer is black and white. It is very individualized.

The same person getting the same treatment is going to respond differently, side-effect-wise and the way their cancer responds.

Their biggest concern is, how am I going to feel? Am I going to be super sick? Am I going to be able to do my daily activities and take care of my family? Am I going to be able to live my life every day without feeling terrible?

DR LOVE: So really what we’re trying to do here this week is bring you the expertise of these people and the experience of these people, just the way we do when we pick their brains when we make rounds, except we have 40 of the best people you can ever make rounds with. Jenny, what are your thoughts as you think about walking into the room of a patient with a newly diagnosed cancer of any type, but particularly endometrial?

MS FILIPI: Yeah. I think first of all Kimberly says something very similar to what I say. This isn’t going to be easy, but we are here for you. I always like to say never worry alone. Starting that nurse/patient relationship knowing that they can call us. We are here. There’s different ways to call us now, over the phone and using the patient apps, ours is Patient Gateway, and just letting them know that yes, this is going to be hard, but we are here for you. And then empowering them, getting them into the side effects and telling them everything that could happen, not to scare them, but to let them know that this is going to be hard. There will be some bad days. And then whatever doesn’t work for this cycle we can try different things next cycle.

DR LOVE: So Shannon, we’re going to talk today about, as always, things on the very edge, the newest developments. Often it’s not, as Kimberly referred to, it’s not always that clear cut what to do. And one of the themes that we want to talk about this week is involving patients in the decisions and also self-advocacy for patients. I’m curious what your thoughts are about that, Shannon. There are patients who may be come in very passive, maybe aren’t going to want to be involved. Do you actually encourage self-advocacy?

DR WESTIN: Yeah. I mean, I think there’s a balance. It’s exactly what you said. Some people are very comfortable, they’re very savvy, they’ve done a lot of research, they come with all their paperwork, and they want to go through all the trials that they have found on the internet. And then you have other people that just throughout their time getting any type of medical care have always said well I’m going to do whatever my doctor tells me, right? So I think you have to kind of thread that needle or find that balance for that patient.

But for me I love what she said. You have to give as much information as you can. You have to know exactly what are the things that they are going to need to hear to help them make that decision, and then they feel more empowered. And you let them know I’m not going to — I don’t need to make this decision for you, but I’m going to help you get there and make sure it’s something that works for you and your family members.

DR LOVE: So Katie, another theme that we got into with the nurses, and again there’s an hour and a half of video content for you to go through all this, we can’t cover all of this in the live meeting, but in terms of the family, the assessment of the surroundings of the patient. Again, when you see a patient newly diagnosed with any type of cancer, but including endometrial cancer, what are you looking for in the family and the support system?

MS LYLE: Yeah. I think endometrial cancer is one of the hard ones when you’re newly diagnosed because you need more information, you need that staging, you need that histology to really understand what the next steps are going to look like, and so sometimes that can be hard to give a full picture to a patient when you’re first meeting them.

But in terms of family and friends and whoever comes with the patient I do try to pick up on cues. Sometimes you have that supportive partner or husband who’s already got the notebook, and they’ve already done some research and Googling and things like that, and they have a lot of really good questions about next steps. Other people come in, and they’re just kind of shellshocked by the whole experience, and so they haven’t even gotten there yet as far as knowing what to ask. They’re really just — they’re trying to learn as much as they can.

But I loved what Kimberly said, where you’re going to have to repeat things because it is information overload at that initial appointment, and so I think that’s where as they get into if after surgery they need treatment and things like that, just kind of reinforcing little things at each infusion treatment appointment becomes very helpful.

Incidence and Biology of Endometrial Cancer (EC)

DR LOVE: So let’s move into the specific management of endometrial cancer. And Dave, one of the interesting trends in oncology in general, we were talking about this last night in the breast cancer session, has been subsetting out, you know, different subsets of patients particularly based on so-called biomarkers, which we’re going to talk about all week now because that is really a big part of oncology, looking at the tissue, looking at the blood. Dave, what are some of the things that we look at in endometrial cancer, and can you talk a little bit about what we’ve learned about the biology of the disease particularly as it relates to immunotherapy, which seems to be really the area of great promise right now?

DR O'MALLEY: Well, it’s pretty amazing. We’ve always talked about precision medicine, personalized medicine, but we really are now living in that era. So when we see a patient with endometrial cancer the first thing we saw, are they deficient for their MMR, so dMMR versus pMMR or microsatellite stable versus unstable. So that’s the first question we ask, and it’s really the algorithm. And then when we look at the proficient patients we’d see if they’re p53 mutated versus nonmutated, and we call that the NSMB — no specific molecular profile.

But that first decision is if they’re deficient their response to immune therapy is markedly better. And so identifying those patients, particularly in the recurrent or metastatic setting, is so important, and then utilizing that information to educate shared decision, like we’re mentioning on the podium here, about what the best treatments are at that point.

DR LOVE: And so just to take this to the next level because if you had to pick up 1 biologic concept this morning it would be this MSI concept that we’re going to talk about, and interestingly, though, as you can see here, you see this in all solid tumors, particularly in adenocarcinomas, and as Dave alluded to we know the checkpoint inhibitors are very effective. Saturday night we’re going to talk about colorectal cancer and GI cancer, both situations, where you can see MSI-high. Shannon, can you talk a little bit more about what the difference is between MSI-high, MSI stable, how you explain it to patients and what the clinical implication is?

DR WESTIN: Yeah. I mean, I think there’s several different tests that you can use to try to break that down for the patient, but ultimately what I tell them is for MSI-high their tumor has a ton of abnormalities, a ton of mutations, and it makes it act a little differently, and it actually makes it more sensitive to specific immune type therapies. And then conversely those tumors that are more stable have less abnormalities. There’s not as much sensitive, although there might be some.

And what we tell all our patients is we want to test for that across everyone because not only does it potentially help guide therapy, but it also can potentially help us identify if they have a genetic syndrome called Lynch syndrome. And in the past we used to just test for Lynch syndrome in people that had suspicious histories; they were young, multiple cancers in the family, that type of thing. But now what we realize is we can identify probably more than 50% of Lynch syndrome that doesn’t have anything like that, right? They don’t have an age that would be suspicious, they don’t have a history of colorectal cancers, endometrial cancers. And so it’s a simple test that we do to look to see if there’s expression of a specific marker, a protein, or not. And then if not that might prompt us to go ahead and get genetic evaluation as well.

DR LOVE: And again, we know that these checkpoint inhibitors — and we’ll be talking about that, of course, obviously they’re used throughout oncology. And Jenny, just kind of curious. I guess one of the issues with checkpoint inhibitors is not just the fact that in some situations they can be very effective, such as MSI-high, but also they have a whole spectrum of side effects that we haven’t seen in oncology, very different than chemotherapy.

What are some of the things that when you are going to use a checkpoint inhibitor, and now in endometrial cancer it’s used in both MSI-high and MS-stable, we’ll talk about how that might be different, but what are some of the things you’re thinking about, particularly in terms of contraindications to using these drugs because if people already have an autoimmune problem you may make it worse. So what are some of the things you’re on the lookout for in terms of prior autoimmune problems?

MS FILIPI: Good question. Well, first of all I think you’re exactly right. You talk about the chemotherapy, and then you have to switch and completely talk about okay, so — and we’re going to add pembrolizumab or dostarlimab, and it comes with a whole different set of side effects, and probably you’ll be fine with a little fatigue, but also it can cause autoimmune issues. So people with some sort of GI autoimmune disorder or hypothyroidism it shouldn’t be a huge deal because you can kind of just fix that, but that is something to keep in mind.

I’m trying to think. I have a patient with a history of colitis that we ended up — we did end up starting her on pembrolizumab, and she’s done fine with careful monitoring, but would be someone that the first sign of some diarrhea you’d want to kind of bring her in and do more testing or really, really keep an eye on if it’s getting to be more than 2 or 3 times a day. Maybe do some stool testing. Sometimes these people will need steroids to fix that.

DR LOVE: Katie, how do you explain to patients what immunotherapy is? What checkpoint inhibitors are?

MS LYLE: Yeah. So patients are very interested in like how their medicine works, and they’re not always looking for a really in-depth explanation, but they’re just curious about it. And so I explain that with immunotherapy it actually activates their body’s own immune system to help fight the cancer. And so when we put patients on immunotherapy we often do PD-L1 testing, so that may be something that you’ve heard of or are familiar with.

And so I basically explain we’re doing a test to see if we think your tumor has certain characteristics that would help it respond better to immunotherapy, and it’s going to activate your body’s own immune system to help fight the cancer, so when that happens we can have all of the itis-type side effects. And so then I kind of go through and talk about dermatitis, thyroiditis, colitis, and that’s kind of my entry into adverse effects.

DR LOVE: There’s a saying; if it ends in itis you can see it.

MS LYLE: Yeah.

DR LOVE: So Dave, any other thoughts in terms of the spectrum of toxicity that you see with these agents?

DR O'MALLEY: Well, first of all, for the people in the audience, the multidisciplinary approach and the entire team is so important. As you all know, these phone calls come in through the nurse line, and identification and really having that suspicion, that high clinical suspicion of anybody on immune therapy or who have had immune therapy in the past to make sure we’re thinking is this an immune-associated toxicity. So I tell my patients about 35% plus or minus 5% will have some sort of immune-associated toxicity. Most of those are manageable; a lot of thyroid, a lot of mild skin.

We then have within that 35% 5% to 10% which will require more serious, high-dose steroids or some other immune modulations to include potentially admission to the hospital. And then of that 5% to 10% 1% to 2%, when I say, life threatening or life altering. If we give somebody type 1 diabetes or we burn out their pituitary it is life altering. If you kill somebody with a myocarditis, which I’ve done, unfortunately, it is obviously life altering.

So I lay it down in those pretty simple numbers but looking across solid tumors it’s really unbelievably consistent. We could argue a little bit about the absolute numbers, but across solid tumors where immune therapy works so you have it on long enough to see these toxicities, that’s the numbers I discuss.

DR LOVE: I want to hear how this plays out in practice in some of your cases, and Shannon, I want to hear about your 65-year-old patient in a second. But first just to come back to you, Dave. One of the things that’s been discussed over the years is if a patient has an autoimmune toxicity, and that could be a dermatologic problem, or a thyroid problem, or as you mentioned even something much more serious, type 1 diabetes, is it more likely they’re going to have benefit, Dave? Because you’re kind of showing that the immune system’s getting revved to cause a toxicity, some people think well those are the patients that are going to respond. Do you buy into that, Dave?

DR O'MALLEY: Absolutely. I always tell my patient we have good news and bad news. The bad news is you have an immune-associated toxicity. The good news is in patients with immune-associated toxicity they seem to do better from the therapy. So if somebody’s having a really bad toxicity I don’t say that, but if they’re having a mild toxicity I’ll bring that up.

So it really is interesting, again looking across solid tumors, that if you have a toxicity you actually have slightly better outcomes.

DR LOVE: Although that is a bit controversial. But Shannon, let’s talk about how this plays out in practice and also the fact that some of these MSI-high patients actually have a genetic syndrome. Maybe you can comment on that. What happened with your patient? You had a 65-year-old patient who got chemo and dostarlimab.

DR WESTIN: Yeah. So this patient had a mismatch repair-deficient endometrioid type endometrial cancer, came very symptomatic from Stage IV disease and was actually bleeding and had liver metastases and abdominal metastases. She ended up having to get radiotherapy kind of to stop bleeding in a palliative setting, and then we were able to transition and get her onto treatment. And so she was receiving paclitaxel, carboplatin, and dostarlimab. And we were treading very lightly with her because she already had some colon issues, she had just gotten the radiation, and we wanted to make sure that we balanced that, and we could take care of her and not have one of these side effects that makes the patient not want to continue.

The great news is that she had a complete response to her therapy. Her tumor melted away with the chemotherapy and dostarlimab, and now she’s actually just on her maintenance dostarlimab and is doing very well. The only side effect really that she came into was a rash, just a light rash, responded very well to some topical steroids, and really she has flourished. It’s been incredible to see how well she’s done.

DR LOVE: So we don’t want to say every patient responds like this. There are plenty of people who do not respond at all, but you do hear stories like this, and you hear them in many different types of cancers, particularly with MSI-high. I see here, too, as you mentioned, she did have some dermatologic issues. And that’s something that, Katie, you hear a lot about, skin issues with people on IOs or immunotherapy. Again, any experience with that? Any thoughts about it?

MS LYLE: Yeah. I’ve had many patients who have had — I would say the dermatologic reactions or kind of more common. And it’s interesting with immunotherapy not all of the side effects happen at once. There has actually been some information that shows that some of the side effects are more prone to happen kind of early on into therapy, some are more delayed, and you can even have some that are quite delayed, but — I would say after somebody’s been on it for years. But the dermatologic toxicity is one that does occur earlier on in therapy, and I’ve seen it anything from mild skin rash but nothing that itches too much. I can usually prescribe some topical steroids and things like that, and if it regresses we’re good. If it stays a Grade 1 I don’t have to really disrupt treatment or do anything.

But I have had some patients where they certainly have had more severe rashes, rashes that take up more of a percentage of the total body surface area, and so those can be a little bit harder to manage. There are times where I’ve had to hold therapy. We have talked about some patients needing a steroid taper and things like that. I’ve had to do that 1 time. I’ve also referred to derm a couple of times when the things that I have tried just have not gotten that patient back to a Grade 1 or where I need them to be. So I have utilized the help of dermatology as well.

We are lucky as APPs to have some really good guidelines, though, when adverse events happen related to immunotherapy. We do have resources where we can go and look up each adverse effect and kind of have an algorithm for what to do, and that kind of helps guide what our decisions are.

Use of Immune Checkpoint Inhibitors as Monotherapy for EC

DR LOVE: So Dave, we put up there a couple different checkpoint inhibitors, pembrolizumab and dostarlimab. There are many others that are approved and being used in oncology. What do we know about differences between these? If you see a trial that uses one of these particular agents, then in general — and that trial’s positive, then in general, we talked about this yesterday with the CDK inhibitors, you go with what the trial shows. But what do we know about the differences between these agents, Dave? Are there substantial differences?

DR O'MALLEY: I don’t think there are substantial differences. The first 2 trials are PD-1 inhibitor, and we’ve talked about those, pembro and dostarlimab, but now we’re seeing atezo and durva, which are PD-L1 inhibitors. So I think as we look at some of the subtle differences and use cross-trial comparison, which we know is not valid but we do it all the time, when we’re trying to differentiate those with the approval of both pembro and dostarlimab in uterine cancer we’re using pretty much only those in our clinical practice. I think as we see potential availability of some of our other checkpoint inhibitors, like the PD-L1 antibodies, we’ll have more experience on that. But right now there’s not significant differences, there may be some subtle differences, but they’ve never been compared, obviously, in endometrial cancer.

DR LOVE: So I want to get a little bit more of a flavor, again, of how this plays out in clinical practice. And Katie, you have a 68-year-old woman who got, again, chemo and pembrolizumab — the patient had dostarlimab, then pembrolizumab maintenance. Can you talk about what happened with her?

MS LYLE: Yeah. This is a patient who I think about 4 years ago, she was in her mid 60s, came into our clinic and was shocked to have a diagnosis of Stage IV endometrial cancer. And it was actually a — it was actually a neuroendocrine tumor of the uterus, so it was also an interesting histology which made it not exactly straightforward for what typically comes in.

So she is an extremely healthy patient. She just came and saw us for a follow-up visit earlier this week. But she was extremely healthy. She was not expecting a diagnosis like this. She had her surgery, was treated with chemotherapy. But right after surgery we were sending her tumor off for testing to see kind of what biomarkers we had, which was going to help determine what we did for her treatment because she really wanted to be as aggressive as possible and do whatever she could.

She comes in. She travels a lot. She’s got grandchildren. So those are her priorities and kind of what she lives for. So because of that she wanted to be very proactive. So we got her testing back, and she was MSI-high, which was great news in terms of counseling her because we talked about adding immunotherapy to her chemotherapy that she was getting. And so we did that for 6 cycles, and then after she had her post-treatment scan we started her on maintenance pembro, and she did that for 2 years.

As far as tolerability, she did have some like oral/gum inflammation, so I did have to do a dex oral rinse for her, and that really did help to maintain that. And interestingly enough, like I was saying before, this is not something that happened in the first 6 months of her being on immunotherapy. I think it happened about a year into her receiving immunotherapy and was something that she kind of dealt with for the last year of her maintenance. That has since resolved now that she has completed the maintenance and is on surveillance.

She comes in and has scans periodically because of her initial histology. And this past week she came, had a scan, and it was still completely clear. So she had a complete response and has had a durable response about 2 years out.

DR LOVE: What’s it been like to take care of her?

MS LYLE: What’s it like to take care of her? It’s great because she comes in now, and she’s just so thankful. She had overall a great experience so now I get to hear about her kids — her grandchildren and trips that they go on. She volunteers with one of our local support groups called CanSurvive, and so I get to hear about the luncheons that they have and the education. She’s very interested now in giving back to the oncology community and kind of working with patients who are now going through what she navigated a couple of years ago.

DR LOVE: Can you imagine the day when most — that would be a typical case in your practice? I mean, that’s obviously where we’re heading or trying to head towards.

First-Line Therapy for Primary Advanced or Recurrent EC

DR LOVE: So let’s get back to the clinical research issues, and Dave, we’ve seen over the last year or 2 pretty — typical kind of scenario in oncology. And again, as we said last night, we’re going to talk about it in endometrial cancer, we’re going to talk about oncology in general also. In oncology in general when you develop new therapies then you start moving them earlier and earlier. So where we were a couple years ago, Dave, was in the microsat — maybe you could talk about where we were a couple years ago in terms of the treatment of metastatic disease, both MSI-high and MS-stable and then what happened in terms of — particularly 2 big trials came out, so-called Phase III trials, that are really trying to make definite statements about how you should treat cancer. Dave, can you capsulize the wild story that’s happened over the last year or two?

DR O'MALLEY: Well, our backbone was always carboplatin/paclitaxel. And that’s really all we had. We tried to change it around, but the reality is that’s what we had. And then with the publication of both RUBY, which was the dostarlimab trial, and GY018, which was the pembro trial, we saw that in patients who were microsatellite — excuse me, microsatellite high or deficient for MMR that they had about a 70% improvement in their outcomes of their patients. And what’s amazing with that, when you’re talking about curves and how much they’re doing — how much better they’re doing, 70% is great. But when you look at the curves, when you look at the flat or the tail of the curve, we are curing, I know that’s a dangerous word, I’m sorry, but I think it’s the reality; we are controlling disease long term and probably curing patients at a markedly higher level. And that’s really what we need to start talking about in recurrent metastatic disease. Yes the differences are amazing, but are we curing more patients with metastatic recurrent cancer?

So we saw that in the deficient population unbelievably consistent with a 70% improvement. More modestly in the proficient or the microsatellite stable group we did see improvements, 40-ish percent, about 40%, and we did see separation of those curves and those outcomes of those patients. When I say separation of the curves I mean those outcomes of the patients, particularly in the tails, with about a higher rate of about 15-ish percent plus/minus, of looking like patients who may be cured of their recurrent metastatic disease.

So drop the mic with the dMMR patients, or microsatellite-high patients. Drop the mic. Like without debate all those patients should be getting carboplatin/paclitaxel with IO therapy at this time.

The proficient patients we’ve shown incremental improvement but there’s still work. And Shannon’s going to talk about her trial, DUO-E, which is looking at some of the things we’re adding, trying to add to checkpoint inhibitors to improve upon the outcomes.

DR LOVE: But Shannon, again, this is kind of a classic issue in oncology, are you better off moving up. Until a couple years ago we would give, for example, lenvatinib/pembro, a combination we’re going to talk about in a second, which includes an IO second line.

DR WESTIN: Right.

DR LOVE: Now we’re talking about moving the IO into first-line therapy. And the question is, is the patient really in the long run going to be better off. If in the long run they’re going to live the same amount why not delay the therapy a little bit? Can you talk a little bit, again, about what we learned from these trials in terms of those questions, Shannon?

DR WESTIN: Yeah. I mean, we always talk about sequencing, right? Like do you want to give everything at one time being mindful not only of future treatments but also the amount of treatment the patient’s getting at a given time, the cost, financials, toxicity, all of that needs to be considered.

And you’re right, Neil, like, whenever we see something good in third, second/third line we’re like okay, can we give it earlier. But the question is if we give it earlier can we get more cures, right, can we avoid that? And I never want to say to my patient “Well, we’re going to reserve this for when you’re cancer comes back” because that sounds terrible, right? Oh, you know what, it just puts them into a place of a loss of hope, right, because you’re telling them well there’s nothing we’re going to be able to do to make this go away completely; it’s going to come back.

So that’s kind of how I think through it. I think lenvatinib and pembrolizumab was absolutely practice changing in the second line. Now we’re in a position where we’re wondering what is the role going to be, right, because if we give the majority of patients chemotherapy with immunotherapy can we then use lenvatinib and pembrolizumab in the case where the cancer does come back. And I think we’re rapidly trying to gather some of those data to help us advise patients that can you go back to the well and add lenvatinib and still get benefit, and we don’t know the answer. There’s some small studies that indicate that maybe yes, you can. But for me, especially with the mismatch repair-deficient patients, if we can cure them in the up front there’s no question that’s what we should be doing rather than reserving these treatments for later.

DR LOVE: So let’s go to another patient, again, to see how this plays out. It always catches my attention when I see a patient in their 80s, Dave, particularly that go on a clinical trial, which your patient did, the so-called RUBY trial. Before you comment on this patient, just to come back to you, Jenny, in terms of clinical trials and also Dave’s about to — she was 85, Dave, and went on the trial?

DR O'MALLEY: She’s 85 right now. When she went on the trial she was 81.

DR LOVE: Any thoughts about how patients react when you bring up the issue of being on a clinical trial, particularly the RUBY trial, where you’re using agents we’ve already used, but we’re just kind of using them earlier? From your point of view how do you present this to patients? It does offer the opportunity of a newer therapy, but how do patients react when you bring up the issue of trials?

MS FILIPI: Yeah. Well, it depends on the person, right? So maybe a more savvy person is expecting the conversation. Someone who is more reserved may I think — sometimes you hear clinical trials and patients are thinking oh gosh, clinical trial, is this the end. Am I going to be experimented on, that kind of thing. And that’s really far from the truth, especially at this point with all of the great trials and exciting drugs we have.

So I do kind of try to shift the conversation to hey, this has actually worked for a lot of people. The side-effect profile, I always go over that. And then just making sure the patient is devoted to coming in all the extra time. There could be extra biopsies, extra trips to the hospital, extra imaging, and just make sure they’re really onboard with all of that.

But I think a lot of — we’ve seen a lot of people on clinical trials have great responses and sustain those responses, and then they get to help patients, when the trial is positive, hopefully, they feel like they’ve contributed as well.

DR LOVE: Yeah. I interviewed — sometimes we do videos with patients, and I interviewed a patient who was on a bispecific, which we’re going to talk about tomorrow as it relates to lymphoma, but who was on a bispecific for myeloma, no side effects, remission, been on it for a year and a half, and the day I did the interview was the day the drug was approved. So he’d been on it for a year and a half already when the drug was approved, and that is what you’re talking about, offering something that you can’t get outside of a trial.

MS FILIPI: Yeah, and just 1 more thing. A lot of clinical trials have line limits, right? So when you’re talking about the next line of therapy sometimes I’ll bring that up and say yeah, we could do standard of care, we can pull chemo off the shelf, but you’re eligible for this now. And especially someone who may not be overly symptomatic, and we maybe have the luxury of time, I always mention that just to say it might not — you might not be eligible forever.

DR LOVE: So what about your octogenarian, Dave?

DR O'MALLEY: Yeah. I think we’re paternalistic when it comes to our older patients. And there’s overwhelming data at this point that just ask the patient what they want to do, what are their goals. And when we look at the data objectively patients in their 70s and 80s want to be offered the standard therapy. And so I really try not to be paternalistic when I talk about this is where we are.

From a surgical standpoint I think it’s a little different because they have a significantly higher rate of complications. But from a treatment standpoint when we look at the tolerance they seem to do pretty darn well compared to their — younger patients.

So I talked to her about her options, and I talked about clinical trials. And one of the things I would say is tomorrow’s therapies today, right? The other thing I say, and we probably don’t talk about this enough in clinical trials — one of the reasons I love clinical trials is because we’re going to take care of our thousands of patients we take care of. But if you participate in a clinical trial you’re not only helping the thousands of patients you’re helping generations, potentially generations of patients that follow, and I tell my patients that. If you participate in this clinical trial you will be helping potentially generations of patients.

So she participated on RUBY and dostarlimab. She actually had some recurrent pancreatitis, which we were really confused about. We thought it was IO associated. We went back and forth. We ultimately unblinded her to confirm she was on the IO at 2 years of therapy. So she received 2 years of therapy. She continues to be in a partial response. She has a little, small pelvic lymph node that persists so we can’t call her a CR. She’s essentially CR, been off therapy for a year now. I just saw her in the last few weeks. Continues to have a PR with disease control, and she’s doing great. The pancreatitis resolved once we stopped the immune therapy.

DR LOVE: Did she actually have pain and clinical pancreatitis or blood work?

DR O'MALLEY: No. That was the challenge. It was subclinical. She was having — she bumped up her amylase and lipase. It was a really, really interesting presentation. And she had some pancreatic cysts and a long history of us following these. So it really — because of the challenge of us making the diagnosis and because the treatment that was required in this lady in her mid 80s we elected to go ahead and unblind her, and actually by stopping therapy it resolved spontaneously, and she did not require high-dose steroids.

DR LOVE: So let’s do 1 more case, and then we want to have a little interlude discussion. But Jenny, I think it’s your case. Let’s see here. Yeah.

MS FILIPI: The 66-year-old?

DR LOVE: Right, right. Yeah. What happened with her?

MS FILIPI: Yeah. So she is a lovely lady, an RN/PhD at a local university, comes in with unfortunately a recurrent Stage I endometrial cancer. But she is dMMR, so we were able to offer her immunotherapy with her chemotherapy. And she was excited to get going. She was kind of into the new combo. And we went through all the side effects and when to call, and of course being a nurse she was all over that.

And she called 11 days in, and one of our nurses, our excellent nurses, picked up on it right away. She had a full-body rash. She came and saw me later that day, and it was the worst rash I’ve ever seen. It was covered head to toe.

We admitted her to the hospital. We had to start IV steroids, get our severe immunotherapy complications team involved. Dermatology was involved so it was confirmed ICI dermatitis. Thankfully it wasn’t — didn’t develop into a Stephens-Johnson or anything like that, but it was really hard for her, and scary for us as well.

And when she came back after she had recovered and gotten through her steroid taper the conversation was we could try again. It might not happen again, or it could be awful, and it could happen again. It could be worse this time. Dermatology was involved and recommended adding an immune modulator. And she is a very intelligent, informed person, and talk about empowering the patient and shared decision making, she did not want to do it again. And maybe one of us would. Maybe we wouldn’t. It’s individual. So she did not receive any more pembro.

DR LOVE: What’s her current status?

MS FILIPI: She’s just getting through her last carboplatin/paclitaxel without —

DR LOVE: She might be cured.

MS FILIPI: I hope so.

DR LOVE: I mean, 1 dose. It’s possible. She had this huge autoimmune problem. Maybe the same thing happened in the tumor. Dave, my story of interviewing this patient, your patient maybe is alive today because she went in that trial.

DR O'MALLEY: Yeah.

DR LOVE: When you think about it.

All right. Well, let’s — we brought up the issue of self-advocacy, and that really is a major theme to this, and I’ll just tell a story. Shannon, I want you to try to guess the answer here.

DR WESTIN: Uh-oh.

DR LOVE: We presented a patient at a webinar recently with — actually had upper GI cancer, metastatic, and the patient gets worked up by a medical oncologist, makes a recommendation, and the patient goes, “Did you check for MSI?” Doc says no. They checked for MSI. It’s MSI-positive. He fires the oncologist, goes to a tertiary center because now he doesn’t trust the doctor, gets treated with an IO, doing great. So my question is, what was the occupation of the patient?

DR WESTIN: Oh. Like an engineer? I feel like my engineers.

DR O'MALLEY: That’s so true.

DR WESTIN: They have like their detailed notes, and they like —

MS FILIPI: Graphs.

DR LOVE: Katie?

DR WESTIN: Graph their labs.

DR LOVE: What do you think?

MS LYLE: Pathologist?

DR LOVE: So come on. It’s so obvious. An attorney.

DR O'MALLEY: I was going to say it.

DR WESTIN: I was thinking of the detail oriented.

DR LOVE: That’s what we want, right? We want people to be attorneys for themselves, to fight for themselves. But anyhow, here’s Ms Richards.

DR RICHARDS: I think it’s important for patients to be involved in the decision-making process because at the end of the day they’re the ones that have to incur the time toxicity, the financial toxicity, right, associated with the treatments, as well as the side effects. And so making sure that patients understand that they do have some choices, and also by giving them choices it gives them a little bit more control over their disease, right, because they’re in a situation where they don’t feel like they have any control, and so anything that you can do to give that power back to the patient is important.

And it may be that the patient doesn’t want to make the decision, right, and they want to defer to you, and that’s okay because they’re still making that choice. It’s important for us as providers to understand that, that part of the shared decision-making model is also giving some control back to the patient, even if they decide they don’t want to make the decision, that’s still letting them be in control of that decision.

And then I think the other piece of that is that we may not always agree with the decision that a patient makes, right? Like we may be going this is not the best decision to be making. But at the end of the day they’re the one that is being affected.

DR LOVE: So Jenny, any thoughts? And getting back to your patient who was a nurse, how was it different to take care of her compared to other patients? It sounds like she was very involved in trying to understand what was going on.

MS FILIPI: Yeah. When Tiffany was talking I was thinking wow, that is the perfect story for the story I just told. It’s different when you’re taking care of a nurse or another medical provider, right? They’re usually more informed. They have been in it, especially oncology nurses. You’ve maybe worked on the floor and seen the awful things, but maybe you’ve seen some good things too. But I think just being more informed and knowing the data a little more you can have more intricate conversations around that. And we did. And at the end of the day she felt the risk was just too great, and we needed to respect that.

DR LOVE: So yeah. We actually — last night we were talking about a patient who also was a nurse in the same — similar situation.

Let’s talk a little bit about — we mentioned the fact that we have seen some really exciting advances in terms of immunotherapy, particularly in the subset the so-called MSI-high, but I want to talk about now new research, particularly in MS-stable, which as you heard the results are not anywhere near like what we’re seeing with MSI-high.

And Shannon, you actually presented a trial that got a lot of attention looking at a strategy. We’re going to be doing another program here on ovarian cancer, and of course there we’re going to be talking about PARP inhibitors. But you talked about bringing PARP inhibitors into the management of endometrial cancer. So what was the thinking behind that idea? What did you see with the study and kind of what do you think it means?

DR WESTIN: Yeah. So you’re right. We’ve really prioritized PARP inhibitor development in ovarian cancer because of the proportion of patients with homologous recombination deficiency and BRCA mutations. And actually we took that back, that lens back to endometrial cancer and found there was a really high proportion of patients or tumors with — endometrial cancer tumors that had abnormalities that might predict benefit from PARP, so not only mutations in things like BRCA but also mutations in something called ERD1A that seemed to predict benefit from PARP.

And so we thought it would be interesting to kind of look broadly across advanced and recurrent endometrial cancer and see if we could improve outcomes with the addition of PARP to immunotherapy. And so this study started right around the same time as the RUBY study, the GY018, but we wanted to kind of look 1 step further. So it had an arm of chemo, an arm of chemo plus durvalumab, which is the PD-L1 inhibitor, and then an arm of chemo plus durvalumab and then olaparib maintenance, which is the PARP inhibitor that was used.

And the bottom line is this is a positive study. Both the durva arm as compared to the chemotherapy control, as well as the durva/olaparib arm as compared to chemotherapy control, improved progression-free survival for the patients, so how long they could go without their cancer recurring.

But when we teased out the biomarkers that’s where I think it’s the most interesting. The population that was mismatch repair deficient, or MSI-high, didn’t seem to get that much more benefit from the addition of PARP. I think it’s because they do so well because the mechanism of action would indicate that they would have had more benefit, but it was — I think that the patients were just doing so well that we didn’t see that much more improvement. But conversely in that mismatch repair proficient group that’s really where the addition of PARPs doubled the 18-month progression-free survival with almost 50% of patients alive and progression-free at 18 months, which was very impactful.

DR LOVE: So in a second I want Dave to kind of remind us about how PARP inhibitors work and maybe why in this situation they may be helping. But what about also in the other study, the RUBY part 2, they looked also at PARP, but now niraparib with dostarlimab. Did they also — what did they see there? What are they seeing?

DR WESTIN: Yeah. The good news is the data are fairly consistent, so that indicates that we are on the right track. They looked at the combination of dostarlimab with niraparib again in that maintenance strategy versus chemo, and they saw an improvement in progression-free survival across the groups.

The problem, and this is always the way this is, when you look back at your trial designs, and this is both for my trial, the DUO-E trial, as well as the RUBY trial, is that we don’t have a PARP-alone arm. So the question comes, is there a population of patients who would benefit just from PARP, like, could we avoid a 4-drug combination? So I think that would have been nice, but it’s also more patients and more cost and more time, and so you do the best trial that you can to get it done in a timely fashion. So we don’t have the answer to that.

DR LOVE: So in a second I want to hear about your 66-year-old patient whose grandfather was kidnapped by Clyde of Bonnie and Clyde. You probably don’t know who Bonnie and Clyde is.

DR WESTIN: It’s a true story.

DR LOVE: But anyhow. So Dave, can you just — again, we’re going to get into this of course with our ovarian session, but can you just kind of talk a little bit about the PARP inhibitors that we have, the difference between them, and how they work, and tolerability issues?

DR O'MALLEY: So there are really 3 PARP inhibitors for ovarian cancer which are available in the US for ovarian cancer, so olaparib, rucaparib, and niraparib. I really should say niraparib second. The reason I put olaparib and rucaparib together is they’re both twice-a-day dosing and niraparib is once-a-day dosing, so that’s a big difference.

We talk about PARP trapping and different mechanisms of the treatments. The reality is these 3 agents are more similar than different, especially olaparib and rucaparib.

So we think, we think how PARP inhibitors work are disrupting the machinery of the DNA repair mechanisms. So by disrupting that machinery with the cells trying to stay alive with repairing changes in the DNA you disrupt that machinery and then that leads the cells to killing themselves, essentially, dying.

So it makes sense in uterine cancer, and I think Jen said it beautifully, that the MSI-high or the dMMR patient doesn’t seem to benefit. But there’s clearly some signal there in the MS-stable, or the proficient patients. And we just had a conversation for 2 hours last night. I had a meeting just talking about RUBY and DUO-E. For 2 hours that’s all we talked about. So we really need to dive down into this personalized molecular signature, to reiterate what Shannon said, in identifying the patients that are most apt to benefit from this disruption in the DNA repair pathway.

DR LOVE: So you know, I mean, in ovarian cancer, Shannon, we have all these genomic markers. Certainly BRCA is a big one, but there are many others, PALB2, et cetera. Do they predict who benefits in this situation?

DR WESTIN: So TBD. So we are doing a deep dive, and we just had a conversation about this. We’re doing a deep dive. I’m very fortunate we have a lot of — a large wealth of translational data from the DUO-E study that I hope will help us define that.

The bottom line. What we’ve looked at so far, as expected, patients that have BRCA mutations or other relevant mutations in the homologous recombination pathway did better. They had a 70% reduction in the risk of progression. Small numbers. This is very small numbers, about 12% of the whole trial had these, but those patients that got a PARP that had those aberrations did extremely well. So that’s probably going to be a low-hanging fruit.

What we don’t know yet, and what I’m hoping we’re going to figure out, is what defines homologous recombination deficiency in endometrial cancer, right? So there’s the test that people can get through different genomic platforms where you can get a so-called HRD score. That score is based on ovarian cancer, and we don’t know if that’s the right cutoff for endometrial cancer. So what we’re going to try to do is tease that out with these data.

DR LOVE: So Katie, if this does play out, and of course we use, as we mentioned, PARP inhibitors all the time in ovarian cancer, if they do come in here, which seems not unlikely, what are some of the toxicity issues that we’re going to be dealing with? What are some of the things you talk to patients about who are about to begin a PARP inhibitor?

MS LYLE: Yeah. We have years of experience managing patients who have been PARP inhibitors, and so I tell patients it’s just in a different disease type from yours. I think kind of going back to patients being empowered and doing their own research and reading. I have a lot of patients who come in trying to find information, and so I do have to have a conversation saying right now, unless you do a deep dive and come across more of the research type papers you’re not going to find mention of these medications as standard of care approved by the FDA in your tumor type.

However, these are not brand-new drugs. These are medicines that we’re very comfortable managing. We’ve been doing it for years. If you include the years in the clinical trial setting before things get FDA approved we’ve really got a lot of years’ worth of managing these things. And so I think letting someone know that provides a sense of comfort in saying okay, this is not some brand-new thing that was created yesterday and nobody knows what it’s going to do to me in terms of side effects.

So that kind of leads to me into talking about the most common side effects with PARP inhibitors, and there are some nuances between different PARP inhibitors. I’ve had patients most recently on clinical trials with olaparib specifically, but in general I say most of my patients, most all have some degree of fatigue on PARPs. Many of these patients have received chemotherapy and things like that, so the fatigue isn’t as severe as it sometimes is on chemotherapy, but it’s more persistent, so it’s something that they kind of have to live with more long term. It’s very rare that I have to discontinue a PARP inhibitor for fatigue. It’s just something that comes up at almost every visit. I ask about it. I make sure it’s not getting worse, and I make sure they get out of bed, do what they want to do and don’t need a dose reduction or something like that.

Then you also have the hematologic toxicities, so I tell them every time you come in we are going to check a CBC. I want to make sure you’re absolute neutrophil count, your platelets, that those 2 are not dropping. I’ll check the hemoglobin/hematocrit. I do have patients on PARP inhibitors that do require a blood transfusion from time to time. Sometimes it’s a one-off thing, and I don’t necessarily have to play around with their dose. If I see it become a repeat issue we do talk about dose reductions and finding that level that kind of agrees with their body and their body’s ability to maintain adequate counts so that we can keep them on therapy.

PARP inhibitors also can cause some GI toxicity. It’s not nausea and vomiting and extreme sickness like sometimes patients get with chemotherapy, especially platinums. So I try to explain the difference there. Sometimes it’s more GI cramping or nausea or just a feeling of feeling sick after they take their dose, so we try to give multiple antiemetics to have on hand so that they can take an ondansetron 30 to 60 minutes before they take their PARP inhibitor.

So I basically just try to reinforce that we do have a lot of experience giving this exact type of medication, this is what you can expect, and these are the ways we manage it.

DR LOVE: Good answer. I just said like what are the toxicities, there are the entire spectrum of toxicity. Awesome.

One other thing I’m curious, Jenny, a tricky, really tough problem that comes up every now and then in oncology. There was actually a few months ago a press release about secondary cancers with CAR T therapy that got everybody all freaked out at the ASH Meeting. And there is an issue out there with PARP inhibitors about an increased risk of acute myeloid leukemia and MDS. Very small, particularly when you use it in earlier stage with people who’ve had prior therapy, but it’s there. Scary to even think about, of course, and the benefit of the therapy much greater than the risk, but still the idea of a therapy that might cause an acute leukemia. Do you bring this up to patients? And how do you discuss it with them?

MS FILIPI: Yeah. I definitely bring it up. It’s usually the last thing I bring up, saying we know this drug well, and we’ll go through all the side effects. I won’t do that. Katie had put it perfectly. But yes, I do bring it up. I say it’s a very rare side effect, and it’s picked up on blood counts that we’ll do usually every month. I think the side effect rate is maybe 1% to 2%.

And so they need to be aware that this can happen, but they also need to know that it is a more rare side effect that — and even if we — it does happen, and I have seen it happen, not up front but someone who had had niraparib but with a second recurrence, and she had been on niraparib about 2 years I believe. So I have seen it happen, but that’s just 1 time in my 9 years of experience. So I do bring that up, and I think that’s helpful for people to know. And she’s doing fine. She was treated for AML and is okay.

DR LOVE: So in a second I’m going to come to Dave and ask him how he manages fatigue and what he tells patients about AML with PARP inhibitors. But Shannon, first what happened with your patient who actually went on the DUO-E study, a 66-year-old woman. What happened?

DR WESTIN: She had recurrent endometrial cancer, disease in the peritoneum and lymph nodes, and was treated on the DUO-E regimen. And obviously it’s a randomized trial, so we never really know what patients are getting, but we highly suspected that she was on the interventional arm, as she had a complete response to therapy during the combination chemotherapy and durvalumab portion, and then within I’d say like a month, month and a half of starting the olaparib portion with the placebo her hemoglobin dropped markedly and made it pretty clear.

So she was on that. She is 3 years on maintenance now, and similar to your experience, Katie, she comes in every month on this trial, and we basically chat. She’s from the valley, which is a little bit of a — low-levels of medical care available, especially for very specific cancer types. So she travels about 6 hours every time she comes to see me, and she gets her money’s worth by chatting. Like she’s a little chatterbox. She tells me all these stories. And that’s what I shared with these guys earlier today, that we just saw her yesterday, and she was very excited to tell us the story about her grandfather who was kidnapped by Clyde of Bonnie and Clyde and lived to tell the tale.

So yeah, other than the anemia she’s done really well, and she’s just very thrilled to still be kind of getting to do all the social family events now that she gets to do and tell really great stories to us.

DR LOVE: And again, we’re not trying to say that every patient is going have these kinds of outcomes. It’s natural that people want to present patients who do well. It’s important to hear about that these people can do well.

Dave, any secrets to managing the fatigue? I hear a lot of people talking about that. I even wonder what the pathophysiology is. You see it in so many different types of treatments. For practical purposes how do you deal with it, and what do you say to patients about AML?

DR O'MALLEY: Well, let’s start with AML. When we look at the background risk of patients exposed to carboplatin it’s about 1-ish percent. And when you look at patients treated in first-line therapy with PARP inhibitors it goes up to about 1 1/2-2%. So you can say it doubles your risk, or you can say it increases by 1%, 1/2-1%.

But in the recurrent setting, where in the first-line setting we treat for 2 or 3 years depending on the trial, in the recurrent setting if we use PARP inhibitors, which we don’t do that much anymore, we treat indefinitely. So the exposure’s much longer, and what else? They’ve had multiple lines of platinum therapy. In those patients the risk originally has been reported about 4% to 8%. But we just wrote a paper recently. We looked at patients who did exceptionally well in the recurrent setting. And that rate went up to about 14% in those patients who did exceptionally well, and one of the predictors seemed to be the time they’re on PARP inhibitors.

So I tell patients on that, if I’m using it in the recurrent setting, do we limit therapy to 2 to 3 years. That’s unanswered, and the data is — that’s not how the trials were set up. But I have that conversation with regards to the risk of AML and MDS, because as patients can do well, if they’re in remission, if they’re in active therapy for ovarian cancer a diagnosis of AML usually kills the patient. So in those regards you have to have those frank discussions.

With regards to fatigue, I have no idea about the pathophysiology. I don’t think anybody does. But we really talk about it. I’m the least like tree-huggy-type person there is, but I love talking about yoga and activity for the management of fatigue. And it really is, as you look, again, across all tumor types, liquid and solid, the 1 intervention which always seems to help is yoga. It’s amazing. I’m clearly not a yoga person, but — I can’t even sit on this stool for very long, never mind the floor. So you guys see me up and down here. But I think as you look at this — but physical activity across activity across all of our tumors helps in the tolerance of traditional cytotoxic chemotherapy but also, also PARP inhibitors; sleep/wake cycles, depression, anemia, all of those things.

But one thing. I just had a recent experience, just recently, she’s — my patient’s a scrub tech, works full time, young woman. But we talked to her about methylphenidate, and I’m going to use a trade name because most people don’t know methylphenidate is methylphenidate, so I apologize for using a trade name, but we talked about it for a while, and we finally — because I don’t like throwing pills at patients who are already on pills, we finally made the decision, shared decision, to start her on it, and she walked into the next appointment, and she said, “O’Malley, you’ve changed my life.” This was a life-changing treatment. And so she’s taking it twice a day. She started at 5 mg. We actually went up to 10 mg, but just for breakfast and lunch. She said it’s changed her life.

So I think we — there is pharmacologic agents that we can introduce that I don’t use that often but keep in the back of your mind for those options.

DR LOVE: Any thoughts, Katie? Have you ever used that?

MS LYLE: Yeah. We’ve done that once with one of our patients and used that medication. And at first it was kind of like “Do we really want to get into this and add that?” And I’m similar, I try not to — I take a less is more approach. If we can do as many things that don’t involve pills to help with side effects that’s great. I just really try to not to add something else to the list if I can help it, but in that 1 unique scenario, again, that actually worked quite well. I’m also really big on emphasizing the importance of getting quality sleep at night by being physically active during the day and maintaining hydration, so I talk about that a lot.

Lenvatinib/Pembrolizumab in the Management of Metastatic EC

DR LOVE: So I can’t remember last year, I’m not sure we were in this era last year. I think we were still lenvatinib/pembro, or maybe that was the year before. But in the last few years clearly second-line therapy of MS-stable disease, which is the most common variant here, has been the combination of lenvatinib, the tyrosine kinase inhibitor, and pembrolizumab.

And that strategy of combining an antiangiogenic, particularly a tyrosine kinase inhibitor, or for example bevacizumab, you see in many areas in oncology. We’re doing a program here on hepatocellular cancer, atezolizumab/bevacizumab, another example of that. Renal cell cancer; there are 3 different combinations they use, immunotherapy, again, and a tyrosine kinase inhibitor.

So Shannon, can you talk a little bit about why we think adding in an antiangiogenic like this to an IO increases the activity, and particularly what do we know about this combination, which really has a lot of activity but also has a few like pitfall challenges?

DR WESTIN: Yeah, sure. I mean, I think the important piece is that when we were using these in the second line, again, MSI-high, mismatch repair deficient, the activity of immune checkpoints alone is well more than adequate and very active. So this was really focused on those tumors that do not have that, that are mismatch proficient. And there was some data to indicate that if you put these tumors into a more hypoxic condition, so low oxygen, that it activates the immune system and allows the immune cells to be more active and to be able to target the tumor better.

And that was borne out by the data, where we saw in patients that had mismatch repair-proficient disease that the use of this combination had well higher response rates, initially, than what we would expect for chemo, where we see 5% to 10% response. We saw 30% to 50% response with lenvatinib and pembrolizumab. And then when it was compared directly we saw improvement in progression-free and overall survival. So a clear winner and a clear FDA approval in this space.

But, as we do with a lot of drug development, we were always trying to do the max dose, right? What’s the maximum tolerated dose? And the maximum tolerated dose of lenvatinib is not necessarily the well-tolerated dose for everybody, right? So we saw quite a bit of side effects and that impacted patients’ ability to stay on therapy.

And when you look at some of the trials that were done there’s something like 70% had Grade 3 tox. I mean it was just very high, right? So I think using some nuance around dosing and also with mitigation strategies is really important with this regimen.

DR LOVE: So maybe we can kind of get into some examples of what happens with this regimen. And Jenny, you have the 83-year-old patient. Can you talk a little bit about her?

MS FILIPI: Yeah. First of all, when one of my oncologists comes and says all right, we’re starting pembro/lenvatinib, I’m like all right, buckle up because this is a drug that’s hard to manage. And this is the bread-and-butter of what we do as oncology nursing being really, really educated on all the small side effects and all of the different little tricks that we do to keep these patients on therapy and the highest dose that they can tolerate.

This patient, a lovely 83-year-old, very robust. She’s a trained chef, an artist. She was 110 pounds soaking wet, so I knew it was going to be an issue because I do see a lot of anorexia, weight loss, stomatitis. in addition to of course high blood pressure and some rashy stuff. But for her the anorexia was a huge problem. So I think we started her — we usually start people at about 14 mg. FDA approved dose is 20. I know everyone does it a little different. But we usually start at 14 and go up if they can.

She had to immediately go down to 10 or 8 because she lost 10 pounds in 3 weeks, and she was under 100 pounds. And we had nutrition onboard, we counseled her on different ways to add protein and small meals, all the stuff we do. We tried oh, maybe she has some underlying GERD or underlying nausea that’s not really — treating, so we tried adding antiemetics and PPIs and nothing was working. And finally, and I’m not sure if we just were kind of glossing over this part or this was the least of our worries, but she had mentioned that her mouth was almost like numb and burning, and when I looked in it I couldn’t really see any ulcers, no sores. It looked a little red, maybe a little dry.

But we said all right, maybe she has some oral dysesthesia going on. We tried a dex mouth rinse, we tried some nystatin, kind of just Hail Mary stuff. And then added gabapentin at night, and I don’t know if it was just a fluke or timing or what, but she actually did really well. The next time I saw her she had gained some weight. We were able to get her back to 14 mg, maybe 10. We were able to get her back up on a dose she had previously been on.

And in that time that she was on a lower dose because of these side effects we did see a little progression, but we gave her the benefit of the doubt, we had the conversation look, you’ve been on a really low dose, and your dose has been interrupted so many times, just a little progression on your scans. You’re doing better now. Do you want to try to increase the dose and try it one more time?

We were able to do that, and she has stable scans now. So I think it just speaks to the intricacies of knowing these drugs you’re giving really well and coming up with a plan for all of these patients, and especially with this drug and the hypertension, which she didn’t actually have. But I’ve even given people my cell phone because it can happen so quickly, and it can be pretty profound. So I would say out of all of the drugs I use, we use, this one is one that you’re going to be in close contact with your patients with.

DR LOVE: I would say that story speaks to how to be an oncology nurse and stay all over it and get the patient through therapy.

Dave, anything you want to say about your special mix of how you approach this situation, particularly in terms of dosing and trying to be creative about trying to get the patient through this comfortably?

DR O'MALLEY: The first thing I do is have an amazing team. We set up weekly visits with the APP/MA team, Courtney, who you guys will meet on Friday. Weekly visits. We do them by video now, and we will continue weekly visits until we have a stable dose. I start at 18 because as you just — that example you gave, there is something to do with the dose intensity. There is something.

And the reason I start at 18 is really pragmatic because if you start at 10 they only — excuse me, if you start at 20 the way the drug is distributed they only get 10 mg pills, and they take 2. If you start at 18 they get 10 and two 4s. And we know that about two thirds of patients are going to require a dose reduction, so instead of waiting for a new script, waiting for them coming down, going down to 10, I’m able to go from 18 to 14 by just telling them to only take the one 4 mg pill and the 10.

So the reason I start at 18 was only pragmatic. It had nothing to do with — but yet it allows me to get that maximum dose intensity. Plus or minus 10% I don’t think is going to make a difference, but you start dropping down 50%, from 20 to 10, in some patients and their pharmacokinetics, absolutely I worry about getting enough dose in them.

Potential Role of Selinexor in the Management of EC

DR LOVE: So a little more about biomarkers. You can never say enough about biomarkers, but some pretty cool stuff came out as it relates to what we’ve been talking about and potentially a couple of new targeted strategies in endometrial cancer that we may see coming up in the future. We were talking, again, at the Society of Gynecologic Oncology Meeting just a month or so ago. So Shannon, selinexor, a pretty interesting drug now approved in a couple hematologic cancers, not used too much, also some tolerability issues. But pretty interesting mechanism, and now we’re starting to see —whenever we see a correlation with a marker in the tumor we start buying into it more, and I guess now the so-called TP53 marker maybe is going to be related to this. So you want to spin that one?

DR WESTIN: Yeah, absolutely. So selinexor is a really interesting compound where it basically blocks exportin, which moves things across the nucleus, and specifically it can move tumor suppressor genes across — or other genes across the nucleus, and p53 is one of them.

And so initially this trial was done kind of in all comers, but because of the mechanism of action they were very smart, and they kind of teased out if p53 was going to be important or not. And when you think of it, if you have mutant p53 it’s not going to do its job as a tumor suppressor. It’s nonfunctioning, so you want that out of the nucleus. However, if you’ve got wild-type p53, and it’s doing its work as a tumor suppressor you want to keep that in, so you want to block that exportin so that then p53 can stop the cell cycle and kill the tumor cells. And so that’s really where selinexor works the best, is if you’ve got that functioning tumor suppressor.

And so the trial that was done, the initial trial that was done, SIENDO, was again an all-comers trial in maintenance, so advanced recurrent endometrial cancer, completed their therapy, had benefit, and then were randomized to either placebo, which was standard of care at the time, or the selinexor. And the study overall did not show a benefit to selinexor, but when they broke out that population that had that functioning tumor suppressor, that wild-type p53, that’s where the boldest improvement in progression-free survival happened. So not enough to get the FDA approval from that trial but now they’re doing a confirmatory trial just in that population.

DR O'MALLEY: I am so glad you asked Shannon that question. I was really nervous. Shannon’s not only one of my best professional friends, also probably the smartest person I know. So I was like please don’t ask me that one, Neil.

DR LOVE: Yeah. I don’t understand any of these diagrams. Upstream, downstream. But actually, Katie, you’ve got a patient who’s got p53 wild-type disease you’re going to put on this study.

MS LYLE: Yeah. So she —

DR LOVE: 58-year-old woman.

MS LYLE: Yeah. 58-year-old. She was more recently diagnosed. She has Stage IV endometrial cancer. Her story is actually a little different from some of the patients that I’ve talked about this morning in that she lives alone. She’s not married, doesn’t have a partner, so she has friends that help get her to and from her chemo appointments, but I mean she chooses to come see me by herself. She chooses to come see the physician by herself.

So her concern and fear as a patient is more like okay, is this going to work. If it doesn’t, what situation am I going to be in because I am all that I have. I think her mother is older and just would not be able to be a caretaker should she become really ill and things like that. So even in the front-line setting her concerns were how do we keep me at a point where my cancer is either treated or controlled. And of course hearing that she was Stage IV coming in was very concerning for her because it made her feel like that outlook of her cancer outcomes might be more dismal compared to a lower stage.

So she actually got 6 cycles of paclitaxel/carbo before we operated on her just to optimize the success of her surgery, and then after surgery she received 3 more cycles. During that time, once we had tissue from her surgery, we sent it for tumor testing, and that’s when the results came back, and she was TP53 wild type.

And so during the course of her last 3 cycles of chemotherapy we started to talk to her about introducing something that could be given in a maintenance-type setting, talking about a clinical trial, so again something that you could not get as standard of care right now, but your tumor has a specific characteristic that makes us think that you may respond very well to this medication because of what you just talked about, about the kind of data that we have so far about using selinexor in TP53 wild-type patients.

So towards the end of her chemo we gave her a consent to review. We did need to first prove that she had responded to the platinum-based chemotherapy. So a couple of weeks ago she came for her post-treatment scan, and she actually has no evidence of disease right now, which is fantastic for someone who started out with Stage IV endometrial cancer. So she’s in a good place right now, took the consent, and she’s currently in the enrollment process to start on this confirmatory trial.

DR LOVE: So Dave, this also kind of leads to another theme, and we’re going to talk about this — when’s the ADC thing? Is that lunch today? Yeah. Lunch. I lose track of where we are and what we’re doing here, but we’re going to talk about it today in terms of these kinds of situations where people go on studies with a drug that — it’s actually approved, but you guys haven’t used it. But I’ll tell you what I’m hearing from the myeloma people and the lymphoma people is this is not an easy drug to use. And you talk about she’s concerned that if she becomes sick.

Dave, any thoughts about now you are using a drug that you all haven’t used, and in other cancers has actually been fairly toxic?

DR O'MALLEY: Yeah. I think part of the informed consent process and as you take on these trials you have the responsibility to familiarize yourself with the drug. I’ll tell you when we started IOs I had my melanoma experts on speed dial.

So I think having those other specialists that you reach out to if you start seeing toxicities, educating yourself about what are the toxicities your patients are going to see, and educate them, and educate the entire team who, again, as these phone calls come in — each practice works a little bit differently. Some practices all the phone calls come into the research team, but other practices they first come into the nurse on the team and then make a decision of whether or not to go to research.

So I think familiarizing yourself. The informed consents are a really nice way to do that because it breaks it down to most likely, to serious and less likely. And I just read through those, and I put those right in my smart phrases. A lot of us use electronic medical record. I put those right into smart phrases. It helps teach our fellow, our residents, our APP team, our nursing team. Right at the bottom of my note are all of the expected toxicities right there, so I can pull up that note and remind myself. I don’t have to go to the protocol.

DR LOVE: Interesting. So do you think this lady would be — I mean remember, it’s an oral therapy. She can stop it if she’s having problems. I don’t think there have been like lethal problems, more GI, quality-of-life type things. So thinking about her as a person do you — again, not the greatest prognosis right now without anything else, do you think she’s the kind of person who wanted to take a shot at something that’s — obviously she signed the consent. What do you think her thought process is?

MS LYLE: Yeah. I mean, I will say she’s a patient that very much uses our patient portal and communicates a lot, which makes me feel better about being on a drug that I don’t have as much experience as some others at managing. So I do know she’s very communicative when she has concerns and questions. So I think that will work in her favor. But like Dr O’Malley talked about, I think frequent visits in the very beginning makes a whole lot of sense as we’re kind of learning what happens with some newer agents. And I think she’ll do okay as far as that.

DR LOVE: You probably know Joe Mikhael, who’s a myeloma specialist, where they’ve used this, and when you hear him describe the way his team supports these patients on selinexor it reminded me of what you were talking about when you deal with lenvatinib/pembro, really intensive follow-up that for them, they say their patients are comfortable.

Incidence and Management of HER2-Positive EC

DR LOVE: Let’s talk about another really exciting development, and again we’re going to get into this today at lunchtime, so we’re not going to spend a lot of time talking about it today, but really this is revolutionary, the use of HER2-targeted therapy, particularly 1 drug in particular, an antibody-drug conjugate that again we’re going to talk about today at lunch, trastuzumab deruxtecan, which we talked about last night in the breast cancer session. This drug was first developed in breast cancer, and just a couple weeks ago after a bunch of trials, including endometrial cancer that we’re going to talk about, biliary tract cancer, lung, now has a pan-tumor approval. So theoretically any patient with a solid tumor could receive this antibody-drug conjugate. And if you treat breast cancer you know that this drug is very effective and has very prolonged tolerability and also some pretty interesting toxicity issues. So we’ll just briefly touch into it because we’re going to get into a lot more at lunch in terms of this.

So first, Dave, can you talk a little bit about what HER2 is, how we test for it, and what we’ve learned about some of these new therapies?

DR O'MALLEY: Well, it’s really a protein that sits on the cell, and those who treat breast cancer have been talking about HER2 a long time. We’ve been talking about it in uterine cancer, but mostly the serous, serous subtype. So when we look at this, we test through IHC. We’ve used the breast cancer criteria in the past, and 2+ would be considered indeterminate, and then we would reflex into FISH.

The most recent data in our practice now are only using immunohistochemistry to test for it. And we’re just asking is it 3+, 2+, 1+ or 0. And we’re really looking and learning from the breast cancer literature with regards to the different ways to define this. The challenge with the all-comers indication, it’s only for 3+, but they did not really tell us what the biomarker was.

So the Pan-DESTINY-Tumor used the gastric criteria, and so now when I send tissue to the pathologist I say please use the gastric criteria because we’ve been using the modified breast for a decade, so just in order so we can really compare apples to apples in some ways about the indication. So the IHC is what we’re doing. I just had a case this week, I actually just read it yesterday, they reflexed to FISH. I didn’t ask them to do that, but it’s not going to make a difference because of the 2+, and the NCCN Guideline indication I’ll use that as a potential agent.

DR LOVE: I just had a flash of you know how they have people who do hand things to translate. I wish I could do this to translate what you just said.

DR O'MALLEY: I did okay.

DR LOVE: Slow down a little bit there, Dave. You went a little bit fast.

DR O'MALLEY: Oh, man. All right.

DR LOVE: That’s okay. Let’s go back to — let’s try Shannon for a second.

DR WESTIN: You just got pulled.

DR O'MALLEY: I tried! I tried!

DR LOVE: This is why we’re spending an hour and a half on it at lunch, okay? Really. No, seriously.

DR WESTIN: Yeah. It’s a lot.

DR LOVE: We’re just dipping our foot in here. But the bottom line is, Shannon, and we can talk about — and we’ll talk at lunch about HER2-low and what that means and where all of this is heading. But the bottom line is if you have a patient with endometrial cancer who’s run out of options with metastatic disease, and frankly if you have any patient nowadays with a solid tumors who’s run out of options with metastatic disease, you need to check the chart and see if they’ve had a HER2 assay. Because this drug, I mean I don’t know, have you got to the point where you — do people respond?

DR WESTIN: Oh, yeah. I mean we’ve been using it. We were fortunate enough to participate in the DESTINY-PanTumor-02 study, so we’ve been — we drank the Kool-Aid a couple of years ago now and have been checking HER2 on almost all of our patients. And importantly it included endometrial, it included cervical, it included ovarian, so tumors to which we need more options.

So I think in my practice now I probably have 10 patients that are taking this medication, and I think 5 of them are patients with endometrial cancer. And it works. I have multiple patients that have a wonderful response to therapy.

In the beginning the toxicity is there, but to your point it’s very manageable. I mean we’ve gotten very aggressive with antiemetic management, antimotility agents, kind of giving patients those things early on to try to get out in front of some of the toxicities so that the patient can stay on.

DR LOVE: Except there is 1 slight problem in addition to the quality-of-life issues, as you mentioned, antiemetics, et cetera, again we’re going to talk about this at 12:15, but Dave, interstitial lung disease.

DR WESTIN: Yeah.

DR O'MALLEY: Yeah. Interstitial lung disease, or pneumonitis, is if you look across the portfolio of T-DXd it’s about 2% Grade 5 mortality.

DR LOVE: Mortality.

DR O'MALLEY: Mortality. Grade 5. So do not pass go. Do not collect 200 dollars. You died.

So 1 in 50. So like AML and MDS in PARP inhibitors I give the facts.

DR WESTIN: We talk about it. Yeah.

DR O'MALLEY: The issue is, again, a team approach. I’m embarrassed to admit just last week a phone call came into our practice, and the patient was on T-DXd, and they said, “Oh, I’m having worsening asthma,” and was having lung. And our triage said go to your primary care. So that was picked up by our APP team, thank goodness, because they saw the phone call then called and evaluated, and it was fine. But it was just one of those that’s a reminder, what we talked about IO therapy, same thing for these antibody-drug conjugates, you have to think pneumonitis because if you don’t identify it patients can die. If you identify it early and treat it aggressively with steroids, always hold therapy, essentially always hold therapy, and treat it with steroids, you can make a big difference in the intervention and the outcomes of these patients.

DR LOVE: And actually Jenny, we have your colleague, Kelly Goodwin’s going to be here at noon.

MS FILIPI: Yes.

DR LOVE: She’s a lung cancer nurse. The other people on the panel at noon are actually breast because they’re the people who have the experience. And they have algorithms that — in breast now that are not even quite out there yet. We actually had a breast person talking at the GU oncology meeting a couple months ago. But the breast people are very aggressive. You’re going to hear about this at noon about looking at pulmonary imaging. Because what they want to do is pick it up before it’s symptomatic. And if you do that you don’t see Grade 5. So now we’re in the process of quickly getting these messages out from the breast cancer people to everybody else. But the bottom line is you’re hearing about patients now who really had no options who are doing well, and we see this all the time in breast cancer. We’re starting to see it now in lung, gastrointestinal cancers you’ll hear Saturday night, as well, really promising results.

So more to come along with our theme of research and what it means to taking care of patients. I want to thank the faculty. Thank you for attending. Come on back at 12:15. We’re going to continue this story. Thank you so much.