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Ursula A. Matulonis, MD: I'm Dr Ursula Matulonis. Welcome to season 1 of the Medscape InDiscussion Endometrial Cancer podcast series. Today, we'll discuss what's new in targeted therapy for endometrial cancer. I'd like to first introduce my wonderful guest, Dr Joyce Liu. Dr Liu is a medical oncologist who specializes in gynecologic cancers and serves as the associate clinical research officer for the Dana-Farber Cancer Institute in Boston, Massachusetts, as well as the associate chief and clinical research director for the Division of Gynecologic Oncology, also at Dana-Farber. Joyce, welcome to the Medscape InDiscussion Endometrial Cancer Podcast.
Joyce F. Liu, MD, MPH: Thank you so much for having me.
Matulonis: There is a lot to talk about today. Let's start off with your thoughts about uterine cancer. This is a cancer that truly is an unmet clinical need right now in the United States, with both increasing incidence and mortality. In 2024, there will be nearly 68,000 cases diagnosed per year in the US, with increased mortality across all racial and ethnic subgroups, which is particularly notable in Black women. Do you have any thoughts about why the incidence and mortality are both on the rise?
Liu: Ursula, this is such an important point. Uterine cancer is one of the very few cancers in the US for which both the incidence and mortality are rising. It's projected that in the coming few years, uterine cancer is going to overtake ovarian cancer as the fifth leading cause of cancer death for women in the US. It is already the leading cause of gynecologic cancer death for Black women in the US. I think the reasons behind this rise in incidence and mortality are probably quite complex.
For a long time, we've talked about uterine cancers being hormonally driven cancers, and we know that the risk for hormonally driven cancers can rise as body weight increases. One thought has been the general incidence of uterine cancers is increasing in part because our population is getting heavier and more prone to obesity. What's complicated about this is that when you think about the uterine cancers that are most hormonally driven, they're the less aggressive, lower-grade endometrioid cancers, and the ones that are rising in incidence the fastest are actually the high-grade ones.
That's especially true in Black women, and that's also probably contributing to the increasing mortality we're seeing with these uterine cancers, because the high grade cancers are more aggressive and in general have poor outcomes. Where these high-grade uterine cancers are the ones that are most increasing in incidence, it tells us that there's questions about whether hormonal or metabolic signaling drive these cancers in ways that we haven't yet fully understood.
Other things that people have talked about are that high-grade cancers increase with age, and as our population is aging and as elective hysterectomies aren't being done as often, that's another risk factor for why we're seeing an increasing incidence of these cancers.
Matulonis: Those are all really great points. Clearly, we also need increased funding from our foundations, but also especially from the National Cancer Institute, which I think is hopefully going to start to be addressed.
For patients with advanced endometrial cancer who come in at initial diagnosis or for those patients who have earlier disease, but then eventually have relapsed cancer, tell us how you decide on treatment for a patient with advanced endometrial cancer and what factors go into these decisions, specifically genetic factors and cell surface marker expression.
Liu: If you had asked me this a few years ago, I think the answer would have been pretty straightforward in terms of how I would think about the treatment for advanced or newly recurrent uterine cancers. But as our knowledge of the uterine cancers has increased, we've really come to recognize that like other types of cancers, we can't just lump all of our uterine cancers together and say they're one type.
If you think back to it, The Cancer Genome Atlas (TCGA) genome-wide analysis of endometrial cancers was published over a decade ago. I think we have finally recognized that each of the molecular classes from that TCGA analysis has prognostic implications that complement our traditional understanding of the different uterine cancer histologic types.
When I think about these patients coming in with newly diagnosed or newly recurrent advanced uterine cancers, the first thing I want to know as I'm thinking through their treatment options is the tumor's mismatch repair or microsatellite instability (MSI) status. For patients with mismatch repair–deficient or MSI-high tumors, we now have data from the RUBY and the NRG-GY018 studies demonstrating a significant improvement in outcomes with the addition of the programmed cell death protein 1 (PD-1) inhibitor to standard carboplatin and paclitaxel chemotherapy.
The hazard ratio for progression-free survival (PFS) in these trials is about 0.3. I really think about this. In the US, dostarlimab is now approved by the US Food and Drug Administration (FDA) for the indication of treatment together with chemotherapy followed by maintenance dostarlimab in these patients. The FDA just set a Prescription Drug User Fee Act (PDUFA) date for pembrolizumab. That's going to be in June of this year. Both of these regimens — carboplatin paclitaxel, and pembrolizumab, followed by pembrolizumab maintenance, carboplatin, paclitaxel, and dostarlimab, followed by dostarlimab maintenance — are already on the National Comprehensive Cancer Network (NCCN) compendium guideline listings. I think this is a can't-miss. If a patient has a mismatch repair–deficient tumor, then they should be getting a PD-1 inhibitor in addition to their standard carboplatin-paclitaxel chemotherapy.
The other big marker that I like to know about immediately for my patients with advanced or newly recurrent disease is HER2. It's the HER2 expression status on the surface of the tumor that you can see by immunohistochemistry, and then looking for amplification. There was a small, randomized phase 2 trial led by Amanda Nickles Fader and Alessandro Santin a number of years ago that showed that the addition of HER2-directed monoclonal antibody trastuzumab to carboplatin and paclitaxel in patients with HER2-amplified uterine serous cancers improved outcomes compared with carboplatin and paclitaxel alone.
The NRG Oncology cooperative group is currently conducting a large randomized phase 3 trial (NRG-GY026 study). That's looking at the testing of adding trastuzumab or trastuzumab and pertuzumab, which is another HER2 targeting antibody to HER2-positive uterine serous cancers and carcinosarcomas. That's a trial that's an option for those patients. For patients who can't enroll in the trial, I'll admit I've extrapolated these results to the p53-mutated tumors in general. I think of these as being very serous-like and sharing biology with the uterine serous cancers. For patients who have HER2-amplified p53-mutated tumors, I tend to add trastuzumab to the carboplatin and paclitaxel chemotherapy.
Matulonis: Those are all fantastic points. I'll make a couple other comments about what tests are ordered up front. Do you think that estrogen receptor and progesterone receptor (ER/PR) tests are necessary for grade 1 endometrioid tumors? Second, how do you incorporate next-generation sequencing? When do you order that?
Liu: I order ER and PR testing because I want to understand that status, especially for low-grade endometrioid cancers. I think there's a lot of debate about whether there is a role for hormonal maintenance for patients who have ER/PR positive tumors, where you're worried that cancer might come back for somebody with advanced stage disease and you're not quite sure what to do with them, but we don't have data for it. I like to have that information. If those patients have recurrent disease, I feel like it helps me think about what my next steps are going to be.
I do next-generation sequencing at the time of diagnosis for patients with advanced stage tumors. It's now incorporated into the staging schema. The new 2023 International Federation of Gynecology and Obstetrics (FIGO) staging guidelines do include this, and we know that has prognostic information.
I think that it has a lot of value as we're thinking both about the immediacy of treatment, but I also like to have that information available to me if that patient's cancer comes back and I'm starting to think about clinical trial options.
Matulonis: That makes sense. You've already talked about the RUBY study and NRG-GY018 and how you incorporate immune checkpoint inhibitors into patients with advanced mismatch repair–deficient cancer. Can you talk about what you think the role of checkpoint inhibitors are for mismatch repair–proficient tumors with chemotherapy, specifically paclitaxel, and where you now see the combination of pembrolizumab and lenvatinib fitting into treatment?
Liu: This has been a topic of a lot of hot debate. What do we do? When it comes to patients with mismatch repair–deficient tumors, the answers are so clear. The data are so positive. In the RUBY and NRG-GY018 studies in patients with mismatch repair–proficient tumors, you still see some degree of activity. It's just not as profound as it is in patients with mismatch repair–deficient tumors. I think it's opened the door to this question that is a gray area of what to do.
RUBY has presented an exploratory analysis based on the TCGA molecular subgroups. I admit that when I saw it, I was a little bit surprised that in the mismatch repair–proficient cancers, it was actually the p53 mutated subgroup that seemed to have the most benefit from the addition of dostarlimab to chemotherapy. This is an exploratory analysis. It's a subgroup analysis. I think we need to see whether this is going to be corroborated in future trials and analyses to say, these are the patients we think are going to benefit.
Neither the RUBY nor the NRG-GY018 regimen is currently FDA approved. The PDUFA date that I mentioned earlier for pembrolizumab does include mismatch repair–proficient tumors. We will see what the FDA thinks. But they're both in the NCCN guidelines irrespective of mismatch repair status.
In the US, we have the possibility of offering them to patients. I think that a gray zone exists. What I'm doing right now for my patients with advanced or recurrent mismatch repair–proficient cancers is I'm talking with them about the data. I feel like it's worth a conversation to recognize that there's some degree of PFS benefit. We don't know that there's truly overall survival (OS) benefit, and it's weighed against the potential side effects of immunotherapy. I've had some patients who have had some truly life-altering complications from immunotherapy, and we can't predict who those people are going to be. Then there's also the cost of being on maintenance immune checkpoint therapy for an additional 2-3 years, the psychological impact, the time, the effort, all of those components to it. I talk with patients about it. I get a sense of how they feel about, and we do a shared decision-making about whether it's worth it for them to do immune checkpoint therapy.
Matulonis: I think that makes sense. That's what I do as well. I think you're right about the potential for significant toxicities. It is a relatively low risk, but it definitely happens. KEYNOTE-775 is now older data. The LEAP-001 trial, which provides newer data, tried to see where lenvatinib-pembrolizumab fits into things. KEYNOTE-775 shows superiority vs chemotherapy, but the LEAP-001 trial poises that against chemotherapy for newly diagnosed advanced disease. Do you have thoughts about where this combination now fits?
Liu: I think we shouldn't forget about this combination. I'm not giving immune checkpoint therapy to all of my patients in the upfront setting, and I'm remembering that many patients with stage 3 disease that's fully resected were not included in the NRG-GY018 and RUBY trials. We don't necessarily know that immunotherapy is the right thing to do in that setting either. There are patients who have recurrent disease who are immune checkpoint inhibitor naive. For me, that's where lenvatinib and pembrolizumab still play a role. It's the FDA-approved regimen. We have a trial, KEYNOTE-775, that shows it is better than our chemotherapy options in that setting. I absolutely think about lenvatinib and pembrolizumab for those patients.
The unanswered question is whether lenvatinib and pembrolizumab is still going to have value in a patient who has had prior immune checkpoint therapy. I think that is something we just don't know.
Matulonis: I want to shift topics a little bit to talk about antibody-drug conjugates (ADCs). These agents are certainly poised to make an impact or are probably having an impact already. You've done a lot of work on these agents in endometrial cancer treatment. How are you using ADCs in your practice right now for patients with endometrial cancer? What targets and payloads are you especially excited about?
Liu: I love ADCs. Right now, in practice, trastuzumab deruxtecan (T-DXd) is the only ADC that we have clinical access to outside of a trial that I think is fully relevant in the endometrial cancer space. It targets HER2. We had the PanTumor02 study showing that T-DXd had impressive activity in the HER2 moderate- or high-expressing endometrial cancers, with immunohistochemistry (IHC) 2+ or 3+ with a gastric HER2 scoring criteria. On the basis of those data, and the fact that now the NCCN has T-DXd on its compendium listings, I have access to it. Earlier this month, the FDA granted a disease-agnostic accelerated approval for T-DXd in HER2 IHC 3+ cancers. I am testing HER2 IHC now in all of my patients with recurrent endometrial cancer.
I do consider T-DXd therapy for any patients with HER2 IHC 2+ or 3+ cancer who have received carboplatin and paclitaxel chemotherapy, but I'm thinking about T-DXd for those patients. I think there's some caveats.
We don't understand HER2 expression and its life cycle as well in endometrial cancer as we do in breast cancer: the heterogeneity, and how it evolves over the treatment course and the lifespan of uterine cancers, are things we don't know quite as well. We have to learn more about that.
Matulonis: I had a conversation with Katie Moore in an earlier podcast episode where we talked about the toxicities of this agent and what to look out for with T-DXd around lung toxicities, bone marrow suppression, et cetera.
Liu: The ADC space is going to be exciting. You were asking about other targets. Folate receptor alpha, TROP2, B7H4 — there's all sorts of agents that are currently being developed there. There's other HER2-targeting ADCs that are being developed in the endometrial space. Most things are with topoisomerase (TOP1) payloads or maytansinoids microtubule targeting payloads. But I think it's going to be very exciting to watch this space evolve in the coming years. Good therapies are coming to our patients.
Matulonis: I totally agree. I want to congratulate you on all the work that you've done on testing a novel type of therapy called the WEE1 inhibitor for patients with uterine cancer — specifically high-grade uterine cancers, uterine serous cancers, endometrial carcinosarcomas — as well as your newly funded program project grant that targets replication stress in high-grade endometrial cancers. Can you talk about what exactly replication stress is and why it's important in endometrial cancer, specifically in high-grade endometrial cancers?
Liu: Thank you so much. Full disclosure, it's a shared investigator-initiated Program Project (P01). It's been such a privilege and a rewarding experience to get to work with you on it. Replication stress is funny. I was just at the American Association for Cancer Research meeting, and it felt like replication stress was one of these major themes that ran throughout the entire conference; maybe I'm just super-sensitized to it now and whenever it's discussed, I think, this is the most important thing, but it just felt like it was everywhere.
Broadly, from a conceptual perspective, replication stress is this phenomenon where DNA replication is slowed, characterized by the slowing or stalling of replication fork progression and DNA synthesis. It's an amazingly complex phenomenon, and there are tons of causes of replication stress. For example, one of the most common causes for replication stress is the presence of unrepaired DNA lesions; these are going to cause a barrier as the replication fork is progressing, and they have to be repaired for replication to continue. The fork has to slow down or stop.
There are other causes, and one of those is oncogenes. They can drive replication stress. They promote increased origin firing and that depletes the deoxyribonucleotide triphosphate pool so that you don't have enough nucleotides to actually do DNA synthesis. They can also cause what are called replication transcription collisions, where the replication fork collides with the transcription machinery. Those make it such that replication has to slow as well. Those are just two examples, but there are a ton of them.
When we were doing this work, we identified that high-grade endometrial cancers have a number of molecular features suggesting that they're under high replication stress. They have p53 mutations. which abrogate the G1/S checkpoint. They have a lot of mutation or amplification oncogenes, such as KRAS or MYC. They have alterations in other cell cycle–modulating genes, such as CCNE1, which is cyclin E, or RB1. These cells that are under high replication stress become dependent on the control of the cell cycle checkpoints because they need more time to allow the DNA to replicate before they enter mitosis. If they go into mitosis and their DNA is not appropriately replicated, they can have mitotic catastrophe in the process of the cell division.
When we started our work with WEE1 inhibitors, we were hypothesizing that these high-grade endometrial cancers, the uterine serous cancers would be highly dependent on WEE1, because WEE1 is a key regulator of the G2-M checkpoint As you know, in our trial of adavosertib, we saw significant activity, with almost 30% of patients having a response and almost half of those patients being without growth of their cancer for at least 6 months. Adavosertib is sadly no longer being developed clinically, but there's a number of WEE1-targeting assets in development.
There's a drug called azenosertib that's in clinical trials in ovarian and uterine cancers. There are other cell cycle–regulating proteins that are going to be very interesting to think about in these replication stress–high tumors. We've seen drugs targeting ATR, PKMYT1, and CDK2. They're all in active development in this space.
Matulonis: There's a lot going on in that sphere of replication stress. I want to pivot to yet another type of therapy, but certainly connected around DNA repair: the role of poly ADP ribose polymerase (PARP) inhibitors for ovarian cancer. You've run a number of trials focused on PARP inhibitors for ovarian cancer and are an expert in the field of this class of drug. What do you think about the use of PARP inhibitors for endometrial cancer, and do you think there's a role for this type of therapy for patients with endometrial cancer?
Liu: What a good question. It's going to be interesting to see this space evolve. Uterine cancers in general are not the same as ovarian cancers. In ovarian cancers, we have a very clear-cut rationale for using PARP inhibition, which is the presence of homologous recombination deficiency. A lot of that is BRCA, but there's other causes as well. In endometrial cancers, it's not as clear-cut when you look even at p53-mutated endometrial cancers, which look the most like high-grade serous ovarian cancer. When we've looked at various ways of trying to assess for homologous recombination deficiency, the frequency of that is just not as high as it is in high-grade serous ovarian cancers.
Now we have some trial data on PARP inhibitors in endometrial cancer, and I think we need more time and we need more information to tease out those results. There have been two PARP inhibitor maintenance trials that are phase 2 trials: the UTOLA trial, which was with olaparib, and a trial that was run out of the University of Colorado with Brad Corr. They showed slightly inconsistent results. One showed benefit. One didn't. We are trying to tease out the biomarkers for that. We had the DUO-E trial, which is very intriguing and looked at putting durvalumab together with chemotherapy, followed by durvalumab maintenance vs durvalumab with chemotherapy, followed by durvalumab and olaparib maintenance, and comparing both of these experimental therapies with a control arm of just chemotherapy in patients with advanced or recurrent endometrial cancer.
The challenge with that study is that numerically, the durvalumab and olaparib arm — the arm that has the PARP inhibitor — did the best. But the study wasn't designed to compare the two experimental arms against each other. We don't quite understand whether olaparib is giving us a lot more bang for our buck. Is there a synergy there?
In addition to that, I think it would be nice to know if there are true populations that benefit. I don't think all endometrial cancer patients are going to benefit from the addition of a PARP inhibitor. It's probably still going to be a selected population, but the biomarker may not be the same as what it is in ovarian cancer. That's where we have work to do.
Matulonis: That biomarker has not been identified. Second, what we've seen in phase 3 trials of PARP inhibitors in ovarian cancer, where there's a very clear rationale for the use of PARP inhibitors, especially BRCA-mutated patients, is that you need to look at survival and make sure there's no detriment in OS results. I agree there's a lot of work to be done in uterine cancer.
I'm going to end the podcast today asking you, what other therapies for endometrial cancer are you excited about right now?
Liu: It's an exciting time in endometrial cancer. It's been rewarding to be in this space and to see all of the developing therapies in a place where we had nothing for decades.
In addition to the therapies we've talked about — the ADCs targeting replication stress and DNA damage response (DDR) — advances are being made in improving hormonally directed therapies. We didn't talk a lot about that. We talked a little bit about ER and PR testing, but as you know, there are studies. Panos Konstantinopoulos, one of our colleagues here has led work adding cyclin-dependent kinase 4/6 (CDK4/6) inhibitors to aromatase inhibitors in endometrial cancer, with some promising signals of activity. I think there's more work to be done there.
Another area of development that's not quite as mature, but could be very interesting, is the area of cellular therapies. On the surface of it, at least from what we've seen, endometrial cancers seem to be much more responsive to immunotherapies than ovarian cancers, even the ones that are mismatch repair–proficient. This could be a space where the evolving cellular therapy field, as it's moving into the solid tumor space, could be something that could be a difference maker.
Matulonis: Joyce, what a great conversation. Today we've talked to Dr Joyce Liu about a number of different new therapeutics and therapeutic strategies for our patients with advanced endometrial cancer, including ADCs, what is the best use of immunotherapy, and drugs that are targeting replication stress. We talked about drugs that also target ER positivity within endometrial cancer. We've covered broad range of topics here.
Thank you so much for tuning in. 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.
Resources
Advances in Chemotherapy and Targeted Therapies in Endometrial Cancer
Integrated Genomic Characterization of Endometrial Carcinoma
Gynecological Cancers Caused by Deficient Mismatch Repair and Microsatellite Instability
Dostarlimab for Primary Advanced or Recurrent Endometrial Cancer
Pembrolizumab Plus Chemotherapy in Advanced Endometrial Cancer
PDUFA VII: Fiscal Years 2023 – 2027
NCCN Drugs & Biologics Compendium
HER2 Oncogene as Molecular Target in Uterine Serous Carcinoma and Uterine Carcinosarcoma
HER2 Amplification in p53-Mutated Endometrial Carcinomas
FIGO Staging of Endometrial Cancer: 2023
Lenvatinib Plus Pembrolizumab for Advanced Endometrial Cancer
Novel Molecular Targets in Endometrial Cancer: Mechanisms and Perspectives for Therapy
Phase II Study of the WEE1 Inhibitor Adavosertib in Recurrent Uterine Serous Carcinoma
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Cite this: What Do We Need to Know About New Therapeutics for Patients With Endometrial Cancer? - Medscape - Jul 24, 2024.
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