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Ursula A. Matulonis, MD: Hi. I'm Dr Ursula Matulonis from the Dana-Farber Cancer Institute in Boston, Massachusetts. Welcome to Season 1 of the Medscape InDiscussion: Endometrial Cancer podcast series. Today we're going to discuss antibody-drug conjugates, or ADCs as they're known, and their use in endometrial cancer. It is my extreme pleasure and honor to introduce my guest, Dr Kathleen Moore. Dr Moore is the deputy director of the Stephenson Cancer Center, and she's a professor of gynecologic oncology at the University of Oklahoma College of Medicine. She is a true pioneer in our field. It's really an honor to have you here; welcome to the Medscape InDiscussion: Endometrial Cancer podcast.
Kathleen N. Moore, MD, MS: Thank you for having me. I'm happy to be here.
Matulonis: The use of ADCs in endometrial cancer is at its beginning stage in terms of the clinical use, but the clinical use has already started. It is a really exciting field and you've done a lot of work on this. What I want to talk about in our podcast episode today is the clinical aspects of the drugs that our oncologists can use to treat our patients with endometrial cancer, specifically trastuzumab deruxtecan, which has now appeared on the NCCN guidelines, and compare and contrast to mirvetuximab soravtansine, the first ADC to be used for ovarian cancer. Obviously we have ADCs to use in cervical cancer, but the field is really just starting to open up in endometrial cancer.
Today I'd like to cover trastuzumab deruxtecan. I know you've worked on other promising HER2 antibiotic conjugates. I'd like to have our audience think about potential mechanisms of resistance and how we can potentially overcome them, and think about other promising targets for endometrial cancer — FOLR1, Trop-2, B7-H4, CDH6, etc. — think about some exciting ADC combinations, and then obviously anything else you'd like to mention. Let's get back to trastuzumab deruxtecan. Can you tell us about the drug and how you're using it in your practice?
Moore: Sure. I think we're just starting to really figure out how to use trastuzumab deruxtecan in clinical practice. It's now in the NCCN guidelines based on the data that were presented by Dr Funda Meric-Bernstam at ASCO and then ESMO in 2023, which is exciting. Most of us have never used this medication because it's really been in breast cancer and gastric cancer. It's a really nice opportunity to talk about it in a little more detail as it's now available for us to use. Trastuzumab deruxtecan is an ADC and it targets HER2. We've actually known about HER2 or ERBB2 as a target in endometrial cancer for quite some time — over a decade. My colleagues, Michael Bookman, Alessandro Santin, and others, have been working on HER2 targeting mainly in serous cancers. It's been a little bit of an elusive target, until ADCs. With just monoclonal antibodies, such as trastuzumab and pertuzumab, the response rates were very low. Also, finding tumors that were what we traditionally called HER2 high, HER2 2+-ish positive or 3+, kind of limited the population. Even with that we have ongoing studies right now by Britt Erickson — that's NRG-GYO26 — that brings in pertuzumab and trastuzumab, with chemotherapy to follow, in serous tumors that are 2+-ish positive or 3+. That's an important study that should finish, but it's going to be a little hard now that we have ADCs. ADCs have roared on to the scene with the DESTINY-PanTumor study, which, just to remind the audience, was a basket trial of trastuzumab deruxtecan in 2+ or 3+ by gastric scoring, which accounts for the more heterogeneous HER2 expression in non-breast cancers. That's why they used it here. It looked at ovarian, endometrial, and cervical cancer. To remind the audience, trastuzumab deruxtecan targets HER2 and it has a deruxtecan conjugate, which is a topoisomerase I inhibitor, which isn't a chemo we typically have used in endometrial cancer and has a drug antibody ratio (DAR) of 8, which means there are eight molecules of chemotherapy on each ADC. When they used this in endometrial cancer in the 40 patients who were reported, the overall response rate was 58% in the recurrent settings. These were patients who had at least seen one line of chemotherapy. They had to be second line and beyond. It didn't really characterize their prior therapies other than that, but they were at least second line and beyond. And I think as we all know, a 58% response rate is pretty much outstanding, which is why it's NCCN listed. Patients came on based on local testing gastric 2+, 3+, then they did central confirmation where they did see drift. In the 13 of the 40 patients who were confirmed 3+, the response rate was 85%. In the 17 patients who were HER2 2+ confirmed, it was 47.1%, both of which are still really good. It was reported across the other gynecologic cancers as well, which we can maybe get to, but endometrial cancer was certainly the star. We're going to see this come into bigger phase 3 trials in endometrial cancer in the frontline, coming soon. I think that's where you're going to see a very rapid shift in how we use this and other ADCs with these trials. For now, I think people are using it in the recurrent setting, as is the NCCN listing.
Matulonis: In addition to those pretty remarkable response rates, also having a median progression-free survival that was not reached, in addition to a median duration of response. Then there's the STATICE trial from Japan that also looked at trastuzumab deruxtecan, but in uterine carcinosarcoma, and which also showed pretty remarkable response rates. In that trial the investigators even went down to HER2 low 1+, but in the NCCN guidelines, it's 2+ or 3+ HER2 via immunohistochemistry (IHC). I think that's another important point for our audience. This is not by fluorescence in situ hybridization (FISH). This is not based upon HER2 mutations. It's based solely on immunohistochemistry, which I think our pathologists are not necessarily always doing. You also pointed out the different types of ways of scoring gastric vs breast, but then there are different antibodies out there as well. Do you have any recommendations or do we just say, "Pathologist, please check HER2 IHC"? Do you have any recommendations for pathologists in this setting?
Moore: That's a great question. I think it's still really one of the unknowns for us in endometrial cancer, where we're catching up but we're really behind those working in breast cancer, gastric cancer, and others who've been really looking at this and correlating it with outcomes for quite some time. We, of course, have fairly large samples, looking just for those true positives again — the 2+-ish or 3+ when we're talking about monoclonal antibodies. But with ADCs, we have to kind of start over, which is why I'm glad we have the NCCN listing, because the patients who have HER2-driven tumors, I think we feel that they are worse prognostically; and we know that endometrial cancer is on the rise, especially among patients of color, and many of those patients don't have access to trials. I'm very supportive of this being made available so that the patients can have access to what really can be a transformational drug for them.
But I'm also equally passionate about us continuing to do clinical trials, even in the recurrent setting, because we really don't know the answer to the question that you just asked me. I'm involved, and full disclosure, in a competitor, which is BioNTech's HER2 ADC BNT323/DB-1303. In that study, we're allowing 1+ and up, and even amplified — really anybody that has [tumors that express] HER2, we're allowing to come on, and then the researchers are doing central reevaluation through a number of methods to try to figure out if there is anyone that shouldn't have access to this. I don't think we know the answer to that yet.
Certainly the updated data that Dr Bernstam presented at ESMO, where she did break out the 2+ vs 3+, does look different. It does look like there's a difference there, which isn't that surprising, but the numbers are very small and we haven't really done our normal study in a homogeneous population. Here we would expect patients to maybe have been exposed to immunotherapy, be a real homogeneous population, look at what their response rate is, and then break it down by the different IHC. I don't think we know enough yet for me to say, "Hey, pathologists, do this assay and this methodology" other than that I would say that HER2 IHC should be a part of the standard-of-care panel for any patient with any gynecologic cancer. Certainly with endometrial cancer, you want to know your mismatch repair proteins and you want to know right now your HER2 status, so that you don't miss any of these patients and their availability to get trastuzumab deruxtecan on compendium — we can't say on label at this point — or access to a clinical trial that allows 1+ and up. I really feel like we have more work to do to figure out who benefits from monotherapy. In breast cancer, there are so many interesting combinations coming out, with these deruxtecan payload ADCs kind of sequencing in scientifically driven ways — a combination therapy for those HER2-low tumors — so we need to pay attention to that as well. I feel like we still have a lot to learn.
Matulonis: Before we go on, when we think about combinations and ways of overcoming resistance mechanisms, I'll add just a few more points on trastuzumab deruxtecan because it's being used in clinical practice. The NCCN guidelines are based upon 40 patients. We also have the STATICE trial in uterine carcinosarcomas, which adds another few, but important things to check: our baseline chest, abdomen, and pelvic CT scans, and checking an echocardiogram because it's a HER2-directed therapy and there can be cardiac toxicities. Once patients start, we don't have an FDA approval here. It's on the NCCN guidelines, and even in the FDA package insert it's a little unclear how often patients should be monitored. Based upon the PanTumor02 study, patients did undergo restaging, which included a chest CT scan every two cycles, and they had an echocardiogram every four cycles, just before they started the fifth cycle. The side effects you have to watch out for are diarrhea, neutropenia, there can be hair loss with this drug, and then there is around a 10% — maybe a little bit higher — risk for interstitial lung disease, which can be pretty significant in this agent. What's clear on the FDA guidelines is that if you see any kind of interstitial lung changes and it's a grade 1, the patient is asymptomatic, that patient should not receive more trastuzumab deruxtecan. You have to watch them until the chest CT scan clears. If they're grade 2 or higher, you have to stop the drug, which is so different from other ADCs that we use in other gynecologic cancers, especially mirvetuximab, where with a grade 1, you can watch and continue to treat. Do you have any thoughts about that?
Moore: I'm so glad you brought that up. I'm a product of Joan Walker, who always said, "I'm going to tell you my mistakes so you don't make them." This is a place where I did make a mistake, tragically. With mirvetuximab, we see ground-glass opacities or patchy infiltrates, and the patients say, "I feel great." They don't have any symptoms and we just kept treating. We didn't do anything. In some parts of the country, you just see these called on chest CTs all the time: inflammatory changes, nonspecific, could be inflammatory or infectious, clinically correlate. These things show up on the chest CT and we thought, It's not cancer, the patient feels great, and we're going to keep treating. We were not looking to halt. The patient had asymptomatic, normal O2 sat, and some inflammatory change on the CT scan. With this class of drugs, with deruxtecan payloads, what I would suggest is that you just make it a checklist on your CT: No cancer, yay. Patient feels great, yay. Any changes on the CT that they're calling inflammatory or fibrotic or questionable clinically correlate, just make yourself a checklist, and if that's yes, you hold treatment and you need to call the pulmonologist. It's not a referral because they will not see these patients for a month because the patient is fine. This is the time to make a phone call and say, "Hey, this is what's going on. I'm holding the patient until you either look at the CT or see the patient and tell me it is or isn't pneumonitis." That's uncomfortable because these patients have this disease that kills them, and you don't want to hold something that's working. When you hold this drug that's working, patients don't lose control while you're waiting to get this worked up.
They actually do fine. You have a grace period to do the workup and make sure you're not treating through grade 1 pneumonitis, where the patient does not want to stop because they feel fine and they are baffled as to why you are worried about them. But you have to make this a checkpoint for yourself and then it's safe to use. If you don't do that, you get into trouble. That's what happened to me and my patient. I don't want it to happen to any of you. There's no need. We learned this from breast cancer. We just need to communicate this so we don't have to have the same learning curve that breast cancer had. But it's tricky. It doesn't say pneumonitis on the chest CT.
Matulonis: If you have the opportunity to take a look at the chest images just to see what and how they're calling it, that's really important as well. I think you're right about calling up the pulmonologists, who are super-busy. Even the FDA package insert is not directed to us in gynecologic cancer, which is part of the issue. We just need to educate ourselves about the toxicities of these drugs. They're very impressive, based upon PanTumor02 and the status trial for endometrial cancer, but they do have pretty serious toxicities. We need to keep educating ourselves. Then, we move on to all the different HER2-directed ADCs that are being developed right now. I think there's always this conversation around having trastuzumab deruxtecan — great activity, so why study other HER2-directed ADCs? Certainly one reason would be to avoid and lessen the toxicity profile that we see with this drug. Can you talk about some of the drugs that you're testing that you're excited about, and that you see as promising next ADCs to HER2?
Moore: You make a great point. I think this is an issue across ADCs, and Dr Anthony Tolcher gave a great talk on this at ASCO Breakthrough last year, where he talked about the ADC bubble because there are 20 TROP-2 ADCs in development and 10 folate, and however many HER2 — I haven't even counted them all yet. The question is, if they're just me-too agents, of course there's competition, so you need a few; but do you need six me-too agents? The answer is no. For a lot of reasons, it's just unnecessary. It diverts investment. In small biotech, if everyone's developing a me-too and you already have four ahead of you, then let's move investment to novel agents. I think this is beyond the topic of this podcast, but we need to stop all these me-too drugs and then focus on things that are really differentiated, because you may have the same target, but it's a really differentiated molecule. Then the differentiated molecule needs to work better. Probably some of the best examples of that are in folate, which we can talk about in a minute. But HER2 is coming. We've kind of already seen the evolution of HER2. We started with trastuzumab emtansine, which had a microtubule toxin payload. It was an anti-microtubule and the DAR was about 3.5 to 1. That has been tested through several basket studies in endometrial cancer. The best response rate we've seen with that agent for endometrial cancer was presented last year at ASCO, with a response rate of about 21%. I will say that that study did some really beautiful translational or correlative work with off-treatment biopsies, which we could talk about. It's really exciting; 21% is not that great, but then you change the payload, you change the DAR, the linkers are different, and you have a differentiated molecule like trastuzumab deruxtecan or BNT323, and you get into these response rates north of 50%.
I think that's quite important. Those are probably the two leading ADCs that I think are in the space right now, both of which have registration-enabling studies in both frontline and recurrent settings. Not everything is in the public domain so I can't be overly specific, but they are different in their biomarker selection, and they both have pretty robust plans for looking at the biomarker. I think both of these are quite important to get rolling out globally so we can make sure that we're testing broadly, just like we did with folate receptor alpha. We know what the best test is, if it matters. Maybe it doesn't matter, and you just need to know if someone's HER2-something. Then what's the best treatment line to use these drugs in? So I think that's where we are now with HER2. There are some interesting bispecific antibodies coming behind this that I'm interested in that are still early, and potentially some more differentiated molecules coming up in the pipeline; but in terms of closest to clinical action, I think it's those two.
Matulonis: You've done so much work on this and we've already talked about FOL1 just a little bit. It's certainly important in ovarian cancer, but there are multiple drugs and ADCs that are being tested right now for folate receptor alpha and then TROP2. Are there any other targets that interest you?
Moore: The next nearest thing are the TROP2 studies with two different TROP2 ADCs, and they are different in terms of their payload. These studies are about to launch in the recurrent setting. These are different drugs; even though they both target TROP2, they have different payloads. They are similar but not the same. I think their side-effect profiles and perhaps efficacy could be different. I think TROP2 in endometrial cancer is probably the next nearest thing to come forward, apart from HER2. Close behind are the folates. Now there's mirvetuximab, which you and I both know and love, so we have to say out loud that it is a conflict of interest that we love mirvetuximab.
Matulonis: Yes, we do!
Moore: Mirvetuximab had some experience in endometrial cancer a long time ago. Finding folate receptor alpha high expression was mainly in serous, and it was pretty infrequent and we didn't really see a lot of responses. I think that's just the truth. So there's probably less interest in that particular agent, but not in folate. When we think about other folate agents, there's a lot of me-too agents out there, but probably from my standpoint, one of the most differentiated agents is the new ImmunoGen 151, which is a biparatropic antibody, so it hopefully binds lower levels of folate better and it has an updated payload. That's up and coming in phase 1 and is enrolling endometrial and ovarian cancer patients. I think we'll get a sense from that whether it has a play in endometrial cancer. Neck in neck with that is ProfoundBio's PRO1184, which targets folate but has an exatecan payload. This also has enrolled endometrial and ovarian cancer patients and is probably in about the same place as 151 in terms of dose escalation and expansions. I haven't seen any data. I don't have any insider information on how they're looking in endometrial cancer, but I'm just excited about them because they are really differentiated molecules. They really are the next generation. There are a few others out there that are a little earlier, but I'm excited to see some of the early presentations of this and I hope we'll see some of those this year. I'm very excited about B7-H4. I don't know if it's going to be an ovary or endometrial focus yet. I'm excited to see some of those readouts. Those are also in the same place as the two drugs I just mentioned, maybe a little further along. We should start to see some readouts of those expansion cohorts. I think those are our top ones in endometrial cancer: HER2, TROP2, folate, and B7-H4. CDH6 probably less so in endometrial cancer, although I'm not ruling it out.
Matulonis: Yes. Tons of work to do. We have just a few minutes left, but in terms of the importance of looking at all these medications, it's also connected with the different mechanisms of resistance that patients' cancers have to ADCs in terms of the measurement of the antigen expression and whether or not you need high levels or low levels; the tumor heterogeneity, which certainly you see in a cancer like endometrial carcinosarcoma; and then the changes over time that occur with antigen expression, and whether or not the ADC actually engages with that antigen. There's just lots of work to do. We mentioned a lot of different payloads and thinking about sequencing. I'm going to wrap up by asking you if you have a favorite or favorites in terms of ADC combinations.
Moore: We've looked at a lot of combinations with the ADCs, and thus far — mainly in ovarian cancer — they've been additive. We haven't really seen synergy with ADCs to date. Maybe with bevacizumab and mirvetuximab that may be one place where we have actually seen some synergy, but with this new class of ADCs with topoisomerase I payloads, there is just quite a bit of preclinical and early clinical rationale for combinations and sequencing a topoisomerase I and then a topoisomerase II inhibitor, like using temporal sequencing, and really thinking about synergistic, targeted therapies. It seems to be just targeted chemotherapy.
I do think that this is a place where we may see DNA damage-response inhibitors come back, whether it's PARP or some of the newer agents that are coming down the pike — USP1 inhibitors, polymerase theta. I'm working on a couple of super-novel drugs that preclinically look like there's quite a bit of synergy with some of these topoisomerase I inhibitor ADCs. I think that we're going to see some of those come back around, and they'll be particularly important not for everyone, but maybe HER2-low does need a combination; I think we're going to see some of those combinations. I would say my favorite thus far are these DNA damage-response inhibitors, but I constantly am learning from some of your partners. I learn from Joyce Liu and Panos Konstantinopoulos every day, and your DNA damage-response institute has led a lot of this work. Whatever you're working on has actually been my favorite thing. I think it's not just the combinations; it's figuring out the patients who need a combination, and then not using combinations in the patients who don't need combinations. I think we're going to see better discernment of that moving forward.
I'm pretty excited about those combinations coming. I just think it's a really exciting time across gynecologic cancers, but specifically in endometrial cancer where, for so many years, we really were not making any progress. It was just paclitaxel and carboplatin and maybe you'd add a little bevacizumab if you could get it authorized on NCCN, but really we were just sort of stuck. Then, all of a sudden we've gotten unstuck, and unstuck in a very rapid way with immunotherapy, with understanding subgroups, even beyond The Cancer Genome Atlas (TCGA). How long have we been talking about the TCGA? We're finally acting on it and then realizing it's even way more than four groups. The nonspecific mutation profile, that copy number-low microsatellite stable group is probably four groups. We're designing studies for those molecular subtypes that are actually working. The HER2 ADCs and these other ADCs are bringing agents in that actually work — and work really well. We have to pay attention to the toxicity. I didn't mean to scare people, but I want you to pay attention to it because otherwise these drugs are transformational for people that otherwise would not be alive.
Matulonis: True. It's been a great discussion. Thank you so much, Katie. It's always a pleasure talking with you. Today we've talked to Dr Kathleen Moore about different aspects of ADCs in endometrial cancer. We talked about some of the medications that are available to us right now, such as trastuzumab deruxtecan through the NCCN guidelines; other promising HER2 ADCs, specifically ones that Katie's been working on; and other targets for ADC which are promising combinations. It's been a great discussion. Please take a moment to download the Medscape app to listen and subscribe to this podcast series on endometrial cancer. This is Dr Ursula Matulonis for the Medscape InDiscussion: Endometrial Cancer podcast. Thank you so much.
Resources
A Study of DB-1303 in Advanced/Metastatic Solid Tumors
DNA Mismatch Repair Proteins: Scientific Update and Practical Guide
PRO1184 for Advanced Solid Tumors (PRO1184-001)
A New Wave of Innovations Within the DNA Damage Response
Center for DNA Damage and Repair
Genomic Landscape of Endometrial Carcinomas of No Specific Molecular Profile
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Cite this: Antibody-Drug Conjugates and Endometrial Cancer: Combinations, Response Rates, and Clinical Trials - Medscape - Jun 25, 2024.
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