Introduction: ASCO 2024 Review

DR LOVE: Good afternoon, everyone. I’m Neil Love from Research To Practice and welcome to Year in Review, as today we talk about what’s gone on over the past year in gynecologic oncology with Dr Dana Chase from the David Geffen School of Medicine at UCLA in Los Angeles.

As always, if you have any questions or cases you’d like to run by us, just type them in the chat room and we'll talk about as many of these as we have time.

As we always do in our webinars, there’s a 1-minute pre- and postmeeting survey in the chat room for you to take. If you take that, you’ll get a lot more out of this experience.

We know a lot of people end up listening to our webinars. If you’re into audio content and podcasts, check out our Oncology Today series, including a program with Dr Chase’s former colleague, Dr Monk, reviewing ovarian cancer.

We do webinars all the time. Tuesday, July the 9^th, we’ll be doing one on multiple myeloma talking about bispecifics, CAR T and everything else going on. We’ll come back the next day on July 10^th talking about melanoma and nonmelanoma skin cancers. There’s so much going on there, the big NADINA trial that was presented at ASCO. And then on July 17^th, we’ll have a great program on ADCs in triple-negative breast cancer. That should be a great program, as well as our ALK program on non-small cell lung cancer on July the 18^th.

But today, we're here to talk about gynecologic oncology, both from the point of view of the gynecologic oncologist as well as the medical oncologists.

And as always, we will be talking about the use of nonapproved agents and regimens. So check out the package insert for more information.

So in the chat room, you have our slides. And we have a whole list of papers to talk about. But really, we want to really just get an update of what’s going on in gynecologic oncology.

Here’s where we’re heading. First, we’re going to chat a little bit about what happened at ASCO and some cool papers presented there. Then an update on ovarian cancer and then including some new papers. Then, we’ll dive into HER2 as a therapeutic target of all gynecologic cancers, and all solid tumors in general nowadays. Then, we’ll drop into endometrial cancer and, of course, get into the issue of IOs and how to use them. And we’ll finish out talking about cervical cancer.

But before we get started, I am just kind of curious. We have a lot of people new to oncology in our programs, Dana. And you’re an unusual case of somebody who started out in the community and then made their way back to an academic center. You were with Arizona Oncology with Dr Monk for quite a few years. And now, the last couple years at UCLA. I’m just kind of curious, again, for people just getting into the field, what it was like in these 2 settings for you.

DR CHASE: Yeah. Great to be here and chat with you. I definitely have a unique situation. Not many people go from kind of a community, private practice type of setting back to academic medicine. We all started in academic medicine, right? So we all pretty much know what it’s like to be in it. But community private practice in a suburb of Phoenix, lots of patients, lots of surgery, lots of chemotherapy. I was very fortunate to have clinical trials, very fortunate to maintain a collaboration with some scientists with the University of Arizona when I was in Phoenix. But I missed some of the ability to train fellows, for example, fellows in gynecologic oncology and be in an academic center in terms of access to grants and research collaborators. And also, Los Angeles just happens to be my home. So it sort of brought together my ability to go home with the ability to be in an academic center where there’s a lot of really exciting research and education going on.

DR LOVE: Yeah, we work with people from UCLA all the time. You’ve got Dr Salani there. She was in a program we had at SGO and ASCO as well. A lot of the medical oncologists, you stole Dr Bardia from MGH in breast cancer and you’ve got Dennis Slamon already there. So I know it’s a really exciting place.

Alright. Let’s get into the content. And, of course, ASCO is not necessarily the first place you think about gynecologic oncology, but you see some good papers there. And these are 3 I just wanted to ask you about. One, I’ve been curious about this in breast cancer because there was a study looking at neoadjuvant PARP. So they had a paper there, the NEO trial. There was another study looking at endometrial cancer and obesity. I was curious what you thought about that. And then in terms of IOs, particularly in MSI disease, this interesting study looking at this, I guess, a new antibody for anti-TIGIT combined with pembrolizumab. So just taking a quick look at that any thoughts about the NEO study? As you would guess, it looks like they had a pretty good waterfall plot and response there. Actually, I think they saw the same thing with breast cancer. It was only, like, about 50 patients. But it kind of never took off, that I know of, in breast cancer. Any thoughts about this paper?

DR CHASE: Yeah. So we did see an approach like this presented by Shannon Westin at MD Anderson a year or so ago, also looking at PARP inhibitor therapy in kind of a neoadjuvant setting.

DR LOVE: Right.

DR CHASE: So this is neoadjuvant olaparib in a recurrent platinum sensitive setting. And important to note, to go on this trial, you had to be a surgical candidate because there was secondary cytoreduction incorporated into the trial design. So if you had a patient that you didn’t think you wanted to take for surgery, that patient wouldn’t be able to go on trial. And I think we’re all really hoping someday, we saw this with checkpoint inhibitors in the recurrent setting for our endometrial patients, we’re hoping that in ovary patients we’re able to de-escalate care, you know, remove our traditional cytotoxic chemotherapies and give them targeted therapy alone and hope to make the same kind of difference. And so I think this trial kind of said well, maybe that’s a possibility. It’s hypothesis generating. It has to be confirmed in a larger study. There were not a lot of patients on this trial. So definitely, olaparib or PARP inhibitors in general do help with ovarian cancer patients. The question is now that we’re giving olaparib front-line, would this drug perform like this in the recurrent setting as a single agent? And that, I don’t know. So interesting, maybe not practice changing, but interesting to still think about. I hope to read the publication.

DR LOVE: Yeah, it will be interesting.

DR CHASE: Yeah.

DR LOVE: So I’ve always been fascinated by the connection between obesity and endometrial cancer. Diet and cancer to start with also has always been interesting. And there was a paper, again, presented at the ASCO meeting about that. And I noticed in your CV, it was funny because I saw that you had done work in microbiome, which I always love to see research in that. But interestingly, when we talked, I didn’t realize this is vaginal microbiome.

DR CHASE: Yeah.

DR LOVE: So anyhow. Can you kind of maybe comment a little bit about the issue of obesity in endometrial cancer, this paper and also this research looking at vaginal microbiome?

DR CHASE: Yeah. So I just want to also make a plug for the presenter of this abstract was a resident at UCLA that graduated last year. So she’s now a fellow at UC Irvine. Anyway. I think definitely, we know obesity is associated with endometrial cancer. This is not something new. This we know for sure. And I think the last bullet point here, though not scientifically causal, the relationship is very clear. But I will say at this point, there’s a lot of obese people in the United States and the majority of obese patients do not get endometrial cancer. So we really have to try to figure out exactly why some obese patients are getting endometrial cancer. And could there be other factors like the vaginal microbiome, which can also reflect what’s going on in the endometrium, could that play a role? There’s definitely scientists around the country at UCLA and Arizona and Ohio State that are looking at, on the East Coast as well, that are looking at different ways that potentially obesity could lead to endometrial cancer. But it’s not necessarily causal. It’s associated, which is definitely something — I think this is a plug to do more research, which I’m happy about.

DR LOVE: So anything else you want to say about the work that was done, I guess when you were in Arizona, on the vaginal microbiome, how you did that research and whether you think it has any future?

DR CHASE: Yeah. It’s still a work in progress. I give all the credit to the PhD, Dr Herbst-Kralovetz, that I worked with in Arizona. We’re still piecing this together and trying to figure it out. But we, at the time of hysterectomy, we obviously consented the patient preoperatively, before we prepped the patient for surgery, we collected a vaginal swab, a cervicovaginal lavage, and then also an endometrial culture. Collected that, proceeded with the hysterectomy. And then before pathology actually starts to process the specimen, we did another culture of the endometrium once it’s out of the patient. And then at the same time, we also collected a rectal swab. So we had several specimens that we could analyze to look at not just microbiome, which can be diverse and different in various patients, but also metabolites and other biomarkers that are potentially in that cervicovaginal lavage. And like I said, it’s a work in progress. But hopefully, we’re going to get further along in it. We collected specimens on benign disease, preinvasive, as well as cancer, so we had a good amount of patients to compare to.

DR LOVE: I’m going to have to practice saying vibostolimab.

DR CHASE: Yeah.

DR LOVE: I’m not even close at this point. But maybe vibo. We can come up with a nickname here.

DR CHASE: Yeah.

DR LOVE: But this paper really, to me, also just brings up the issue of the fact that not everybody with MSI-high disease does well on a checkpoint inhibitor, and the question about why. What if you add in anti-TIGIT or some of these other agents? Any comments about this? I guess it’s a small number of patients that had MSI-high disease. They had a 65% response rate, but maybe that was, it seems maybe a little higher than pembro alone. But I guess just more an exploratory analysis.

DR CHASE: Yeah.

DR LOVE: It seemed like they had a fair amount of autoimmune toxicity. Any thoughts about this?

DR CHASE: Yeah. Definitely, just to highlight that point. Definitely, more toxicity. I think it was 30% to 40% Grade 3 or 4 toxicity when you added this anti-TIGIT agent. And you’ve got to remember, this is in the recurrent setting. And so now, we’re giving anti-PD1 or anti-PD-L1 in the front-line setting. I will say it’s definitely very important and very effective for a dMMR patient to get checkpoint inhibitor therapy. It’s not a slam dunk for everybody, meaning it’s not a cure for everybody. So could some subset of patients in the front-line setting maybe benefit from the addition of this anti-TIGIT agent? Will you allow for the toxicity if you cure more patients? That’s to be told, but maybe that’s where this is headed to try to cure more patients in the front-line setting. I just worry a little bit about the toxicity, which is already a little, honestly, in the real world, already a little challenging sometimes with these checkpoint inhibitors. But we’ll see in future trials.

DR LOVE: Do you think in terms of, it’s interesting you brought that question up because I’ve asked this a number of times over the years which is, the toxicities, autoimmune toxicities, the way they play out. Anything different about it in gynecologic oncology patients? You immediately think about the abdomen, obviously. Do you see more problems with colitis? Or if they get colitis, is it more of a problem? Does radiation add to it? Any broad comments about the types of toxicity you see?

DR CHASE: I haven’t seen necessarily a different toxicity profile than other cancer types. I think when you look at the trials like, for example, GY018 or the RUBY trial, you get pretty reassured that there’s very minimal Grade 3 or 4 toxicity with these checkpoint inhibitors. But then in the real world, if you’re not careful, yeah, you’re going to run into a colitis or a pneumonitis or a nephritis or a dermatitis or definitely we see a lot of thyroiditis potentially that maybe we just weren’t used to seeing previously.

But just because you asked, one time, I did see a patient who had a pretty bad case of what’s called lichen sclerosus when she was on a checkpoint inhibitor therapy. It might not be related, but there is some thought that lichen sclerosus, which is a condition of the labia that’s very uncomfortable for women, it could have an autoimmune cause. And so could that lichen sclerosus have been associated with her checkpoint inhibitor therapy? Not much in the literature about it, but I was curious because she developed it on treatment. But just something to think about, not necessarily related.

DR LOVE: Does it go away with steroids?

DR CHASE: It does go away — doesn’t go away necessarily, but some of the symptoms are ameliorated by steroid cream, for sure.

Ovarian Cancer

DR LOVE: Alright. Let’s get into the nitty-gritty here of some of the papers related to specific issues. But first, let’s go from the chat room, a quick case for you from Uzoma. A 75-year-old woman, Stage III serous ovarian cancer, somatic BRCA2 mutation. Declined PARP inhibitor maintenance in the front-line. Now, it’s 2 years later. She’s got platinum-sensitive recurrence. Would you use a PARP inhibitor? And which one, I’ll add.

DR CHASE: Yeah. So I think I heard BRCA mutated.

DR LOVE: Right.

DR CHASE: Didn’t want PARP inhibitor in the front-line. I’m assuming she’s getting platinum-based treatment again and she’s responding to her platinum-based chemotherapy again. As long as she has a response, I think it’s appropriate in a BRCA mutated patient to use it second-line maintenance. Yes, I would do that.

DR LOVE: While we’re talking about it, and we’ll get into this later, but as long as this case really brings it up. What are the situations where you will use a PARP inhibitor in the recurrent disease setting? This case where the patient hasn’t had PARP inhibitor and has a BRCA mutation, I think that clearly is one thing. Any other scenarios?

DR CHASE: Yeah. I honestly am using PARP inhibitor therapy so commonly in my homologous recombination deficient and my BRCA mutated somatic or germline patients front-line that it’s pretty rare for me to give it again to them in recurrence. But I will consider it, for example, in a patient that she was on PARP inhibitor maintenance, she completed her 2 or 3-year course, she’s been disease-free for a year. I have done that in clinical practice. I have re-treated with PARP inhibitor maintenance after they got second-line platinum-based chemo. So that would be a patient that I would consider using it again in. If they progressed on PARP inhibitor treatment or had very bad toxicity with it, I might not use it again even if the patient is BRCA mutated.

DR LOVE: A really good follow-up question from Uzoma who says, how long would you use it in this patient, metastatic disease?

DR CHASE: Yeah. So in the front-line setting, we do 2 years with 1 PARP inhibitor with olaparib, and 2 years with niraparib. In a recurrent setting, not sure you’re going to get that 2 or 3 years disease-free, chemo-free interval again, but it’s possible. So I would just go to 2 or 3 years and kind of see how it’s going. Initially, I thought nobody was going to want to come off PARP inhibitors. But in my kind of real-world practice, some of them are pretty thankful to come off due to toxicities like low-grade fatigue or low-grade GI toxicity. Some are like, yes, I’m going to come off, I’m ready to stop, after 2 or 3 years. But in the recurrent setting, technically, you’re able to go until progression or toxicity.

DR LOVE: Yeah. Well I hear you though that if you get to 2 or 3 years, you’d be happy. But, of course, the other thing is a lot of people are keeping AML and MDS in their mind and get nervous with longer duration.

DR CHASE: Yes.

DR LOVE: Although I’m not sure we know that for sure. But it makes sense that you get nervous about it.

DR CHASE: Yeah. Yeah, that’s true for sure. Definitely should mention that. Yeah.

DR LOVE: So we picked out a bunch of papers. Honestly, I’m not even sure how important some of these are, but I think it leads into topics that I know people ask a lot of questions about. So one is the issue of bevacizumab, when to use it and for how long. There was this paper in the JCO this year, the BOOST study, a Phase III study looking at the optimal duration of bev. But really what I want to ask you about and what oncologists ask me about is first of all, when you have an up-front situation, when do you use bev? Do you use it neoadjuvantly and adjuvantly? Would you ever use it adjuvantly if they hadn’t had it neoadjuvantly, but they had neoadjuvant chemo. And then, what’s the KELIM score and do you use that in trying to decide about bev?

DR CHASE: Yeah. So now you go around the country and you hear mixed views on this. So I’ll just tell you, for me, neoadjuvant patient, I use bevacizumab. So preoperatively, hold the dose in your chemo pre-surgery. Do your surgery and hold the dose post-surgery. And then keep giving bev in your follow-up adjuvant cycles, and then bev in maintenance. So I do not use bev in maintenance if I haven’t used it with the chemotherapy. We had GOG-0218, I think, that informed us maybe not to do that. So definitely, if I use bev with chemo neoadjuvant or adjuvant, I’ll use it in maintenance.

And we used to treat with bev kind of forever. But with this study and also with the PAOLA-1 study, I’m pretty comfortable now giving it for, like, 15 months including the months that the patient got it with chemotherapy. So it’s nice to be able to stop it and it’s nice to have data to allow us to stop it.

The algorithm study that you’re mentioning, the KELIM study or the KELIM algorithm, you can actually go on a website, type in the patient’s CA-125, and it’ll calculate kind of the prediction of whether or not she’s responding to her platinum or not based on the CA-125. I find it interesting, but I’m not using it in clinical practice. And it really hasn’t, they haven’t studied it as a way to allocate treatment. It’s more like an interesting fact that maybe you can use to talk to the patient, but I don’t know if I would necessarily use it to stop treatment and switch an agent without a study, like a prospective study that tells me to do that. I hesitate a little bit. Although I encourage you to go online, try it out and kind of see how it applies to some of your patients. But I haven’t been using it to change treatment allocation.

DR LOVE: And it looks like adding a longer duration of bev doesn’t seem to help, at least in terms of this particular study.

DR CHASE: Yeah.

DR LOVE: So again, we saw a lot of papers coming out this past year, but most of them, other than the DUO studies that I want to ask you about, so the classic up-front studies, there were several presentations in terms of longer follow-up, et cetera. But here are the questions that we hear from oncologists and gynecologic oncologists all the time. And the first is, it kind of, after these last few years of sort of going back and forth about trying to break people out, it kind of seems like we’ve rolled into a situation where people are either HR deficient, they’ve got BRCA, they’ve got a high LOH score, or PALB2. You can tell us what you consider. And then there are, I guess to me, like the wild-type patients.

DR CHASE: Yeah.

DR LOVE: But to me, the real advance has come in the people with HR deficient tumors. And I guess the first question is, how do you approach the issue about whether to use a PARP inhibitor in a patient in the first-line primary maintenance situation? And then how do you decide which one and for how long?

DR CHASE: Yeah. So in the last year, we’ve gotten some updated presentations and publications about long-term follow-up, which for both the SOLO-1 trial which is olaparib in BRCA mutated patients, the PAOLA-1 trial which is olaparib with bevacizumab in HRD and/or BRCA mutated, and then the PRIMA trial which is niraparib maintenance. So we’ve gotten some, at least for the first 2 studies that I mentioned, we’ve gotten some updated follow-up information.

So in this study, for example, the PRIMA study, we’ve gotten progression-free survival and safety at 3 and a half years using niraparib in patients that have a response to platinum. And this is an interesting and potentially very meaningful drug in a BRCA mutated or an HRD patient. I personally don’t use it in my HR proficient or HRD negative or LOH negative, however you’re going to say it, patient. For me, that patient goes on bev and I don’t use a PARP inhibitor. But in a BRCA-mutated HRD patient where you’re not using bev, niraparib definitely has long-term follow-up data in an HRD patient, BRCA mutated or not, with some definitely separation in the curve there. It doesn’t do the usual banana effect. It stays separated.

And then in terms of SOLO-1 which was olaparib maintenance in a BRCA mutated patient, we have 7-year follow-up data. Again, very meaningful, I think, for BRCA mutated patients. So I’ll use PARP inhibitor, olaparib or niraparib, in all my BRCA mutated patients. If I use bev with chemo, I’ll use the PAOLA-1 which is olaparib with bev. If I don’t use bev with chemo, I’ll consider niraparib or olaparib after I talk to the patient about the kind of benefits of each.

DR LOVE: In the HRD patient, if you were going to use niraparib, would you use it for 3 years?

DR CHASE: Yeah. I would. I’m pretty strict in terms of following what the studies do because I feel as though if you use the regimen that the study used, if you look at the eligibility criteria, you use the same regimen, you use the same biomarker testing. Maybe hopefully, you get the same results, right? So I’m pretty strict about that. Of course, if the patient is having toxicity and she can’t tolerate the 3 years, I’ll pull her off. If she’s really, really set on staying on post 3 years, I’ll bend the rules and allow her to stay on. So before 3 years or after 3 years, it’s like a shared decision making with the patient as long as she’s tolerating it.

DR LOVE: I noticed you took a deep sigh before you answered that question which, to me, means you probably don’t use niraparib too much. Anyhow. Let me ask you about this other question, speaking of Shannon Westin, the issue here, a couple issues. So in ovarian cancer, it’s the question of whether anti-PD1 antibodies has an effect. We’re going to talk about endometrial cancer about whether PARP inhibitors have an effect. But what about the issue here of IO, and specifically, this durvalumab study, the DUO-O/ENGOT?

DR CHASE: Yeah. Let me just make one comment about a specific patient that comes to mind. She’s a IIIA ovary cancer, so advanced ovary cancer, but had complete resection. She is HRD. I didn’t use bev with platinum-based chemo, and she is on niraparib. She’s on niraparib 200 mg a day, tolerating it pretty well. So in a complete resection HRD patient not using bev, she liked the once-a-day dosing, and it’s been good for her. But anyway, just a little bit of a side patient story there.

But in terms of DUO — sorry, were you going to say something?

DR LOVE: No, go ahead.

DR CHASE: Oh, okay. In terms of DUO-O, interesting. I’m not sure really who to use this in. Meaning, okay, let’s say I’m already using bev and olaparib like the PAOLA-1 regimen in an HRD patient, do I add durva? Do I add a checkpoint inhibitor therapy to my already olaparib and bevacizumab combination? Now the problem with the study is there isn’t a PAOLA-1 arm, so there isn’t an olaparib/bev arm. So that makes it a little hard for me to interpret. It’s not on this slide, but in my HR proficient patient where I’m not going to be using a PARP inhibitor in combination with bev because they’re not your PAOLA-1 patient, in that patient, should I use durva with a PARP inhibitor to make her PARP inhibitor work better? I don’t know. I don’t know. That wasn’t the primary endpoint of the study and I question whether or not I want to introduce that toxicity. So it’s still kind of, I think, an unknown for that patient population. Currently, I really won’t add durva to my PARP inhibitor, to my PAOLA-1 regimen to this day. I wonder if anybody else will. But maybe somebody will speak up and say they’re doing it, and share.

DR LOVE: Yeah, I think people maybe are, most people I’ve heard, react pretty much the way you did. Here’s another paper from ASCO. I think people know I’m a big fan of cool trial names. I like the idea of CAPRI as a trial name. But anyhow. I’m not too familiar with ATR inhibitors, but I guess they combined it with olaparib. Anything you want to say about these ATR inhibitors and whether they have any kind of future with ovarian cancer?

DR CHASE: Yeah. I think definitely, hopefully, in certain BRCA mutated patients, we’re curing them with single agent PARP inhibitor maintenance, right? But it’s, like I said, another situation that’s not a slam dunk for everybody. And so the question is if you target 2 different DNA repair pathways, are you going to have more of an effect of the PARP inhibitor? And so I’m hoping maybe we see more of this in Phase III clinical trials and certain clinical situations. Definitely looks like it could have an added effect to the PARP inhibitor and kind of mechanism of action sort of makes sense, the synergy makes sense.

HER2 as a Therapeutic Target

DR LOVE: So let’s talk a little bit about HER2 in gynecologic cancers in general. Of course, we have the pan-tumor approval of T-DXd that just occurred in patients who have IHC 3+. So I think everybody outside of breast cancer is seriously looking at that and we’re talking to these people all the time, including gynecologic oncologists. And this agent is potentially a consideration in all 3 of the cancers we’re talking about today. Before we get into kind of specific issues, any sort of general thoughts? You’re at the place where Dennis Slamon is who started this whole thing. But any general comments about how HER2 is going to fit into the gynecologic cancer scene?

DR CHASE: Yeah. I will tell you, at our tumor boards, this is coming up a lot. The trainee presents the patient and, like, the next question out of the mouth of the attending panel is, what’s her HER2 status? So it’s in every line of therapy even. So in every disease site also, we’re asking, what’s her HER2 status? Just based on IHC, which is nice, we don’t necessarily have to go to FISH. So I’m really excited about this in the 3+ patient. The question is how soon to use it. Let’s say, for example, she’s an endometrial patient, she got her front-line treatment with or without checkpoint inhibitor therapy and she progresses, I don’t know, a year or so later. Is the next line of therapy T-DXd alone, single agent T-DXd? In a 3+ patient, maybe. It would be hard to beat that response rate in a clinical trial. So that could be a good patient to use T-DXd next. And we’re very eager to do it. I think it’s in the 1+/2+ that maybe it’s a little bit more of an unknown, maybe don’t use it quite as soon, you know, in lower lines of therapy. But definitely keep it on your plate for recurrence, maybe second, third, fourth-line. At UCLA, we’re seeing so many patients with multiple lines of therapy. I think I saw last week or 2 weeks ago in clinic, a patient with good performance status, 7 lines of therapy. And she wants more treatment and she’s doing well. She’s walking 2 miles a day. She’s ready to go on her next agent. So to have more drugs that patients have available to them even if they’re 1+ or 2+ is great for patients like her that are in their 7th line, they’re not eligible for clinical trial, and they have the biomarker and they have a good performance status. So definitely exciting world with this new medication.

DR LOVE: I was actually just flashing on the fact that tomorrow, I have scheduled to do a 90-minute recording, and the topic is HER2. And the person I’m doing the video with is a pathologist.

DR CHASE: Oh, perfect.

DR LOVE: So we’re going to spend 90 minutes talking about the pathology of HER2.

DR CHASE: Yeah.

DR LOVE: Which gives you a little bit of an insight. I looked at the slide deck and it’s an unbelievable amount of content to go through. But it also comes down to practical issues. As you said, right now, you have this indication for IHC 3+. In breast cancer, we have HER2-low, which I don’t think there’s much data outside of breast cancer, but you were alluding to that. You also, as you alluded to, can have patients with IHC 1 or 2+ who are FISH positive. I don’t know how that’s going to play out with ovarian cancer or the gynecologic cancers.

DR CHASE: Yeah.

DR LOVE: But in breast cancer, they would call that HER2-positive. But the excitement about this, and certainly, oncologists are excited about it because they’ve treated breast cancer, but there’s also a big caveat which is the tolerability issues. And I wonder, you know, we talked to all the other disciplines, GI, lung, et cetera, and they really are not exactly tuned in at this point. But I’m just kind of curious what you’re hearing, what you’re talking about at your institution about 2 things. One is even though it’s an antibody-drug conjugate, it has been associated with acute “chemo-like” toxicity, nausea, vomiting, et cetera. Pretty aggressive antiemetic prophylactics, for example. Any thoughts about that? Have you yourself used T-DXd? Because I’ve had a lot of people who have not.

DR CHASE: Yeah. I personally have not used it in a patient as of yet. We share patients a lot of times, so we’ll cross-cover and have patients in the hospital or in the ER or in clinic kind of come see us that are on this therapy. But it’s funny because you go to training, you go to — to be a GYN oncologist, you’re an OB/GYN first and then you’re a GYN oncologist. And so you have comfort with certain chemo regimens. And with some of these antibody-drug conjugates, well I will say with bevacizumab, we got comfortable with hypertension. With some of these antibody-drug conjugates, we’re now getting comfortable with ocular care. And now, we’re having to get comfortable with pneumonitis. So I think if you’re not already familiar with kind of the pneumonitis triage for this therapy, definitely, I think it’s in the slide deck, you could probably reference it or pull it up, definitely get comfortable with the pneumonitis triage because it’s not something you want to miss. And it’s one of those toxicities that you want to hold therapy for a Grade 1. So typically, we don’t hold therapy for a Grade 1. You wouldn’t necessarily do that for neuropathy or GI or even ocular toxicity. But for pneumonitis Grade 1, you hold. And for pneumonitis Grade 2, you stop. So this is more aggressive than some of our other toxicities, definitely, which again, now gynecologic oncology, we’re having to get familiar with pneumonitis on top of all the other things that are new in our world. But hopefully, if you’re comfortable with it and do the appropriate triage, the appropriate holding of therapy when you need to, you can keep patients on treatment.

DR LOVE: So here’s the FDA approval just on April 5^th that came out, again, IHC 3+. We’ll see where that heads. Here’s some of the data looking at T-DXd in the basket trial. There was biliary patients in there, et cetera. But in terms of gynecologic patients, and you can see they have IHC 3+ there in the middle is the highest rate, but you see with ovarian cancer, response rate of 60%, cervical cancer, 75%. Where am I? Oh, endometrial cancer, again, is at 84?

DR CHASE: Yeah, I think so.

DR LOVE: Yeah, 84%.

DR CHASE: Yeah.

DR LOVE: So really high. And, of course, the thing about T-DXd that we know from breast cancer is these responses are often for a very long period of time. So really a great drug to have as an opportunity. But I think you point out the big caveat there in terms of pneumonitis. And it’s interesting that that algorithm, a lot of the, again, outside of breast, I don’t hear people verbalizing that algorithm that you just verbalized which we know from breast which is, like you said, you’re trying to, if they’re going to get pneumonitis, you want to pick it up before they’re asymptomatic, Grade 1, stop the drug, give steroids. Hopefully, they respond. And maybe you even restart again, which we’ve heard a lot of cases like that.

DR CHASE: Yeah.

DR LOVE: So that’s the objective. I guess the one thing we’ve been thinking, we’ve been even, when we were at the Oncology Nursing Society meeting, the idea that when you see a patient who has a solid tumor nowadays who has run out of treatment options and still has good performance status, and there are a lot of people like that, you need to make sure they have at least an IHC at a minimum.

DR CHASE: Yeah.

DR LOVE: A lot of people are going to, they get NGS on these patients, but that’s not going to give you the protein overexpression. You may see amplification which would be a clue for you to look at it. Is that kind of the way you’re sort of thinking through it?

DR CHASE: Yeah. So the nice thing is you can do this in-house pretty much across the country. You can get HER2 IHC staining. What you’ll hear people talk about and what I’m interested to hear about in your discussion with the pathologist is the difference between gastric criteria versus breast. And so we’re supposed to be using gastric criteria for this indication. But if you’re not careful, probably I would guess mostly your pathologists are doing the breast scoring. So that would be something to be careful about. But I’m going to be curious to hear what the pathologist says about that.

DR LOVE: Yeah, me too.

DR CHASE: Yeah.

DR LOVE: I want to find out whether there’s anything as HER2 0, ultra-low, like, anything right now at this point in breast they’ll use to treat.

DR CHASE: Yeah.

DR LOVE: But I guess all the other cancers are going to be a few years behind breast.

Endometrial Cancer

DR LOVE: Alright, let’s talk about endometrial cancer. A lot happened over the past year, particularly related to IOs. Saw a couple big randomized studies coming out. But there are still a bunch of questions. When you think about metastatic endometrial cancer, particularly first-line therapy, first of all, we’re going to break them down into MSI-high or MSI stable. So I’m just kind of curious in general right now what your approach is first-line therapy MSI-high disease. Outside of gynecologic cancers, colon cancer, they use IO alone. But you guys studied IO plus chemo. So what are you using nowadays for first-line therapy MSI-high?

DR CHASE: Yeah. So if you have an advanced-stage endometrial cancer patient, there’s going to be a couple different factors that might alter your kind of prescription in first-line treatment. One is definitely dMMR or pMMR. So proficient or deficient in MMR is definitely going to drive some decisions. But then also, measurable/non-measurable. So patient has measurable disease, patient might not have measurable disease but had bulky lymph nodes, or there’s the patient that just had a IIIC1 based on a microscopic area in 1 of her lymph nodes. So for me, definitely in my measurable Stage IIIC or IV first-line dMMR patient, I’m using either pembro or dostarlimab with platinum-based chemo in the first-line, in front-line. It’s the pMMR patient that I’m not necessarily giving it to everybody. I think definitely if they’re — we saw some data at the meetings this year looking at p53 mutated patients that are pMMR. So pMMR, p53 mutated metastatic endometrial cancer, that patient, I probably will personally use a checkpoint inhibitor in. It’s the p53 wild-type patient that I might not use it in based on the SIENDO trial and some updated data that you have in this slide deck on that. So just kind of to summarize, dMMR advanced metastatic, checkpoint inhibitor therapy with platinum-based chemotherapy in almost everybody. And then pMMR, picking and choosing a little bit. It probably will be interesting to see, we had a press release looking at lower-risk endometrial cancer patients getting checkpoint pembro with chemo first-line. Should be interesting to see that actually presented and published. But in my lower-risk, Stage IIIC1, microscopic to the node, pMMR, I might not use checkpoint inhibitor therapy in that patient. It’s kind of got to be a shared decision with the patient as long as she kind of understands the potential risks/benefits.

DR LOVE: So Hassan in the chat room wants to know, what about using pembro/lenvatinib after CPI first-line in MSI-high?

DR CHASE: Yes. Well, I’m assuming that participant means using that in maintenance after you’ve given checkpoint with chemo. Is that what they mean?

DR LOVE: No, I assume it means second-line if they progress.

DR CHASE: Oh, okay.

DR LOVE: Let’s say they progress on chemo/IO, for example.

DR CHASE: Yeah. I think, I’ve heard, I haven’t done it myself yet, for example, patients progressing on pembro. I’ve heard people add lenvatinib to pembro to try to get more response. I think that’s reasonable. Let’s say she progresses post-pembro. I’ve heard some people say they want to give platinum again with IO again. And I’ve heard other people say they’re going to use lenvatinib/pembro if they progress, even if they progressed after the pembro was completed, so reasonable. We don’t have necessarily data to tell us what to do in this situation. So I don’t know. It’s kind of going to be up to you and kind of the clinical situation.

DR LOVE: So actually, I just see a great case. I’m just sort of kidding. I see a great case actually that you told me about before we came on that I want you to tell the audience about.

DR CHASE: Yeah.

DR LOVE: But it relates to this question we have here which is, how often do you see BRCA or other HRD pathway abnormalities in a patient with endometrial cancer? And can those patients, and we hear a lot of questions about that, benefit from PARP inhibitors?

DR CHASE: Yeah.

DR LOVE: And then we have the DUO-E and the RUBY Part 2 that really looked into this. So first of all, can you tell us about this patient that you were telling me about?

DR CHASE: Yeah. So I recently got a patient as a second opinion who is dMMR, IIIC based on lymph nodes, non-measurable. So meaning, she doesn’t have disease present on imaging after her surgery. But she had multiple lymph nodes positive. It wasn’t just 1 little site in 1 node. She had multiple on each side. So dMMR, non-measurable on postop CT. She was started, she already got cycle 1 of platinum-based chemo with dostarlimab. And the question was she came to me for a second cycle and she wanted to know if I was going to add a PARP inhibitor to her IO maintenance because her Caris profile said she had a BRCA mutation, a somatic BRCA mutation. Now that’s, you know, DUO-E gives us some of that data. Honestly, in the dMMR patient, I’m not sure of the added benefit of olaparib to the durvalumab. It’s an interesting question. I think with her, I definitely have to talk about toxicity. Definitely increases toxicity when you add the PARP inhibitor to durva or checkpoint inhibitor maintenance. She potentially would be the patient that you would want to use it on. Although there was an abstract at ASCO saying BRCA mutated, not BRCA mutated, on this study, they looked like they responded similarly. So maybe doesn’t necessarily, BRCA maybe, especially somatic BRCA, which shouldn’t necessarily be used as a biomarker to choose to use PARP inhibitor therapy. But nonetheless, I have to have the conversation with her and talk to her about the risks/benefits.

DR LOVE: So a few other questions related to this issue of IOs and immunotherapy. I don’t know if you’ve ever seen a patient with POLE, but that sort of hypermutated state. In some situations, they don’t even treat it. But any comments?

DR CHASE: Yeah. I have yet to get one in my practice. I’m waiting for the day that I actually have a POLE mutated patient. So yes, but yes, you hear people talk about POLE. Maybe you can de-escalate therapy, maybe not as important to be as aggressive. Hopefully, in follow-up studies, we’ll get more information about this very small subset of patients. I am waiting to see my first POLE mutated, ultramutated patient.

DR LOVE: So what do you do if you do have one? Do you treat them or not?

DR CHASE: Yeah. Like I said, I think you can potentially de-escalate. That patient, for example, might not need checkpoint inhibitor. Will I be brave enough to not give her platinum-taxane for a Stage III or IV disease? I don’t know if I’m brave enough yet. I hear some of my partners talk about it, but I don’t hear people necessarily doing it yet. But I think in that subgroup, it was a small number of patients, maybe like 5 patients on the RUBY or GY018 study, didn’t look like there was a benefit to checkpoint inhibitor therapy. Meaning, they all did really well. But it was such a small number of patients, I just don’t know if I feel comfortable making a clinical decision based on a small subgroup analysis, very small subgroup analysis.

DR LOVE: Here’s a case maybe encouraging you about your patient. This is from Hassan. A 48-year-old woman, uterine cancer, liver mets, progression postchemo/bev, BRCA mutated. Second-line olaparib, now in CR for 2 years plus!

DR CHASE: Yeah, interesting.

DR LOVE: Sounds cool.

DR CHASE: Yeah. Very cool.

DR LOVE: So I wanted to ask you, also, because this sort of jumped out at me at the SGO meeting. I was like, where did this come from? You mentioned p53, and I know it’s kind of like a little bit early in terms of clinical practice, but maybe it actually, you know, you mentioned the fact that when you have MS stable, p53 mutated, they have really great responses, right? But then on the wild-type, what they saw was now a benefit from selinexor.

DR CHASE: Yeah.

DR LOVE: So maybe we’re going to be moving in the future towards an algorithm driven by p53. Anyhow. Any thoughts about selinexor? It’s approved in lymphoma and myeloma and not that easy a drug to use. But it looks kind of encouraging here. What do you think?

DR CHASE: Yeah. We got some signals in this p53 wild-type group that really were very remarkable, like game-changing. So we’re currently enrolling to a trial to look at the addition of selinexor maintenance to a p53 wild-type patient population. And hoping that patients enroll on this trial and hoping we get the results soon because I really would love to know that it’s for sure a game-changer. It’s not available commercially, right? It’s not like T-DXd which you can get for your 1+, 2+ or 3+. It’s not available to give off study. So we really need to enroll on this study and get the results to maybe make this a reality for our patients. But yes, adding selinexor to the p53 wild-type patient population in maintenance, the subgroup analysis results look amazing.

And I will mention that on the most recent endometrial trials, the GY018 and the RUBY trial, it’s the p53 wild-type patients that don’t look, in the p53 — I’m sorry, in the pMMR patient population that’s p53 wild type, it looks like they just don’t get the same benefit from the checkpoint inhibitor. So really, really excited to enroll patients on this trial using selinexor in maintenance. And yes, there is GI toxicity. And yes, you have to be prepared for it and have to be prepared to intervene and have supportive care for your patient to make sure that they can tolerate it.

DR LOVE: Well, they’re given 60 mg q-week, so that’ll be helpful. But the drug is approved. So theoretically, you could try to get it, I guess. But I think it’s probably too early.

DR CHASE: Maybe. Yeah.

DR LOVE: But yeah, I’m really curious how they’re going to build in the tolerability considerations for this drug. Because I heard a lot of stories about it. It took a while for oncologists to get used to it in myeloma. So it looks like, I know one thing, it looks like they went to q-week. So that should be helpful, but I also wonder how it’s going to go down in this trial. But we’ll see.

DR CHASE: Yeah, we’ll see.

Cervical Cancer

DR LOVE: So cervical cancer. One thing I was really curious about, of course, we followed in non-small cell lung cancer the story of the PACIFIC trial, patients with locally advanced nonresectable disease who got a great benefit out of post-chemoradiation IO. It was durvalumab. Now it’s standard of care. And I’ve been looking for other trials using that kind of strategy. And then this popped up in cervical cancer. Just makes so much sense. You wonder whether you get a little boost because of the radiation and chemotherapy maybe. I don’t know if it prepares the IO. I don’t know. Anyhow. This is now approved in cervical cancer. Can you talk about how this is going to play out in the clinical practice?

DR CHASE: Yeah. So I think the results were impressive. It wasn’t a slam dunk, but it’s definitely improving survival. So I think using a checkpoint inhibitor with chemo/RT in a locally advanced patient should be standard of care. Meaning, the FDA approved it for Stage III or IVA. In the subgroup analysis on the A18 study, it was the Stage III or IV patient population that kind of looked like they benefited the most. And so the FDA chose to approve it for that subgroup. But the study did include other stages within the patient population. So for a Stage III to IVA, chemo/RT with pembro should be standard of care. Definitely looks like it can improve outcomes for patients and cure more patients. Again, in this situation, we’re trying to cure more patients. We want to improve the cure rate from 50 to 60% to 70+%. We want to cure more patients. And in this Stage III to IVA patient population, that could be very meaningful. The question is, what are you going to do with your other lower-risk locally advanced patients? Are you going to kind of bend the rules and also give them pembro with chemo/RT? Or are you going to do something else? So that kind of truth will be told in real-world studies in the future whether or not people are doing that.

DR LOVE: So here’s the approval for this strategy that came out in January. Here’s the paper from Lancet looking at it. And as you said, here’s the benefit. Hazard rate for progression-free survival, 0.7. See that in a lot of trials. Survival, 0.73. It depends how the plot, how the graphic looks, but hazard rate is hazard rate. And those kind of hazard rates end up with things getting used.

I’m curious also about, you know, we’re talking about antibody-drug conjugates all the time, and this is one of the earlier ones I started hearing about, tisotumab vedotin in cervical cancer. Interesting agent and interesting toxicity too in terms of ophthalmic issues. I think that was the first ADC I heard about that had eye issues. How has that actually played out? I know you don’t see too much cervical cancer. And that’s another question I have. Where are the cervical cancer patients, particularly those with advanced disease? Where are they located?

DR CHASE: Yeah.

DR LOVE: Are they — yeah.

DR CHASE: Yeah, I mean cervical cancer does not make it to the top 10 most common or top 10 most deadly cancers in women in the United States. But there’s definitely certain pockets, unfortunately, in the United States that have a higher incidence and … from cervix cancer. It just so happens kind of in my certain area of Los Angeles, I don’t see a lot of cervix cancer. But in other areas of Los Angeles, there are more. I saw more cervix cancer in Arizona, for example. But when you see these patients, it’s heartbreaking, they’re, especially the metastatic, advanced and the recurrent patients. They tend to be younger age, they tend to be kind of participating a lot in terms of working, having young children. These patients, and other patients also, break your heart, but this disease is particularly heartbreaking. And we really didn’t have anything great to give them second-line or third-line. Post-systemic chemo, we didn’t have anything really great to use. Less than a 10% response rate to treating a second-line cervix cancer patient with traditional single agent chemotherapy. So having this new antibody-drug conjugate, tisotumab vedotin, to use in second-line or third-line for these patients is an improvement to what we had previously available, which is great for these patients.

DR LOVE: What do you see in terms of quality of response? A lot of these ADCs seem to really lead to pretty significant responses. What about tisotumab?

DR CHASE: Yeah. So complete response or partial response, a little under 20%. But if you add stable disease onto that, you really bump up the response rate. So meaning, when you add stable disease into the mix, it’s called disease control rate. So for me, a patient with a 2 cm node, if you’re able to keep her with just the 2 cm node for months and months and months, meaning she has stable disease, she’s not responding or progressing, she’s just got stable disease. To me, that’s very meaningful. And that’s the type of patient where you can see them on tisotumab vedotin for cycles and cycles and cycles. Unfortunately, if the patient has bulky disease and she’s symptomatic, she’s going to want a response, right? She’s not going to suffer through stable disease for months if she’s having symptoms from that disease. So for that patient that’s having symptomatic recurrence, you really want to have partial or complete response. And I’ve had that, I’ve had long responses in some of these patients which is great.

DR LOVE: What about the ophthalmic issues? That was the first time I heard about ice packs being used. It seems like it makes a lot of sense. But what have you been doing?

DR CHASE: Yeah. So there’s a very clear eye care protocol for this drug. And you can reference it online, you can look at the drug company website. These patients have to see an eye care provider before they start treatment and they have to show up for their treatment having had seen an eye care provider. Because you want to establish a baseline and that there’s no preexisting ocular disease. And then they’re supposed to see an eye care provider before each cycle for at least 9 cycles. They just capped it at 9 recently. It used to be, like, every cycle. But for the first 9, they want to see an eye care provider. And then they have to have 3 eye drops, the corticosteroid, the vasoconstrictors and the lubricating eye drops. There’s very specific recommendations about using this with the treatment and then after the treatment is completed. And then, yeah, you put the ice packs on the eyes during treatment, I guess, to help probably with some of that vasoconstrictor effect, maybe helps the drug not to get into the eyes. But with appropriate eye care, you can limit Grade 3 or 4 toxicity, which is obviously very important. I think patients get very, very nervous when they start to read about blurry vision or ocular toxicity. They get very nervous. But with appropriate and adequate eye care instructions, we can hopefully avoid that in the majority of patients.

DR LOVE: So Dana, thank you so much for joining us tonight.

DR CHASE: Yeah.

DR LOVE: Audience, thank you for joining us. Be safe, stay well and have a great night. Thanks so much, Dana.

DR CHASE: Thank you. Thank you.

DR LOVE: Have a good one.

DR CHASE: Have a good night.