Introduction: Overview of Endometrial Cancer

DR LOVE: Good morning, everyone. I’m Neil Love from Research To Practice, and welcome back to “Understanding the Current Paradigm and New Approaches in the Care of Cancer Patients.” This is the ninth of 11 programs we’re doing here at the ONS Congress. We’ve been coming to the ONS Congress for 17 years, and it’s always a great pleasure.

This morning we’re going to focus on the management of endometrial cancer. We have a great faculty today. We have Dr Brian Slomovitz, unfortunately — hi Brian, good to see you there. Unfortunately, he was not able to make it, got stuck there with a canceled flight, but we’re bringing Brian in from the Mount Sinai Medical Center in Miami, Florida, our hometown. We’re also joined by nurse practitioners Ms Katie Lyle from the University of Alabama at Birmingham, in Birmingham, Alabama; Ms Jaclyn Shaver from Oklahoma — Stephenson Cancer Center OU Health in Oklahoma City, Oklahoma; Dr Ritu Salani from the David Geffen School of Medicine at UCLA in Los Angeles; and of course Dr Slomovitz from Miami.

So as in all of our programs, we will be talking about the use of unapproved agents and regimens. Please consult the package insert for the various agents for more specific information.

We are recording all 11 of these programs. We’ll let you know when they’re available to be watched or listened to, including on our new podcast, Oncology Nursing Update. To get that, just go on your phone, go to podcasts, hit search, put in “Oncology Nursing Update.” We already have a couple programs there, and all 11 of these programs will be put on that feed as well.

As I mentioned, this is the ninth of 11 programs. We really view this as an experience that’s parallel to the major conference here. We try to get more into oncology strategy, what physicians are thinking, and particularly how they interpret clinical research information, put it into practice, and then from a nursing perspective how to help patients get through these therapies, particularly new treatments.

I always loved making rounds when I was an intern and resident, and we really pattern all of our work based on rounds. It’s just really a thrill to be able — these are the faculty we’re bringing here this week. We managed to get 42 out of the 44 here, but 2 of them got stuck actually yesterday on the same flight, and Brian we’ll be bringing in today virtually.

So here’s where we’re going to be heading today. We’re going to chat a little bit and provide a little bit of an overview of endometrial cancer, and then we’re going to really mainly focus on advanced disease. We’ll talk about first-line therapy of recurrent or metastatic disease, then the use of a common second-line regimen in patients who’ve not had first-line immunotherapy, lenvatinib/pembrolizumab, then we’ll talk about some of the new approaches coming up in this disease, and finally a topic we’ve talked about several times now already, HER2-positive disease, and in this case HER2-positive endometrial cancer.

So we're just going to take a step back and take a deep breath and talk a little bit about in general endometrial cancer. And Ritu, can you comment a little bit — it’s a very common cancer, but particularly the fact that the incidence is increasing, as well as the mortality?

DR SALANI: Yeah. Endometrial cancer is one of the most — it is the most common gynecologic cancer in the United States. And just like Dr Love mentioned, both the incidence and mortality is rising, which is actually pretty rare for cancers in this day and age. And we don’t quite understand why it is. There are multiple things that may be contributing to it, the obesity epidemic, but also maybe environmental factors. The problem is we’re seeing these higher-risk histologies, and that’s why we’re seeing higher rates of death. So this is something that we’re really trying to address. We’re also seeing disparities in cancer care that are also kind of increasing. So these are really important issues that we continue to deal with.

DR LOVE: So Brian, again, we’re going to focus on advanced disease, but most patients present with localized disease. Can you talk a little bit about the typical presentation of a woman with endometrial cancer when she has localized disease, which is usually the case, how she’s managed initially?

DR SLOMOVITZ: Yeah, sure. Thanks, Neil.

So typically the most common type of endometrial cancer is endometrioid subtype. It’s the one that’s associated with obesity, diabetes, hypertension. So importantly, a lot of times these women present with postmenopausal bleeding. So the first take-home point is if there’s any abnormal symptoms they should really come to the doctor, because that’s when you get diagnosed in earlier-stage.

The traditional first steps in the management is a hysterectomy. A lot of times these are done minimally invasively, where we remove the uterus, the tubes, the ovaries, the cervix. We also do something called the sentinel lymph node. But the bottom line is we rely on the pathology report. About 65, 70% of patients are treated with what I call “one and done”, surgery alone. Rarely do we use radiation, very rarely chemotherapy. But it’s in those cases that are the subject of the talk today, advanced and recurrent disease.

And another point I just want to highlight. There are more deaths now due to endometrial cancer each year than ovarian cancer, which is a number that really is remarkable given the fact that we always thought that ovarian cancer was a more deadly illness.

DR LOVE: Brian, what about the use of kind of an adjuvant treatment strategy after local therapy with surgery. Is this ever used, and if so, what type of therapy?

DR SLOMOVITZ: Adjuvant therapy typically we’ve used radiation. Vaginal cuff radiation is what we call mini-doses of radiation, where it doesn’t give a whole pelvic effect. For those patients with higher-risk disease there’s a role for whole-pelvic radiotherapy, and in some of the higher-risk histologies really we’re finding that chemotherapy may work the best. We’ve done studies with immunotherapy in this setting. There is a subset of women that may benefit from immunotherapy, but the overall — the large study was done overall was negative.

DR LOVE: So Jaclyn, you’ve worked with us before, and you know one of the themes we have when we come to ONS is not just focusing on the tumor but also the patient. And one of the themes we’ve had over the years is why was it different to take care of this patient than another patient in the same oncology situation but a different person, different value system, social support, et cetera. Can you talk about some of the questions that come up and issues that you deal with in the initial diagnosis of endometrial cancer?

MS SHAVER: I think they question why did I get this cancer. Is it something that my children can inherit? And so generally speaking a lot of the endometrial cancers are in the setting of postmenopausal. They are due to extra-adipose tissue, which then in turn thickens the endometrial lining, which causes the abnormal bleeding. And so most generally in your type 1 cancers it’s going to be due to excess estrogen, then being postmenopausal.

You can get a hereditary syndrome called Lynch syndrome, which can put the patient at higher risk, and their family members, for getting endometrial cancer. And so yes, at the time of surgery, at pathology, we’ll do some testing of the tumor, IHC testing, to see if there are any of those tumors — those proteins that are missing. So then we can go down the cascade of if they are missing then we can send them for genetic testing.

DR LOVE: So Ritu, today we’re going to focus on advanced endometrial cancer. What’s the typical path that a patient takes to get to metastatic disease? Have they usually been managed with local therapy? Do they present with first diagnosis of endometrial cancer with metastases?

DR SALANI: So you can see both. And as you can see from this graph here that a majority, about two thirds of patients will present with localized disease. So if they recur, we kind of clump advanced and recurrent disease together if they haven’t received prior systemic therapy. And you can see regional or distant disease are less common. They make up about a third of the patients.

And so the way they may present. Brian mentioned postmenopausal bleeding or abnormal bleeding as initial presentation. It still may present that way, even in the metastatic setting, because that’s a symptom the patient can report. Otherwise it may be vague symptoms like what we see with ovarian cancer, abdominal pain or discomfort, bloating, so it really depends. But it’s not uncommon for them to present similarly. Maybe just longer delay of presentation.

DR LOVE: And I’m curious, Katie, too. I know there’s a spectrum of how people respond to the diagnosis of metastatic disease. They’ve already been through therapy hoping not to. Ritu, incidentally, if a patient asks you — with metastatic disease, could this be curable, how do you answer it?

DR SALANI: I think yes, depending on what the situation is. But now, in this day in age, and you’re going to hear some really exciting data, I think it’s actually — it’s actually in the realm of possibility.

DR LOVE: So Katie, you know you have a patient coming in, prior local therapy, now they have metastatic disease. You’re going to be seeing the patient in a tertiary center. Maybe you might not have even managed them primarily. They may be coming to you, and you’re meeting them for the first time. What are some of the things you’re thinking about as you go in to assess a patient and their family with newly diagnosed metastatic disease?

MS LYLE: Yeah. I think number 1, we’ve talked a little bit about symptom burden and trying to figure out exactly what’s happening that we need to help with from that standpoint in terms of pain and other things. But I think you have to think of the patient as a whole. So there can certainly be other stressors. A lot of my patients travel a long way to see us, so sometimes patients can have some financial toxicity, some social barriers. Sometimes transportation is an issue.

So sometimes I’m using social worker resources to help patients. Other times you think of the psychosocial aspect of having a metastatic recurrent cancer, it could be widespread, it could be terminal, and so those are challenges that certainly affect patients. So a lot of times I will also enlist the help and support of our supportive care clinic. So those are just a few examples, but I think you really have to take the situation and the patient scenario into consideration as a whole and really try and figure out all of the challenges and the ways that they need support.

First-Line Therapy for Advanced or Recurrent Endometrial Cancer

DR LOVE: So one of the key issues we’re going to talk about today is the use of immune therapy, checkpoint inhibitors, anti-PD-1/PD-L1 antibodies. And Brian, all week long here, and in oncology in general, one of the key themes is biomarkers, looking at the tumor itself to try to get some clues about what’ll be the most efficient therapy. And in this situation, and in checkpoint inhibitors in general, a key biomarker relates to the issue of mismatch repair, either mismatch repair-deficient, which we’re presenting a clinical scenario here of a patient with metastatic disease. But Brian can you — and we’ll talk a little bit more about it, but just as a way of introduction, because it is such a critical issue. Can you kind of talk about your vision about mismatch repair and MSI-high disease?

DR SLOMOVITZ: Yeah, sure. So the molecular subclassifications of endometrial cancer, which we started to elucidate back in 2012, really helped us to define different subgroups of those that may — of the cancer, and what we found is there’s 2 what we call hot tumors, meaning tumors that the body recognizes as something that shouldn’t be there. The most common of these is what you were pointing out, microsatellite instable or the deficient in mismatch repair proteins.

So as we go through the data — I’m looking forward to Ritu’s talk. As we go through the data we’ll see with immunotherapy having an agent that could help identify something that’s nonself or deficient in certain proteins eventually to improve efficacy of the assets you’re using. So it’s, in my view, we talk about the word “cure,” and we’ll see from the data, this may be the subgroup of patients that we can cure if they have this molecular classification.

DR LOVE: So Ritu, another very rare subtype, but even more sensitive — and one of the things about these mismatch repair-deficient tumors, they’re very sensitive to checkpoint inhibitors. You can see this in almost any solid tumor, and regardless of where you see it these patients are going to be getting a checkpoint inhibitor very early on if they have metastatic, even if they don’t have metastatic. We’re going to be talking about that today later on with GI cancers as well.

There’s another subtype called POLE, much less common, but even more sensitive to checkpoint inhibitors. Have you seen patients with that?

DR SALANI: Yeah. And so when we did the study they looked distribution of the distribution of the molecular mutations, or molecular findings, and POLE’s pretty rare in the advanced setting, and probably it’s a more favorable prognosis. So these patients may present early on, and then they don’t recur. But when they do have advanced disease these tend to be really exquisitely sensitive to probably all therapies, but particular immunotherapy.

DR LOVE: And there’s an assay called tumor mutation burden, too, and the higher it is the most likely it is that a patient will respond, because the more mutations there are the more the immunotherapy can work. And you can actually see — get a quantitative value. If it’s over 10 you can — there’s actually an approval for the us of immunotherapy. But these patients with mismatch repair in POLE can have much higher TMBs, so another clue to sensitivity.

Alright, Ritu, let’s talk about really the revolution that’s occurred only in the last couple years, immunotherapy in the first-line setting.

DR SALANI: Yeah. So good morning, everyone. Thanks for joining us. And I’m going to — my name is Ritu Salani. I’m going to talk about the first-line therapy really focused on the advanced and recurrent setting.

And so this is what you just heard about. And Brian mentioned that this has been around for just a little bit over a decade, where we’ve classified endometrial cancer into these 4 molecular categories, POLE, which you’ve heard about, and you heard about TMB. So these are mutations that we’ll see the tumor mutational burden 100, 500, so really high rates of tumor mutational burden. However, it’s rare. We see it probably in about 5-10% of endometrial cancers. It’s still worth looking for, but it’s not a common finding, kind of the unicorn of endometrial cancers.

Then next category is dMMR, or microsatellite instable cases. And you can see here the tumor mutational burden may be a little bit higher. This is the one that’s associated with Lynch syndrome, what Jaclyn mentioned, and this is about 20 to 30% of endometrial cancers. I’m going to focus on that for the most part of this — majority of this talk.

Then there is something called copy number low, which we often refer to as NSMP, and that stands for nonspecific molecular profile. This is actually the most common type of endometrial cancer, so it makes up about 50%. These are your typical low-grade tumors, the ones that are estrogen receptor positive, PTEN mutations. So this is what we typically see. And then there’s the opposite, copy number high, and this is often referred to as p53-mutated groups. As you can see from the survival curves, these tend to have the worse prognosis or worse overall outcomes, and these are the ones that are associated with high-risk histologies, like the serous and carcinosarcomas that we see.

And even though we’ve known this data for about 10 years, we’ve only been able to really make this actionable over the last couple of years. And this has really developed how we assess these patients. So now it’s typical to do biomarker testing on almost all endometrial cancers, and this is taken from the NCCN, but it’s just a reminder of how to do the testing. You heard about POLE, mismatch repair immunohistochemistry, and then the p53 testing.

Now, I’m going to highlight some other biomarkers that might be influential in our decision-making, but this is a nice schema to kind of provide an overview. And I know it’s in your slide deck, so please kind of reference it or use the NCCN Guidelines.

So when I think about biomarker testing in my own practice there’s a couple of things I like to do. Mismatch repair testing is really essential. It’s not only essential because it can influence management, but it may inform which patients need genetic testing for Lynch syndrome. And so — excuse me. So that’s part of it. I’m just going ahead I guess.

And then there’s also other testing that our pathologists can do. Now, we can do some other this in house, some of it may be sent out, but all of the IHC testings are listed first here, mismatch repair testing, p53 to see if these patients are copy number high, HER2, ER-positive. Now, if you want to do NGS testing and check for POLE, if you have a patient, and you’re worried about it, the TMB status and microsatellite instable and stability. But MSI and MMR overlap significantly, so sometimes you don’t need to get both.

And I just want to highlight that there are other considerations for primary and recurrent for biomarker testing. The stage, so you may not need to test everybody all the time with the exception of the mismatch repair testing. And then comorbidities, because that might influence how you can treat these patients.

But I want to get into the meat of today’s talk, and that’s the management of advanced endometrial cancers. There were essentially 4, but 3 pivotal studies in the United States that looked at chemotherapy with the addition of a checkpoint inhibitor, whether it was pembrolizumab, dostarlimab or durvalumab, and I’m going to focus on the immunotherapy standards. These were all compared to chemotherapy alone with carboplatin and paclitaxel, and then in the study arm there was always a maintenance phase, which was continued for a varying duration, depending on it. And the name of the trials are listed on the far right side here.

And to go briefly through the data. NRG-GY018, the primary endpoint was progression-free survival, and you can see here those patients who had deficient mismatch repair findings had a significant improvement with the addition of a checkpoint inhibitor, in this case pembrolizumab, with a hazard ratio of 0.3. We also saw a significant difference in the pMMR, or proficient group, with a hazard ratio of 0.54, and this actually was something that was pretty profound.

Going on, the overall survival also shows kind of the trend towards benefit in the dMMR population, as you can see here, with a hazard ratio of 0.55, and a trending significance — a trend in the pMMR population.

RUBY is a similar study, but it used dostarlimab. And once again, the dMMR population, you can see that separation in the survival curves. Hazard ratio of 0.28. Now, the overall survival in the dMMR population continues to be significant, and once again you can see that disparity in those curves, with a hazard ratio of 0.32. This was presented in March, and we had an FDA approval in August, which was pretty impactful.

And then the last study I want to highlight is DUO-E. This study’s a little bit more nuanced because it includes a PARP inhibitor, but focusing on the immunotherapy, or checkpoint inhibitor only, with durvalumab you can see that the addition of durvalumab, whether it was with olaparib or not, had a significant impact in the PFS, with a hazard ratio of 0.4 — 0.42. And then the pMMR, we also saw a benefit, with a hazard ratio of 0.77.

And here’s the overall survival, where you continue to see the impact of the checkpoint inhibitor, and this has been FDA approved. And I failed to mention that pembrolizumab is also FDA approved in these populations, durvalumab in the dMMR cohort.

And I just want to highlight that molecular testing is really essential. Immunotherapy really should be incorporated in patients with advanced dMMR status, and NGS may help identify immunotherapy candidates outside of the dMMR.

DR LOVE: So one thing I just want to point out. We pointed it out earlier this week, but I want to bring it up again.

Ritu mentioned the hazard rate, which is something that we look for, and here’s an example.

You saw curves like this for several different checkpoint inhibitors. This is the study with dostarlimab, the RUBY trial. And if you look on the left, it’s progression-free survival. So these are people with metastatic disease, they all started out without progression, obviously, and then as they progressed it starts dropping down. You can see that the patients who got dostarlimab, it doesn’t drop anywhere near as far down.

And if you look there at the top it says HR, that’s the hazard rate, as Ritu was just talking about, of 0.28. So when you see that, visually you can see the patients do a lot better, but it depends how you graph it. But if you look at that number you really get a feeling for how effective it is.

And the way you look at it is if it’s 0.28 you subtract that from 100, so that’s 72, and that means that at any given point in time a patient is 72% more likely to be free of recurrence or not dying than a patient who hasn’t been treated. So the lower the hazard rate — a lot of drugs get approved with a hazard rate of 0.7 because they have a 30% improvement at any given point. These effects are much greater, 0.28. On the right you see survival benefit, whether somebody’s alive or not, 0.32. So at any given point there’s a 70% more likelihood a patient’s going to be alive. These are very impressive numbers.

And Brian, it brings up the issue that, again, we’ve talked about all week. It happens all the time in oncology, which you have multiple agents with the same mechanism, and you have to compare then indirectly because it’s very unusual to see trials comparing 2 different agents in the same class, and it’s always a challenge to try to do that. We talked about that with PARP inhibitors, in many cancers. We talked about it with CDK inhibitors the other night in breast cancer. It’s a real challenge for an oncologist to pick which of these agents to use, Brian.

And from the point of view of PD-1 agents, we have PD-1 and PD-L1 agents. What I’ve observed is that people follow the trial. If a trial’s positive they’ll use that particular agent. The analogy I always bring up is in lung cancer, where most of the positive trials were with the PD-1 agent pembrolizumab. But when the trials in the locally advanced setting were looked at the trial with durvalumab was most impressive indirectly, and so that’s what everybody uses.

What about in endometrial cancer, Brian? We have multiple agents that have been studied. From your point of view, how do you differentiate that? Do you use the agent that has the most positive trial?

DR SLOMOVITZ: Yeah. Neil, thanks for that question. I think there’s really 3 factors that I look at when choosing which drug to use. One, yes, is cross-trial comparison, which drug, which asset may be more active or not, and obviously we want to use the one that seems to be the best one, whether it’s exactly the same or similar. For example, we saw 0.28 and 0.30 in the studies. In my mind that’s similar. So that’s one factor the effectiveness.

The second is how comfortable I am using it. Sometimes I’ll already use one of the assets for another disease, and if it gets approved in this disease, just because of my comfort, my nurse practitioner’s comfort, the nurses’ comfort in administration, that may lean us more towards using one or the other.

And then the third factor, which we don't often talk about, in my mind, is the payor. Oftentimes I’ll prescribe one agent, but the insurance company actually will say well, it’s very similar to the others, and obviously it costs them a little bit less, so they would push us in one direction or the other.

But the good news is it seems like a class effect, so the days of fighting with insurance companies, if they said you have to use pembro not dostarlimab, or agent X or Y, as long as the effectiveness is the same I’m okay in doing that. And of course the safety profile.

DR LOVE: So we’re going to get into some of the nursing considerations with the use of immunotherapy, and Katie in a second is going to talk about that in terms of potential tolerability or toxicity issues. I was just flashing on the fact, Katie, that it was just about literally 10 years ago, we were actually in San Francisco for — doing a prostate cancer conference, and there’s a little video on the internet of me saying I think the checkpoint inhibitors are about to be approved. This was in lung cancer.

And at that point we weren’t using — this is only 10 years ago, and I was saying I think things are going to be a lot different in the infusion rooms. And of course now, 10 years later, we’re using checkpoint inhibitors in multiple cancers. It’s a completely different paradigm, particularly in terms of toxicity. At that point, this is only 10 years ago, this is a complete change in how we view toxicity. People are very focused on chemotherapy-type toxicity, now we’re in a completely different paradigm.

So let’s get into this. This is a major issue today, not only relevant in endometrial cancer, but of course many other cancers, lung cancer, head and neck, bladder, et cetera, et cetera. Let’s talk a little bit about some of the things you think about in patients about to begin a checkpoint inhibitor, Katie.

MS LYLE: Yeah. And to your point, it was at one point paclitaxel/carbo was really what we had, and now we can talk about immunotherapy, something that we’ve used in other tumor types, which I think is fantastic, so we’ll talk about some nursing considerations.

But first, when I talk to patients I kind of want to explain to them how does it work and why are we giving it. Patients are very familiar with chemotherapy, and it’s really important to educate them and help them understand how immunotherapy can help chemotherapy but also understand how it’s very different from chemotherapy in terms of what to expect.

So endometrial cancer cells express PD-L1. We’ve talked about biomarkers. I think at the end of the day for advanced or metastatic or recurrent endometrial cancer it’s extremely important to talk to patients about why we’re doing tumor testing and to get that as quickly as possible because that then drives what your treatment decision is.

And then in a nutshell, basically you can see on the slide, a more in-depth explanation, but I basically tell patients that we’re using immunotherapy to rev up your body’s own immune system to attack the cancer cells. So endometrial tumor cells express PD-L1, T cells with the immune system have PD-1 receptors, and when those are bound together it’s like the foot is on the brake for the immune system. It’s not really revved up, the T cells aren’t attacking the cancer cell, and so if we can give some of these drugs that are inhibitors they inhibit that interaction. If you can block that it’s essentially like you took your foot off of the gas pedal, and now all of a sudden you can activate the T cells to go attack the cancer cells. And that’s really the premise of why we are giving immunotherapy, sometimes by itself, but oftentimes in combination with chemotherapy to these patients.

So I’ve kind of talked about how it works. One thing that’s different about immunotherapy compared to chemotherapy is sometimes it can take a little bit longer in terms of response time. So when we’re doing imaging on these patients I like to explain up front that I’m going to do a CT scan fairly early just to track the progress of your response, but there is a chance that there will be something called pseudoprogression, or we may not see as big of a reduction in the size of your tumor or the distribution of your disease like we would with chemotherapy.

And so pseudoprogression really just means false progression, and what’s happening is the T cells in the immune system are flocking to the cancer, and on imaging that may look like the lesions are actually measuring a little bit larger, or maybe you haven’t seen a reduction in size like you would hope to have had with chemotherapy, but that’s actually not always a bad thing with immunotherapy specifically. Sometimes that’s just a byproduct of how this treatment is working.

And so I’ll tell patients don’t get discouraged if on that first scan we don’t see a lot of changes in the sizes and the measurements. What we’ll do is continue your therapy, and then on the secondary scan that we’re doing at the second timepoint, that’s really when I’m looking more for that reduction in size.

And then one thing that’s unique to immunotherapy is you can also have a durable response. So what that means is we can stop immunotherapy and these patients are still responding very well to having had immunotherapy up to a certain point, so that’s another benefit in using this as part of the kind of treatment paradigm in these patients.

When we think about immunotherapy, if you’ll look to the image on the right, this is a little bit different from chemo. So the timing and the onset of certain side effects can be very different, and I like to educate patients that — so if you look on the bottom, this is talking about what’s happening in terms of where we are in the duration of treatment by weeks.

So if you look at the first, I don’t know, 4 to 6 weeks, month, month and a half, usually if you’re giving immunotherapy every 3 weeks, that might be the first couple of cycles, you can expect to see some of the dermatologic effects like skin rashes, some GI upset, some diarrhea. So those are things that I like to educate about really early on because I want to stay on top of that if it’s happening.

I want patients to have antidiarrheals on hand at home. I tell them to buy them before they even start the treatment because once you’re in a situation where you’re having 5, 6, 7, 8 episodes of diarrhea it’s kind of too late. You already need to have that antidiarrheal on hand, because from a nursing standpoint I don’t want these patients to call the clinic and talk to the nurses line or send a portal message once their severely dehydrated or malnourished or they have electrolyte imbalances, and then we’re kind of playing catchup to get them back to where they started.

And then you can look. Some of the endocrinopathies can happen a little bit after the first couple of months of therapy. We might see some liver toxicity. And then you can have some later side effects. Say maybe they’ve been on for 3 months, now they might be calling with a cough or some respiratory symptoms or things like that. I might need to get a chest x-ray to rule out infection, but also be pretty quick to get maybe a high-resolution chest CT to rule out pneumonitis, because that can snowball pretty quickly.

So I think the takeaway from this slide is that as nurses and as clinic staff and care coordinators it’s really important to listen to what the patient is saying and make sure that they’re aware that we want them to tell us anything that’s different. I don’t want them writing this off as something that happened because of what I had for dinner last night or justifying it in some other way. It’s really important to know about it.

And so as providers we’ve got some great guidelines that help us manage patients. Sometimes that involves holding therapy or giving a steroid taper. In severe cases, which is less common, we may have to hospitalize the patient. So I just really think education is key.

And this is just a patient example of mine, but I think it’s a really important scenario for me to kind of discuss just to shed some light on exactly what can happen when things get really out of control with side effects.

So I have a 38-year-old Spanish-speaking patient. She’s been my patient for, I don’t know, 6 or 7 years now. But she was on immunotherapy, and she was coming to clinic. We were checking her labs. We checked her thyroid function to rule out hypothyroidism secondary to the immunotherapy, and she was normal for a while, and then all of a sudden — I think one cycle her TSH was low, which you might look at that and say oh, well, that’s hyperthyroid, but what really happens with immunotherapy is the pendulum swings the other way, and they actually settle in a hypothyroid state, to where we give levothyroxine for thyroid replacement.

But in her case, unfortunately, she had a lot of social issues and financial barriers. She was Spanish speaking only, so we did all of her visits through interpreters. If I called her on the phone at home I had to go through the interpreter. She had a challenging work and home life situation, where she, with endometrial cancer on treatment, was working for a roofing company. And so sometimes she wasn’t able to do her job, sometimes the job offers weren’t there, and so at one point she no longer she no longer had a vehicle to come to and from clinic. She was relying on her family and friends.

And she came in, and she told me at one point she had stopped taking the thyroid replacement because she didn’t like the way it made her feel. So to her, she just stopped it, and I didn’t know, and it had been weeks. And so that was challenging. And then other times cost of prescriptions was a big issue for her, so her social worker would help her.

But ultimately the scariest part of this is she was off and on medicine a lot. We had stopped the immunotherapy at this point, but we ultimately had to hospitalize her. Her TSH was the highest I’ve ever seen. I said greater than 100, but it was in the 150s. She was very symptomatic. We had to admit her, and she — and consult endocrine to help us.

The interesting thing is after all of that she’s actually still disease free, even though we had to discontinue the immunotherapy due to a very severe side effect.

DR LOVE: Yeah. Again, thinking back 10 years, that was another thing. We would hear about these toxicities, therapy would be stopped, and the patient would stay in remission, just like this patient.

Jaclyn, one of the things that I know is very common, and Katie just mentioned, are skin changes with immunotherapy. What are some of the things you see, and what do you do about it?

MS SHAVER: Yeah. So the most common skin change is going to be usually a rash. Most of the time it is an itchy rash that can occur really on any part of the body. And how we manage it is based upon how spread the rash is on the patient, how itchy it is, how concerning to the patient, how symptomatic that it is. And so there’s different strategies that we can use depending on the grade of the rash.

So sometimes we can just continue the immunotherapy. If it’s just localized and not really very symptomatic we can continue immunotherapy. If it begins to be symptomatic and Grade 2 we can use some topical steroid cream for those. And if need to then we’ll do an oral steroid taper, hold the drug until that rash has gone back to a Grade 1.

DR LOVE: So Brian, one of the things we realized early on about this treatment is in terms of autoimmune toxicity. One key issue is whether the patient had a prior autoimmune disease. There are many autoimmune … from systemic lupus to colitis, multiple sclerosis. And there we saw that if you give a checkpoint inhibitor these underlying diseases get worse. Sometimes it can be a real tradeoff because maybe the immunotherapy really is the only thing that could help the patient.

A related issue would be a patient who’s had a prior transplant, particularly a kidney transplant, where you could end up rejecting the kidney. It wouldn’t necessarily be life threatening, but then the patient would have to go on dialysis. If they’ve had a liver transplant or heart transplant, obviously, it could be fatal. How do you think through, and how careful do you look for prior autoimmune disease, Brian? And how do you decide whether to use immunotherapy in a patient with that type of history?

DR SLOMOVITZ: Yeah, no, thanks. That’s a great question. Actually, it’s a question I dealt with yesterday in my clinic. Oftentimes the patients does have a history of it or there’s some symptoms that will lead us towards an autoimmune problem that they have, so that will give us the heads up. Rarely will we diagnose it while we’re treating them.

But the question, to your point, is when do we treat through it. I had a patient come in yesterday who had a really significant history of autoimmune colitis really affecting her every meal, every morning, and it’s really disruptive, and her quality of life. She has a deficient mismatch repair endometrial cancer with metastatic disease. And up until now, including now, we’re holding off on checkpoint inhibition. She is going to go on her second line of therapy, which is actually clinical trial.

But I talked to her yesterday, and I said eventually we may have to take that chance, and we may have to go for it, as a life and death alternative, right? But right now she still has a — overall her performance status is as good as it’s ever been, so we’ll try one more line, but we go down the point of treating through it. Which, milder symptoms, I’d be okay with trying, but someone like this, who’s severe, I try my best to avoid the checkpoint inhibitors.

DR LOVE: So we’ve talked a lot this week, and all through oncology is the issue of patient involvement in difficult decisions. This is one of the most difficult decisions in oncology. Thinking about your patient there, we know she would benefit, very likely, from immunotherapy, but are you going to lead into maybe even a life-threatening problem with colitis?

Well, we’re going to be continuing this theme of talking about tolerability and side effects as we go through.

Role of Lenvatinib/Pembrolizumab in the Management of Progressive Advanced Endometrial Cancer

DR LOVE: I wanted to get into second-line therapy. And Ritu, you went through some of the new trials that have come out in first-line use of immunotherapy for metastatic disease. Prior to that it was used second line, and this is one of the common regimens, which is not just immunotherapy alone, but with the tyrosine kinase inhibitor lenvatinib. Very effective, but a whole new set of tolerability issues. Really one of the most challenging, I think, side-effect issues in oncology in general. And there are still plenty of patients who have not gotten first-line immunotherapy who are being treated with this combination.

We asked you to talk a little bit about what we know about it, and we’ll get into patient education in this scenario.

DR SALANI: Yeah, and this is a field that’s really being researched heavily because we need new therapies because we don’t have as easy of a time with the management of symptoms or the responses.

So I’m going to focus on recurrent endometrial cancer, but this time I’m going to kind of focus on the proficient mismatch repair. And the reason why I wanted to do this is because in the deficient we’re seeing really provocative responses, and a lot of these patients are being cured. In the proficient we’re seeing some profound responses, but a lot of patients are recurring, so we still have to deal with second-line therapy, as you just heard Brian mention.

And so I’m going to talk about KEYNOTE-775. And this is a study designed to look at patients with recurrent endometrial cancer after prior treatment with platinum-based chemotherapy. And these patients — they did measure these patients’ mismatch repair status, and I’m going to focus on the proficient because at this time, when the study was kind of maturing, we already knew that immunotherapy alone was really — patients had really good responses to immunotherapy in the deficient mismatch repair population.

So this study was lenvatinib, which you just heard is a TKI, so those of you who’ve used bevacizumab a lot, or if you — it has kind of that same principle of antiangiogenesis with a little bit of other activity, and pembrolizumab versus physician choice chemotherapy. And unfortunately the standard arm for chemotherapy are doxorubicin and paclitaxel. I say unfortunately, and I’m going to show you why in about a second.

Before I do that I’m going to just show you the baseline characteristics, and this is an area that I think we need to kind of work on. You can see the race distribution, we need to make sure our enrollment in trials kind of represents the patients who experience the disease, the mismatch repair status, with 84% being pMMR. And you can see a lot of these patients had the classic type, the bread-and-butter endometrioid cancer, but there were some patients who had high-grade types.

But what was really profound were the survival outcomes. And here you can see that the progression-free survival and overall survival were both significantly improved with lenvatinib and pembrolizumab compared to the single-agent chemotherapy arms. And you can see here — I love the explanation of the hazard ratio, because otherwise if you just get the months it’s one point in time. So I use hazard ratio, and here you can see it's 0.6 and 0.7. And so this had a significant impact in the reduction of progression or death from endometrial cancer.

But what I really like to highlight to patients is the objective response rate, which is down on the bottom of the table. The objective response rate to chemotherapy, what we considered standard of care, was only 15%, and that, to me, is pretty dismal. Here with lenvatinib and pembrolizumab we were able to double it to 32%. We were happy about it, but it clearly is not good enough. And then you can see the duration of response was improved with lenvatinib and pembrolizumab, as was the overall survival.

And here is just once again … and I just want to highlight the dMMR population also benefitted, but it was pretty comparable to pembrolizumab or dostarlimab alone, so the addition of lenvatinib wasn’t really necessary in these patients. And that’s important because we’re going to see more toxicities.

And so these are the calls that you might get in the office. Lenvatinib and pembrolizumab were associated with higher rates of hypertension, so similar to what we see with the antiangiogenic effects of therapies, we do see a significant increase. And you can see, about 40% of patients have Grade 3 or higher toxicity in hypertension. So these are patients who need the initiation of management or increase in management because many of these patients may have baseline hypertension.

Diarrhea. And this is interesting because you heard about colitis earlier with pembrolizumab, dostarlimab or checkpoint inhibitors, and lenvatinib also adds to this. So now you have 2 agents that may be contributing to diarrhea, and this can be significantly morbid for these patients.

And then you can have changes in appetite or eating, which can also lead to weight decreases.

On the right side I have highlighted the side effects that were higher with the chemotherapy, but that doesn’t mean they were nonexistent with lenvatinib and pembrolizumab. We do see some proteinuria, same thing with the antiangiogenic effect. Anemia and neutropenia were higher in the chemotherapy arms, not unexpectedly, but still notable in the len/pem arm, as we call it.

What I do want to highlight, and Neil mentioned this earlier, is this can be a tough regimen, and you can see that about 66% of patients required dose reductions. And this is important to monitor these patients and manage them appropriately, because if they require dose reductions to be able to stay on an effective therapy you want to do that. Same thing with dose interruptions, about 70% of patients, and discontinuation about a third of patients. So this is a regimen we need to pay close attention to.

Kind of what Katie showed you in the beginning with the adverse events. This is a timeline of when these side effects occur, and you can see that hypertension and diarrhea occur early. This is on weeks to onset, so within usually that first month or 2 months you can see a majority of these side effects. Hypothyroidism can be a side effect of both pembrolizumab and lenvatinib, so something to monitor for. And it’s not uncommon. Women actually have a lot of hypothyroidism in general, so it’s a good thing that we’re measuring this and monitoring this.

And then I just want to highlight that len/pem, when you are able to give it, although I talked about the toxicities, it did show it improved quality of life in these patients over standard chemotherapy. So managing these toxicities and encouraging patients to report them is really important so that we can keep these patients on these therapies.

I just want to give 1 brief second to LEAP-001. This was a front-line study of len/pem versus chemotherapy with carboplatin and paclitaxel in the front line. And this was a negative trial, but we did see some benefit in the subgroup of patients who had prior chemotherapy, once again highlighting a key role for lenvatinib and pembrolizumab in the recurrent setting.

So I think it’s really important that we think about alternative options. You’re going to hear about some novel therapies, emerging therapies, trastuzumab deruxtecan. Chemotherapy still plays a role, as does hormonal therapy.

So I just want to kind of remind us that molecular testing is necessary to be integrated into routine practice. We heard about how important it is in first line, but it is still important, even “negative” testing or proficient testing can have treatment implications. And this is standard second-line therapy in pMMR immune checkpoint-naïve population. Now that immunotherapy’s moved up, how you use this may change. And then we’re going to hear about other things, so I won’t belabor them, but don’t forget about hormone therapy, it can be an option, but really the highlight is new therapies are needed in this population. So thank you.

DR LOVE: So Jaclyn, in a second Katie’s going to go through some of the nursing considerations with this regimen, but I’m curious specifically about this issue of diarrhea. As Ritu mentioned, either of the agents can cause diarrhea. How do you — when you have a patient who comes in on lenvatinib/pembro with diarrhea do you stop both agents? How do you think it through?

MS SHAVER: Yeah. I mean, it’s difficult to discern which one is — what’s causing what, and so what we do is usually hold the lenvatinib and see if the diarrhea has begun to kind of decrease on its own. If we know that it decreased on its own it’s probably the lenvatinib. And so if it doesn’t, then we need to start — probably starting some steroids getting onboard because it’s likely an immune response to the pembrolizumab.

DR LOVE: So Brian, Ritu mentioned hormone therapy of endometrial cancer. Of course, we did an entire program the other night on hormone therapy of breast cancer. Can you talk a little bit about when hormonal therapy is used in endometrial cancer, Brian, and what type of hormonal therapy?

DR SLOMOVITZ: Yeah. Great. Thanks, Neil. I think first is who for hormonal therapy, which patients. I like to consider them in the estrogen receptor positive, the classical type 1. Now we call them the no specific molecular profile patients. Particularly we see in these patients the disease has a slow, indolent growth, maybe 1 isolated lung met or liver met, quality of life is still good, and the patients (1) want to avoid some of the toxicities of more aggressive therapy, but (2) would truthfully benefit from a more cytostatic approach than a cytotoxic kill with the toxicities associated with it.

A lot of times we consider hormonal therapy as a combination of biomarker-driven therapies, like the mTOR inhibitors or the CDK4/6 inhibitors, with a hormonal agent. Classically the hormonal agent in those situations has been either an aromatase inhibitor, letrozole or fulvestrant. I’ve done some work with everolimus, which is an mTOR inhibitor. There’s been a lot of work recently with ribociclib. Dr Mirza from the ENGOT group published a palliative study looking at a benefit there.

But again, the advantages, it can have a good effect with good, longer progression-free survival, but it also is a little bit more tolerable and gives patients a chemotherapy break or a break from more aggressive therapies.

DR LOVE: Yeah. So speaking of multiple agents in the same class, we have 3 approved CDK inhibitors. And again, the other night we went through some of the differences between then in the breast cancer setting.

So Katie, let’s talk a little bit more about this challenging regimen, one of the most challenging regimens, I think, in all of oncology, lenvatinib/pembro, and how you think through managing these patients.

MS LYLE: Yeah. So we’ve talked about the indication for lenvatinib/pembro, or len/pem. They do have a synergistic effect, so kind of back to the patient education of what do I say when a patient’s starting on this therapy. Part of my initial education is you’re getting a medication called lenvatinib to help the pembrolizumab work better. They work well together in your specific tumor type. And so from there I kind of explain how immunotherapy works, and then, as Dr Salani mentioned, lenvatinib is an antiangiogenic agent, which means that essentially cuts off blood supply to the tumor and starves the tumor, and that results in cell death. And so I give a brief explanation.

The dosing can be very interesting. I’ve talked to — I’m a nurse practitioner. I’ve talked to nurse practitioners across the country. The label indication, the FDA indiction, is for a starting dose at 20 mg. But as Dr Salani talked about, this is a very — this can be a very toxic regimen, and it can be very difficult to give patients. And some of these patients, well, they all have had prior chemotherapy, so they’re all pretreated, so sometimes that plays into how they tolerate this regimen. Sometimes comorbidities affect this as well.

But in practice, when we first started using lenvatinib, we were starting at 20 mg in our patients. And we found out very quickly that we were having to delay almost everyone, we were having to dose reduce, and we were a little bit worried that the interruptions in their treatment was becoming problematic because it was happening for such a large number of patients. And so as a division where I work we have all kind of settled on starting at a reduced dose. We’re aware of the FDA label, but in practice we actually start at a reduced dose, and we found that patients tolerate the regimen better and stay on track with their treatment a lot better for that reason.

We’ve talked about some side effects and kind of the timing. I would say the hypertension and diarrhea and fatigue are some of the things that I’m talking about after treatment number 1, so they do happen pretty early on.

And like we just talked about, sometimes it’s really hard to tease out what side effect is coming from the lenvatinib versus the pembrolizumab, or is it a combination of both? And so we do the exact same thing. We hold the lenvatinib, the pembrolizumab we keep on track, and we see if there’s a change. If there’s a reduction in the severity of the diarrhea or some of the adverse effects, then we can say okay, let’s attribute that to the lenvatinib, and we’ll oftentimes consider doing a dose reduction. But that’s one strategy for teasing out which is which. And I educate patients. I say these side effects could be coming from one or both of your medications, so again, it’s really important for you to call me the moment something changes, as opposed to waiting 3 more weeks when you come back, and now you’ve had 3 weeks of uncontrolled diarrhea, weight loss, fatigue, and now you’ve got that snowball effect again.

I do go over a lot of helpful over-the-counter medications and sometimes prescription medications with these patients. So I start a lot of patients — if they don’t have preexisting hypertension, I start them on blood pressure medication if I need to. It’s really important that they all have a blood pressure cuff at home, so I’m big on show me your blood pressure log. Let me see. Clinic is one snapshot in time. I want to know when you’re checking it every day, what does that look like? And then I can identify a trend over time and see when we may need to start someone on an antihypertensive agent.

There are antidiarrheals that are over the counter. There’s also prescription strength. Again, similar to immunotherapy, I want them to go ahead and have the over the counter at home so that they can start it at the first sign of diarrhea.

I do have a lot of patients who end up needing some mouth rinse for oral mucositis. So that might be actual mouth sores, but it could also be inflamed gums. So we have magic mouthwash or dexamethasone oral rinse. I use a couple. Sometimes insurance dictates what they are going to cover and/or what would be affordable, so it’s nice to have a couple of options to try there.

And then sometimes we’ll use topical steroid creams or in a minute I’ll speak to a patient example where we needed to use urea cream topically for PPE, which is a side effect that can happen, where on the palms of the hands and the soles of the feet, the skin can kind of blister and peel.

But I think I covered this. Patient education is just really important. Having what you need at home. Checking the blood pressures. Every visit I’m going to ask about all of these side effects and just check in and make sure nothing has changed.

Weight loss is a big side effect that can be extremely challenging. And I’m talking weight loss to the point where I know what the patient looked like when we started, and they walk in, and I say oh my gosh, you look emaciated. Like it is pronounced. It’s not just my scale at home disagreed with your clinic scale. And so that can be a challenge. I really pay attention to nutrition, try to focus on protein intake. As I’ve talked about, the diarrhea sometimes can only make the weight loss issue worse, so sometimes there are multiple factors at play, but the weight loss is challenging. We do have some patients where I will set up a nutrition appointment just to try and help them find some strategies for trying to maintain the weight that they have and eat a balanced diet because the weight loss can be so profound.

But the example that I was talking about is the next bullet point. And this is a patient who was on len/pem. At the time she was on 14 mg, and she developed the PPE, so the blistering and the peeling on her feet, specifically, more so than the hands. And so she came in, and I mean if there’s any foot complaint, the first thing I want you to take your shoes off. I want to look at it. And when I looked, I mean, she just — the skin was peeling. It looked red, inflamed. She couldn’t even wear certain shoes anymore. She was having to modify that. Walking was uncomfortable.

So first step, hold the lenvatinib. I had her stop that. And we ultimately had to hold it for over a month. And one thing that helped was time, time off of therapy, remove what’s causing the effect. So that was really important to stop the therapy, and then we gave her some topical cream to apply, similar to what I give with this side effect that can happen with chemotherapy as well.

Ultimately she was able to restart. I did not have to discontinue the drug altogether, but it did disrupt her treatment. And I think this important because this was a recurrent endometrial patient who was on len/pem for a year and a half maybe, maybe a little bit longer, that was unfortunately her last line of therapy. After that she progressed and opted to go on hospice.

But I can tell you, her daughters came with her to every appointment in this regimen, and being able to stay on it and achieve some degree of stable disease allowed her more years and time with her family, and that really mattered. So I think these treatments, even if we’re not seeing a cure necessarily, like we do with some agents, it is giving them time, and that’s something that’s extremely important to patients and families.

DR LOVE: One of the themes we’ve talked about here is the issue of how people shift their goals in life when confronting a disease that’s not curable, and I think what you just said is a great example.

I think we should point out probably the weight loss is more related to the lenvatinib. When I first heard about it a few years ago I was thinking, well, maybe this could be a weight loss thing like the GLP drugs, but obviously it’s a little bit tougher than that.

I think another thing, again, we’ve talked about it a number of times, is to keep in mind, of course you’re very focused when a patient comes in with symptoms that it might be related to treatment, but it could be completely not related, and so we have to keep in mind a differential diagnosis.

And Ritu, that brings in one other complication I’m curious what your experience has been with, which is pneumonitis from these agents. We’ll talk later on about T-DXd, which has interstitial lung disease, but what kind of pneumonitis do you see with checkpoint inhibitors? How do you manage it? I also remember when COVID was out people would come in, and we weren’t sure was it COVID, was it pneumonitis. What’s your experience? How often do you see it? What do you do about it?

DR SALANI: Yeah, so pneumonitis can be a side effect with the checkpoint inhibitors, and fortunately I haven’t seen it too often, or I’ve been able to manage it early on. So you do see it, and patients may have shortness of breath. They may have symptoms. I think now, as we’re going to hear about new agents, we’re maybe a little bit more attuned to it, and now our radiologists are as well.

But pneumonitis with checkpoint inhibitors can be significant, and patients can progress, their symptoms can get worse. So you do want to kind of be mindful of it and make sure you’re monitoring it, checking oxygen levels in the office. And then oftentimes you may have to hold the therapy if the patient’s symptomatic. If it resolves, which in my experience it has resolved when it’s been mild, you can rechallenge patients, but you want to monitor them closely. If it’s persistent, then it may be a reason to discontinue therapy.

My partner had a patient who did require intubation from severe pneumonitis and unfortunately was not able to be weaned off. So these can be oh, it’s not that bad, and then all of a sudden it is, so you want to be really mindful of it.

DR LOVE: Do you see cardiac issues with the checkpoint inhibitors?

DR SALANI: Yeah. So there are myocarditis, and there are cardiomyopathy reports of checkpoint inhibitors. So we think — oftentimes patients are like oh, it’s a lot easier to tolerate, but some of the side effects can really be severe and even fatal.

Novel Investigational Strategies for Newly Diagnosed Advanced Endometrial Cancer

DR LOVE: So we’re going to move on now and talk about investigational strategies, clinical trials. We’ve already alluded to it a number of times this past week. The idea that participation in a clinical trial can be a great option for patients. This is not just about helping future patients, but we see patients all the time who are treated with new therapies that you can’t receive in the community, are not approved. And we’ve seen patients who do great before a drug’s even approved on new therapy.

So Brian, let’s talk a little bit about some of the new areas that are being looked into right now in endometrial cancer.

DR SLOMOVITZ: Thanks for the opportunity here. I’ll be discussing novel investigational strategies for newly diagnosed patients with endometrial cancer. And in this talk I’m really going to focus on 2 aspects, both PARP inhibitors and then nuclear transport inhibitors.

So here we can see a cartoon of the mechanism of action of PARP inhibitors. PARP inhibitors block the activity of PARP enzymes leading to — that leads to the accumulation of DNA damage. Single-strand breaks go unrepaired, and during DNA replication these single-strand breaks can turn into double-strand breaks, a more lethal form of damage. There is also trapping PARP on the DNA. PARP inhibitors trap PARP enzymes at the site of damage, physically blocking repair and replication machinery, which is especially toxic.

The key concept here behind PARP inhibitors is that normal cells have functional homologous recombination repair, or HRR, and they can fix these double-strand breaks using the BRCA1/2 and related proteins. It’s the cancer cells that have BRCA1/2 mutations that lack this repair mechanism. They rely more on PARP for DNA repair. And essentially what happens is when you block PARP in these cancer cells DNA damage builds up, and cells can’t repair themself, and they die, but normal cells survive.

So here’s another cartoon basically showing — looking at the potential synergy that we see between PARP inhibitors and immune checkpoint blockade. There’s an increased tumor mutational burden that we see on the left. By inhibiting DNA repair PARP inhibitors can lead to genomic instability. This can result in more neoantigens, making tumors more recognizable to the immune system.

We also see something called the activation of the STING pathway. DNA damage from PARP inhibitors can lead to systolic DNA accumulation. This activates the STING pathway, which is a key immune-sensing pathway within the cell, and it triggers what we call a type 1 interferon response, promoting immune cell recruitment and activation.

On the right we see that PARP inhibitors can lead to an increased PD-L1 expression on tumor cells. While this helps tumors evade the immune response, it also creates further rationale for the combination of PARP inhibitors with immune checkpoint inhibitors.

I want to go through 2 studies that really looked at the incorporation of PARP inhibitors with checkpoint inhibitors. Now, Ritu did a really nice job looking at the 4 landmark studies incorporating checkpoint into the first or metastatic line — metastatic or recurrent setting.

One of the trials, the DUO-E trial, which was led by Shannon Westin, it actually did a nice job incorporating the evaluation of PARPs into the same trial. So the trial was a 1:1:1 randomization. It looked at the effect of durvalumab, with a PARP placebo in Arm 2, but in the third arm we can see it looked at durvalumab and olaparib, a PARP and immune checkpoint, in addition to the standard chemotherapy with carboplatin/paclitaxel. The primary outcomes here were progression-free survival based on immunologic RECIST criteria. Let’s look at what the results showed us in the quadruplet.

So here are the 3 arms, basically, in the study. The control arm being on the bottom, carboplatin/paclitaxel, the durvalumab-alone arm in the middle. And we can see that there was an improved benefit in the overall intent-to-treat population in those patients who received durvalumab and olaparib.

One of the problems with this study is it really wasn’t designed to compare Arm 2 to Arm 3, so when we looked at the statistical significance of the hazard ratios, in the chart on the right, we — the durvalumab and olaparib is really compared to the — designed to compare to the placebo versus durvalumab alone. And we can see when we looked at the durvalumab with olaparib the hazard ratio was 0.55.

Going on with Neil’s statistical lexon, if the confidence interval doesn’t cross 1, then it’s statistically significant. And here we see it didn’t, so it was. And that’s compared to the 0.71 with the durvalumab alone. When we did the head-to-head comparison of Arm 2 to Arm 3, though it wasn’t prespecified, there was also a benefit of durvalumab and olaparib versus durvalumab alone.

So what we did in this forest plot is we tried to figure out which group of patients may benefit from the addition of PARP inhibitors. Now, my sense is it’s not all of them, and we need to do a better job to identify which patients may actually benefit from PARP inhibition in addition to the checkpoint inhibitors.

I’ll focus your attention now to the second category, those with the POLE or the p53 mutational status. And we’ll see in those cells that are p53 mutated, which is below the POLE mutation here, there’s clearly a benefit, and that benefit line doesn’t cross 1, so it may be the p53-mutated patients that most likely benefit from PARP inhibitors.

In a similar study, now this was done sequentially. This is RUBY Part 2. Ritu gave us a nice overview of RUBY Part 1. This continued after Part 1 looking at the traditional arm chemotherapy versus chemotherapy, dostarlimab and the PARP inhibitor niraparib.

This study reported out. On the left we can see that in the overall survival there was benefit, with a hazard ratio shown here, the hazard ratio of 0.6, and specifically in the pMMR population a hazard ratio of 0.63, both showing a benefit of the addition of PARP inhibitors.

We can see here similarly, on the right side, the p53-mutated patients. They also had a benefit here of PARP inhibitors, with a hazard ratio of 0.29, suggesting that maybe that’s a subgroup that would most benefit, the p53-mutated patients, most benefit from PARP inhibitors.

Nuclear transport inhibitor selinexor. It works by helping the cell retain normal functional tumor suppressor genes, what I like to say, keep in the proteins within the cell, inhibit mRNA export of select oncogenes.

We did this study of selinexor in the maintenance setting after complete response or partial response to chemotherapy for these patients with advanced or recurrent disease. And we can see here adding selinexor for the whole population didn’t affect the outcome. However, on the next slide, we can see a prespecified subgroup analysis of the p53-mutated patients. Those patients had a hazard ratio of 0.44, benefitting with selinexor, suggesting maybe that in these cells, unlike the PARPs where it may work in p53-mutated, it may work better here in a p53-wild-type group of patients.

Unfortunately, the study didn’t have statistical power to demonstrate this, so we’re following it up.

This is an ongoing trial in p53-wild-type patients specifically looking at selinexor in the maintenance setting to see if in fact in a prespecified statistically designed study adding selinexor after chemotherapy can truly benefit and prolong the better outcome for patients, specifically in the p53-wild-type patients.

DR LOVE: So Ritu, getting back to the issue of PARP inhibitors, of course yesterday we did a program on ovarian cancer. We spent most of our time talking about PARP inhibitors. There are, again, multiple agents available. I’m curious, here you see immunotherapy and PARP inhibitors, as Brian was discussing here, dostarlimab and niraparib, one of the drugs we talked about yesterday with ovarian cancer. And we talked about the hazard rate, and these are pretty good hazard rate, 0.6, so 40% improvement.

What would it take for you to be able to want to — is this enough for you to want to take action? Do you want to see more data? Do you think the FDA will approve it? And also, do you ever see patients who have BRCA mutations in endometrial cancer? And does that change how you approach this?

DR SALANI: Yeah. I think it’s a little nuanced, and I’m still kind of deciding how I think PARP inhibitors are going to play a role in advanced and recurrent endometrial cancers. I think Brian’s really nicely highlighted the data, and I think it is — there is a role. I’m struggling with which patients, because you heard about toxicity with immunotherapy, there are toxicities with PARP inhibitors, so I think one size fits all is not the right approach. HRR genes or BRCA mutations, like you referred to, are pretty compelling. That seems really attractive to me. The p53 mutation, maybe there is some synergistic effect. I would like to see more data.

Now whether that’s feasible or not, if the FDA does approve it, I may be selective in my choices. I think the selinexor data is really exciting, and we have that trial open. So I think it’s going to become this area where we have these kind of maybe divergent paths depending on what your molecular profiles are, what your tolerability is, and at some point patients may see different — see it sequentially instead of at front line.

DR LOVE: Any comments on the difference between PARP inhibitors? Again, we have a lot of experience in ovarian cancer. Niraparib, we think a little bit more about thrombocytopenia. Olaparib, we hear more about anemia. In your experience, any thoughts in terms of differences there?

DR SALANI: Yeah. We’ve been using them for quite some time now. I feel like we’re pretty comfortable managing it. The other one with niraparib is hypertension, which you also heard with lenvatinib. And so these are symptoms — I mean side effects that I think we’re getting better at managing. I do think there’s a class effect. I am very study driven, so I’ll use the evidence to support my decision. I usually don’t cross over. But when you have multiple approvals, it may be if a patient has baseline hypertension, that may be a reason to maybe use olaparib as opposed to niraparib in this setting.

DR LOVE: Yeah. And again, I think usually people follow the data, particularly if there’s not that much difference in them.

So Jaclyn, we asked you to talk a little bit about selinexor. Right now it’s not being used. As Brian was pointing out, the data looks very encouraging. We kind of make a joke, we wake up in the morning, oncologists and gynecologic oncologists, we check our phone to see what’s been approved, and then we start thinking about what we’re going to do about it. We may wake up one day and there’s going to be a press release saying selinexor’s positive. All of a sudden we’re going to need to figure out how to use it. Fortunately, it already is approved, and it is used quite a bit in multiple myeloma and lymphoma, and we hear a lot of challenges there. So Jaclyn, can you talk about what you’re thinking about at this point if and when selinexor comes to endometrial cancer?

MS SHAVER: Yeah, sure. So what I am anticipating telling my patients is kind of explaining, again, why is this therapy good for you in your particular tumor. And so selinexor is used with the p53 wild type, so explaining that, that p53 wild type just means that your gene is functioning normal, the p53 gene is a normal gene. So it’s a tumor suppressor gene. It has a critical role in maintaining genomic stability and preventing cancer. It detects DNA damage and triggers the repair, cell death or damage of cancerous cells and stops that cell division. So studies have shown that selinexor works better in patients with a normal-functioning gene like theirs.

And so as we have heard earlier, that there is an ongoing clinical trial right now called XPORT. So it’s a Phase III randomized, placebo-controlled, double-blind, multicenter trial of selinexor in maintenance therapy after systemic therapy for patients with p53-wild-type, or your gene is functioning normal, in advanced or recurrent endometrial cancer.

We have this trial going on at Stevenson Cancer Center. We are still screening patients right now. We currently don’t have anyone on this particular trial just yet, but we are in the screening processes.

So I wanted just to point out some side effects that you can get from this drug. Number 1 in the GI is nausea. And so it’s really important if you do get this drug approved that’s one of the big things that we need to educate our patients about, is they are going to likely have some nausea, and getting those antiemetics onboard with this oral drug. And so using a combination of 2 agents is really important, and if need be moving on to your third and fourth line agent is essential, because if they’re nauseous, they’re not eating, they’re losing weight, it’s just … effect on those patients, and they don’t tolerate treatments very well, and it’s an oral drug. So what happens when you feel bad on an oral drug? You stop the drug. And it’s really important for those patients just to know that it is important to stay on those drugs, and if you’re having difficulties please call us and let us know, and so then we can do some adjustments to how we need it.

So again, the decreased appetite and weight loss goes again with the nausea and vomiting.

You can get some thrombocytopenia, so again, if patients are calling in and saying I’ve had this abnormal bruising. I’m just bruising really easily, or my gums, when I brush my teeth, are just — they’re starting to bleed more than normal, then that would need to trigger you to say hey, maybe we need to bring you back into the office. Let’s get some blood work on you. Let’s get you evaluated and see how we can get this managed for you.

Another one, too, is altered taste. So again, you have the nausea and vomiting, you have the altered taste, and this all goes into kind of the nutritional value of how the patient is doing with this particular drug.

And then the fatigue and weakness. I encourage them to be as active as they can on this drug. Exercise at home is really critical to keeping their activity level up.

They can also have some cough, some dyspnea, some pneumonia. They can get respiratory infections from this. So again, fevers, chills, make sure that you educate them on that and bring them back into the office. And then they can have some myalgias with this.

Some less common side effects, as you can see here, even tumor lysis syndrome with this drug, confusion, delirium, so the patient’s family is calling and saying hey, my family member is not correctly. They’re telling me things that are not correct. And make sure that we need to get them into the office and be evaluated.

So on this clinical trial, the XPORT trial, it is, again, an oral medication, like I said. They need to be drinking water with it, taking it whole, avoid contact with the skin, take it the same day each day. There’s no diet restrictions. Make sure they’re maintaining adequate hydration and oral intake. It is a weekly pill. It’s a 28-day cycle dosed at 60 mg day 1, 8, 15 and 22. If they miss a dose, take it the same day. And again, talking about doing that 2-drug antiemetic regimen for at least the first couple of cycles.

So I have this patient. She’s a 49-year-old, Grade 1, Stage I, had a hysterectomy/BSO with a mini lap. She had no LVSI, no myometrial invasion, no adjuvant therapy that was done. She was proficient in her MMR, and she was p53-wild-type. She had uncontrolled diabetes at baseline, CHF, AFib, morbidly obese, really not a compliant patient with taking her diabetes medication.

I discovered a recurrence at her vaginal cuff and ended up having transmural colonic involvement. And that was biopsied in May of ’20, and then she did have some confirmatory biopsies by colonoscopy in June of 2020. She had carboplatin/paclitaxel times 6 cycles and actually had a complete response, which was amazing.

And so then she was put on a clinical trial, 3055. It was a maintenance trial with selinexor. And as you can see from her previous history, she wasn’t the most compliant patient. And so she had difficulty with nausea and vomiting. She did not take her nausea medications, as we had tried to instruct her to do, gave her other antinausea medications, but again was not compliant with those.

And ultimately she was off trial. She did not want to continue with the maintenance therapy. But she continues to be NED, as far as I know. She did no-show her last surveillance visit, but she hasn’t called with any symptoms. So again, just picking your patients, making sure you’re giving the selinexor to the right patient. So that’s very important.

DR LOVE: That’s a really amazing case. When you were going through that list of side effects I was thinking about some of the ads on TV. You see the happy patient, and they go oh, but it might cause A, B, C, D, E.

Incidence and Management of HER2-Positive Endometrial Cancer

DR LOVE: Anyhow, we’re going to finish out talking about something, again, that we talk about a lot in various cancers: HER2-positive disease. We were just at the Society of Gynecology Oncology Meeting, where we did a program on ovarian cancer, but we did another program just on HER2-positive endometrial cancer. And it was really amazing, we showed videos of docs in practice who’d put patients on T-DXd, and for the first time we were hearing cases of people responding. Really exciting. It reminded me of 3, 4 years ago when we started to hear this in breast cancer.

But Brian, let’s talk about the patient who’s already been through immunotherapy, chemotherapy and is found to be HER2-positive. We know the antibody-drug conjugate — again, on Wednesday we did an entire program on antibody-drug conjugates, check it out if you weren’t there, now consideration for T-DXd — trastuzumab deruxtecan. What do we know about HER2-positive endometrial cancer, Brian?

DR SLOMOVITZ: Yeah, no. Thanks, Neil. And this is super exciting. For me, this is going to be game changing, really not just HER2, but the use of ADCs in endometrial cancer, and we’re introducing — going into this area through — with the HER2 ADC. I’ll talk about the incidence and management of these cancers.

So what is HER2? Human epidermal growth factor receptor 2. A lot of you all know this. I’m just going to go through it quickly for you. It promotes cell growth and division, commonly overexpressed in breast and gastric cancers. Within endometrial cancer we see HER2 overexpression mainly in serous carcinomas. About 25 to 30% of serous carcinomas have HER2 overexpression. Rare in the endometrioid subtype, less than 5%. But we also see it in other histologies, carcinosarcomas about 16%. And it’s present on the cell. And when it’s present it’s associated with an aggressive tumor behavior.

So I know, again, ADCs are what I like to say changing the world, particularly in gynecologic cancers and endometrial cancer. A lot of you know this, very quickly, there’s 3 components. There’s the antibody component, which targets the ADC to the cell. If a cell, a cancer cell’s overexpressing a protein, in this situation HER2, the ADC will get attracted to the cell through the antibody on the ADC. The third component is the payload, that’s the kill, oftentimes a chemotherapy, and we’ll talk about specifically with trastuzumab. That’s what’s going to help kill the cell, like the chemotherapy we give in the arm.

The key here is the linker. What the linker does, it holds the antibody onto the kill through the circulation system, and then when it gets to the tumor it’s smart enough to release the kill, release the payload into the cell so it can have its cytotoxic effect. We can see that from the cartoon here.

So here’s specifically trastuzumab deruxtecan, an anti-HER2 ADC. It’s a humanized anti-HER2 IgG1 antibody. It has a highly potent topoisomerase inhibitor payload. We know that topoisomerase I inhibitors are generally active in a lot of cancers we treat. There’s an 8:1 drug-to-antibody ratio, and it has a cleavable tetrapeptide-based linker. High-potency payload, high drug/antibody ratio, payload with a short systemic half-life. Really what we’re finding out, and what we’ll see in the data, an active ADC in a lot of the drugs that we treat.

Game-changing study, something called the PanTumor02 study for trastuzumab deruxtecan for HER2-expressing solid tumors. I’ll highlight here on the right the 7 tumors that were evaluated. Primary endpoint here, confirmed overall response rate. What I’m most excited here — and this was presented a couple years back by Dr Funda Meric, really game changing. What I want to highlight is the endometrial data, which I’ll show you on the next slide.

Again, this is 40 patients, so we have to remember, it’s not a huge number of patients, but it did show a significant signal. In those tumors that had HER2 3+ overexpression the response rate in heavily pretreated patients was 84.6 or 85%, 2+ positivity 47%, for all patients 50% response rate. Now we’re talking about in endometrial cancer, first-line therapy is carboplatin/paclitaxel, first line of 50%. This is 85% in the subgroup of patients in the heavily pretreated population.

Based on the ASCO presentation the FDA granted accelerated approval to trastuzumab deruxtecan for unresectable and metastatic HER2-positive solid tumors. It got NCCN listing in the 2+ and 3+ populations and ultimately a full FDA approval in the — well, the accelerated approval in the 3+ populations in April of 2024.

There’s also data not only all endometrial cancers, but in the carcinosarcomas, heavily pretreated. We see here in the HER2-high population on uterine carcinosarcomas, which is, again, a rare, aggressive subtype of endometrial cancers, response rate of 54.5%. Even in a low population the response rate in this small study was 70%, suggesting that there’s definitely a role — suggesting there’s definitely a role in the high expressors, but a signal here in the low expressors, Neil, similar to what you’re seeing in breast cancer, the ultralows may actually respond too. More work needs to be done.

DR LOVE: Brian, in the interest of time we’ll let the audience take a look at the case. If you look at your slides you’ll see a really cool case of a patient, like a lot of the ones we heard at the SGO Meeting, who responded to T-DXd. As you mentioned, we talked about this, again, on Wednesday in breast cancer. We’re not only using it in HER2-positive, as Brian mentioned, HER2-low, we’ve seen good responses there, even ultralow, where you can barely see any HER2. So to be continued. Hopefully this will become even more prevalent as we move on.

And Jaclyn, we asked you to talk about some of the things you think about in a patient who’s going to get HER2-targeted therapy, specifically T-DXd.

MS SHAVER: Yeah. So again, just there is NCCN Guidelines for at least second-line therapy with T-DXd for HER2-positive tumors, IHC 3+.

So T-DXd, again, is unresectable, metastatic, HER2-positive, IHC 3+ solid tumors who have received prior systemic therapy and have no satisfactory alternative treatment options.

So in endometrial cancer it’s 5.4 mg/kg every 3 weeks, so it is IV. The first dose is given over 90 minutes, and then subsequent doses over 30 minutes, and it is given until disease progression or unacceptable toxicities. And then there is also room for dose reductions, as you see on the slide.

So this drug has a warning, a boxed warning for interstitial lung disease and pneumonitis. It did have some fatal cases that have been reported, so extremely important when your patients call. If they have a new cough we need to know about that. There has been an overall incidence of 12.3% with this drug, with the median onset about 5 1/2 months. So we, again, need to promptly monitor, investigate any symptoms, to include cough, dyspnea, fever or worsening respiratory symptoms. It is permanently discontinued in all patients with Grade 2 or higher pneumonitis. So we just really need to advise patients to let us know if they’re having any of these symptoms and kind of know what their baseline is.

There has been some higher incidence with patients who have moderate renal impairment, so just good to know that when you’re looking at patients. If they’re calling, look at their kidneys. If you have a moderate kidney impairment patient, and they’re calling in with cough, then we really need to have that on our radar. This could be interstitial lung disease and pneumonitis.

At least getting CT scans at baseline and then every 12 weeks or so. We usually do it at my institution about every 3 cycles, about every 9 weeks, but at least every 12 weeks, and then sooner if they’re having some baseline symptoms.

So if we suspect that they have interstitial lung disease/pneumonitis, this can be picked up on CT scan. The patient could not have any symptoms. So we need to be paying attention to that. If we suspect someone does have that we need some high-resolution CT of the chest, refer to pulmonology, bronchoscopy, pulmonary function tests, and rule out any other causes. It may not be that, but we need to have that, again, on our radar. Getting some blood work, a viral panel and so forth.

For Grade 1 we would interrupt until resolved to Grade 0 and consider systemic steroids at this point, with a gradual taper and really close follow-up. So if this is in a patient that you’re okay, I think it’s maybe pneumonitis, and we’ll see you in 3 weeks. We need to be calling these patients, bringing them into the office specifically, how are they doing, getting their O2 sat monitor. And then if they are — their symptoms resolve to Grade 0 in less than 28 days we can maintain their dose. If not, then we’ll need to reduce their dose.

Grade 2, again, we need to discontinue and then start on systemic therapy. And then Grade 3/Grade 4 we’ll need high-dose steroids inpatient.

They can also have some cardiac toxicity, the overall incidence about 4.6%, with Grade 3 being less than 1%. So we need to assess their heart and make sure that it’s functioning appropriately before we start therapy and then again every 3 months. If we see some reduction in heart status then we can have a — hold the drug and then reassess and have the cardiologist continue to follow them.

Some common side effects. Again nausea/vomiting is the number 1 side effect. You have the fatigue. You have your decreased appetite. You can have some alopecia, and this is not like chemotherapy-induced alopecia. It can be just kind of spotty, where they don’t lose their hair all the way, but you do need to kind of let them know. Say hey, you may have some thinning of hair, so they’re not surprised by that. And some rash, again some cough and some headache that will come with that.

So this is just a clinical example that I have from my practice. So we have a 74-year-old recurrent Stage IV serous carcinoma of the uterus. She had a hysterectomy in November of ’21 she had some residual disease of the small mesentery less than 1 cm. She was HER2-positive 3+. She was p53-mutated, ER/PR-positive, and proficient in her MMR status. She had 100% invasion and positive LVSI and met to the vagina.

So she did go on the DUO-3, as we saw earlier. She had 6 cycles of carboplatin/paclitaxel plus or minus the immunotherapy followed by immunotherapy maintenance. She had a complete response. So again, we’ve had this Stage IV recurrent endometrial cancer patient that had a complete response, so that’s an amazing thing.

But as we continued to monitor her, her mesenteric node began to increase, wasn’t measurable, but then finally got a measurable lesion in March of ’24, which led her to having new treatment, was started on T-DXd. Again, she was HER2-positive. So we got an echocardiogram, her heart looked great and so was able to start that. And she was, again, placed on antiemetics on day 1 and then continued p.o. olanzapine day 2 to day 4.

She has had 16 cycles of this and really doing very well. Her node has decreased now to less than 1 cm. She’s really tolerated it very well, with no big dose reductions or no signs of pneumonitis and echo remains normal. So we’re doing great with her.

DR LOVE: So not an uncommon story to hear with this agent. This woman has had a year already that maybe she wouldn’t have had before.

We’re going to be coming back here today at 12:15. Have you ever heard of claudin 18.2 and zolbetuximab? We’re going to talk about that today. It has GI toxicity unlike anything we’ve seen in oncology before. So please come back for our program at lunch.

Thanks so much to the faculty. Thanks to Brian. Have a great day.