 Krish, before all these trials come out, after carboplatin with paclitaxel, how are you sequencing these MSI [microsatellite instability]-high and MMR [mismatch repair] proficient patients?

Until these trials report, I have the GYO18 trial open at 2 of the sites I go to, and you’re not biomarker restricted to enroll patients on that. If they have measurable disease, that’s where they’re going. In the absence of the trial being open at the third site I practice at, I am going to need to know their MSI status. I’m going to treat those patients who are MSI stable with pembrolizumab plus lenvatinib. If they’re MSI high, I’m going to give them pembrolizumab.

 Don’t forget dostarlimab. There was a 46% response rate in 103 patients, FDA-approved on August 17th, 2021. Dostarlimab is a good medication, and it’s here to stay. The RUBY trial hopefully will integrate it into the front line.

 Perfect. MMR proficient patients are treated with the RUBY trial. Let’s say you unblind her, and you find out she was treated with dostarlimab. What are you going to do now?

 I have to put her on a clinical trial, and we don’t have good clinical trials for that, so we have our work cut out.

 How about lenvatinib with pembro [pembrolizumab] after previous I/O [immuno-oncology] therapy?

 There is no data. We need that trial, don’t we?

If there’s no clinical trial, that’s a good option.

 We don’t have that data. Those patients were not allowed to enroll onto the KEYNOTE-775 trial. But a lot of us have used it; clearly, that’s off label. I shouldn’t say it’s off label. It just says you had to have previous chemotherapy; it doesn’t say you couldn’t have previous I/O. It has had some benefit, but I want that trial to be done to see what our true response rate is in those patients.

 It’s about prioritization. As you know, we have the antibody-drug conjugate [ADC] tisotumab vedotin in second-line cervical cancer. We have positive data for mirvetuximab soravtansine, a folate receptor antibody-drug conjugate in ovarian cancer, and it will be the next ovarian cancer approval. We need an antibody-drug conjugate in this I/O-exposed population, whether its Trop-2 or whether its tissue factor. There are other tissue factor ADCs like tisotumab vedotin; tissue factor is overexpressed in endometrial cancer.

 Yes. We need to take a playbook out of these folate receptor alpha or tissue factor ADCs. I think rather than trying to pound the I/O square peg through the I/O-exposed round hole, we need to shift to another class of agents as we’re doing in cervical and ovarian cancer ADCs.

For a long time, I think the progress in endometrial cancer has faltered compared to the other cancers we take care of: ovarian and cervical. I think the next 2 years are going to be the years when we really break down the walls that have been hindering us and preventing us from giving patients who are struggling with these advanced and recurring endometrial cancers really effective therapy. I’m really encouraged.

 Thanks, Krish, I agree. It’s been great being here today.

Videos

A discussion on the best way to sequence therapies for patients with MSI-high and MMR-proficient endometrial carcinoma.

Sequencing Therapy for MSI-High and MMR-Proficient Endometrial Carcinomas

 Let’s go to our third case. This is a 64-year-old post-menopausal patient who presented with a big uterus. She’s tender, she has a bunch of blood, and she’s feeling unwell. With an 18-cm uterus, we did an exploratory laparotomy on her, and because of our visualization, we also did a full bilateral pelvic lymph node dissection.

 We got 12 out. She had a 44% invasion; I hate these grade 2 tumors. Grade 2 tumors, let’s call it 54%.

 It’s a big tumor, a bunch of blood, and a lot of symptoms. Molecular testing shows mismatch repair proficient. They did checkHER2/neu [human epidermal growth factor receptor 2], though I normally wouldn’t check in a nonserous cancer. We talked to her, sat down, and guess what we recommended, Brad?

I agree with that. The pelvic sidewall is clear.

It’s definitely not crazy, but the way pelvic radiation is delivered today, through IMRT [intensity-modulated radiation therapy], bladder and bowel sparing, it’s almost tougher to do vaginal brachytherapy. It’s more lucrative for the radiation doctor. I don’t mean to imply that’s why they do things, though. It’s a controversy. However, the PORTEC-2 trial was randomized, so the data would support vaginal brachytherapy, and that’s fine.

 These grade 2 tumors drive me nuts. There are some data that show about two-thirds of them are going to act like low grades, but maybe as high as one-third are going to act like a high-grade, more aggressive tumor. Unfortunately, about 17 months later, the patient recurs—a big right pelvic sidewall recurrence—and we took out those 12 pelvic lymph nodes, but maybe we missed the sentinel.

 Seven percent will be outside the usual boundaries, which is something to keep in mind. She has a right pelvic recurrence, we give her a carboplatin with paclitaxel, and she gets a nice response, with a little disease left at that point. Brad, what are you going to do with any recent data that may help us here? Do you complete the 6 to 8 cycles of carboplatin, paclitaxel?

 Both of you have been passionate advocates of maintenance PARP inhibitors in ovarian cancer. You get a response and you know that the risk of recurrence is very high. We have multiple 

 papers showing maintenance, and bevacizumab in maintenance. We have addressed that same question in endometrial cancer, where you’re going to recur; you get your 6 doses, and go ahead and get maintenance therapy. There’s a study that was reported on February 8th through a press release that will be presented very soon at a scientific meeting, called SIENDO, which stands for selinexor in endometrial cancer. This is a randomized 2:1 maintenance trial, once weekly of the selinexor, 80 mg, and it improved progression-free survival. I can keep talking about it, but I know, Dave, you’ve done a deep dive here. Tell us about the results of this trial and what you think about it.

 What’s interesting is it’s an XPO1 inhibitor. We have this novel target. We saw a hazard ratio of 0.7, so about a 30% improvement in all populations. With what we’ve reported, we’ve only seen the press release, 

 wild type seemed to benefit the most. The observation arm was right about 3.8 months improvement in progression-free survival, so that makes sense in national history.

 The results are the same whether it’s 

 Great point. When we looked at all-comers, not quite double, it was about 5.7 versus 3.8 months. But in the 

 wild type, there was about a 3-fold improvement in the median progression-free survival.

 Yes, 0.38, precision is important. This is another positive phase 3 trial, run through GOG Partners.

 The GOG-3055 trial, thank you. When we’re looking at this group, we know the FDA loves biomarkers. Ultimately, what will the approval look like? Will it look like the 

wild type, or will it be all-comers? I don’t know.

I don’t know. Think how novel this is. In the 

 is known as the guardian of the genome. 

 causes G1/S arrest and allows DNA mutations to be repaired, so that works in the nucleus. XPO is an export of

 stays in the nucleus and does its job. The wild-type functional 

This is so exciting; we’re going to be ordering 

 testing on all our patients with endometrial carcinoma. Are we going to order it up front or are we ordering it later?

We’re going to need to traffic through this, but this is here to stay. I’m going to give you the medians now. This is 6 cycles in stage IV recurrent of carboplatin, paclitaxel, then maintenance, once weekly, with a low discontinuation rate. You take 1 weekly fixed dose of 80 mg, and if you’re 

 wild type, which can be assessed by immunohistochemistry staining, you go from 3.7 to 13.7 months, a 10-month improvement in progression-free survival. Bingo. This is exciting, and the mechanism of action, a nuclear pore inhibitor, is amazing. I don’t care what mutated 

 does. I can’t turn it back on, but I can relocate the 

that’s functional and keep it in the nucleus where it can maintain the integrity of the genome and help patients in the long run.

 We have another phase 3 trial that is positive. We have the KEYNOTE-775 trial, we have, what did you say?

 SIENDO stands for selinexor in endometrial cancer. I love it. It’s another phase 3 trial. We have at least 4 phase 3 trials that are going to read out within the next 1 to 2 years with regard to metastatic recurrent disease looking at immune [I/O] therapy, and does it help the backbone of carboplatin and paclitaxel? Then we have the adjuvant setting for locoregional disease. Then we have high intermediate risk, patients with MSI [microsatellite instability] high or MMR [mismatch repair] deficiency. Can we or should we add I/O therapy too to improve their outcomes? We know their recurrence rates will be 25%-plus. We’ve already talked about how hard it is it to salvage in recurrent settings.

Oncologists debate the proper treatment of a patient with a grade 2 endometrial carcinoma tumor.

Endometrial Carcinoma: Clinical Case Scenario 3

 Actually, I think Brad has the next case.

 I have the pleasure of working here in Arizona where there’s a very large Native American population. It’s my pleasure to take care of them and collaborate closely with the Indian Health Service. Obesity is a serious problem there. We’ve learned and we’ve already addressed that how these patients are treated depends on the type of provider. This idea that they need chemotherapy as an adjuvant treatment is important, but sometimes the patient will see someone who may not be as familiar and say, “We’ve given radiation forever.” This particular patient has 3 positive nodes and needs systemic therapy. If you want to give vaginal brachytherapy, that’s fine. We already talked about the negative GOG-258 trial in the 

, presented by Daniela Matei, MD, which showed that adding radiation to systemic therapy did not improve survival.

This woman got radiation, and I didn’t treat her. Since it was done outside of a high-volume center, this center did not have the molecular testing. We had realized that and were trying to work through the state. I want to ask Krish, you, or Dave, when you do mismatch repair deficiency testing, when do you do germline to look for Lynch syndrome [hereditary nonpolyposis colorectal cancer]?

 If they have loss of any of these proteins, as long as it’s not MLH1,or it is MLH1 and promoter hypomethylation has been ruled out, we send them for genetic counseling and we get them tested for Lynch syndrome.

 Do you send them to a counselor, or do you counsel them at the point of contact in your clinic?

 It depends on where I am. At UCI [University of California, Irvine], we counsel them, and we order the tests ourselves. At one of our other sites, we have an organized genetics program that sees the patient the same day in our office, and they get counseled right there.

 You begin to develop 2 groups of patients who are MSI [microsatellite instability]-high or mismatch repair deficient. One group is a promotor hypomethylation, MLH1 generally, so that’s epigenetic silencing or epigenetic loss. The other group can have a mutated gene that can either be somatic or germline. I think we’re learning, Dave, that those sorts of subsets are different. Tell us about how that group of patients would respond differently.

 We’ve learned a lot from the colorectal data, and I think as we look at the mutated gene group, clearly those are benefiting the most. We need to better describe those patients and further refine our testing, but again, we continue to do that. We have some research that is just coming out and is now accepted for publication. This research calls into question the thought that we should only send certain patients who have loss of one of the mismatch repair proteins to get genetic testing. We are identifying another potential 10% to 15% of patients with genetic predispositions beyond even Lynch syndrome, particularly in our high-risk type of uterine cancer. At the current time, I’m still going to treat patients with hypomethylated versus genetic abnormalities with a single-agent PD-1 inhibitor, but I think we need to answer that question more clearly. What do you guys think?

 Germline testing is becoming so cheap and so prevalent; it’s just easy. To talk yourself out of it when a woman has cancer, particularly at a young age–I hear you. To your point, Krish, you can counsel those patients right at the point of care, and patients want to know what their germline testing shows. I think that’s evolving.

Experts explain the need for germline testing and genetic counseling for patients with endometrial carcinoma as demonstrated by a patient case.

Endometrial Carcinoma: Clinical Case Scenario 2

 This patient got started on 20 mg of lenvatinib along with pembrolizumab. As you know from the trial, most patients end up getting dose reduced. How do you dose the drug, Brad?

 I follow the recipe. Just because you reduce the dose, doesn’t mean you started at the wrong dose. Patients get dose reduced on our PARP inhibitors in ovarian cancer, paclitaxel, all this. If the patient is protocol-like—healthy and has good end-organ function—then I’d treat her like the protocol. There are exceptions, and Dave’s going to tell us about what those exceptions are, where patients wouldn’t have been eligible because they’re too fragile. That would be a lower dose. It goes 20, 14, 10, 8 mg. Dave, when do you not use 20 mg as a starting dose?

It’s exactly what you’re saying with regard to performance status. I have a patient who’s quite frail. We call her an ECOG 2; she’s really a 3. You look at that and the creatinine clearance, which we’ve reduced if we look at the investigator brochure. You start at 10 mL/min, and that’s at 40 mL/min now. I always check to make sure what my calculated creatinine clearance is. I know it’s 10 mL/min, but the creatinine clearance said 40 mL/min. If I have a question in a patient who’s older, I’ll get a 24-hour measured urine. Brad and I go back and forth on this all the time, Krish. I’m pragmatic to a fault. When I have to reduce—and I know that two-thirds of patients are going to need to be reduced, maybe even 80% but probably two-thirds to three-quarters—I start at 18 mL/min. I know it’s not the formula and it’s not the FDA indication, but then they got the 10, the two 4 mL/min. When I have to go down to 14 mL/min, I don’t have to wait for a new script. I don’t have to call anything in. I just go take the 10 mL/min and the 4 mL/min. From that pragmatic standpoint, that’s what we started. It’s not an extra prescription and it allows you to dose reduce without missing a day if that’s appropriate.

 It’s all about efficiency. In the historical past, they’d have to pay another co-pay, but now there’s a drug replacement program. If the system isn’t very fast, then there can be a big interruption. I want to emphasize that point that you made: 18 mL/min is pretty close to 20 mL/min. But it’s not financial anymore; it’s about the efficiency of your claim.

 I want to emphasize Brad’s point. If they’re very protocol-like, I encourage starting at 20 mL/min. There’s some thought that the loading dose in the beginning is important, even if you ultimately have to dose reduce.

A lot of these patients are coming in symptomatic. When we look at the KEYNOTE-775 trial and Vicky Makker, who presented lenvatinib-pembrolizumab vs chemotherapy in patients previously treated in the 

 in January 2022, those response rates were doubled in the lenvatinib-pembrolizumab arm, 30 vs 15. You have survival advantage and PFS [progression-free survival] advantage. Even though we had to dose reduce two-thirds to three-quarters of patients, the quality of life was the same. Once you figure out that dosing— it usually takes a couple of months—their tolerance seems to be quite good, particularly when you can get disease reduction and then maintenance.

 Krish, have you seen a lot of hypertension with the lenvatinib anti-VEGF activity?

 No, not a lot. I’ve seen a little but mainly fatigue. That’s the biggest issue my patients have.

 As the audience knows, Krish developed bevacizumab in cervix and ovarian cancer, so you have a lot of experience with bevacizumab and other anti-VEGF therapies. They probably check their blood pressure at home. That’s what we learn together, and you have nursing staff and support, which are key. It’s a team approach, no question.

The team approach is huge. Even though you don’t see as much as we originally thought about it, I make sure those patients have access to a prescription for antihypertensives. They don’t have to get it, but they have to have access. In addition, what we started instituting with the use of video visits is that APPs [advanced practice providers] have video visits weekly to make sure we’re keeping on top of this. I’d strongly encourage that. Now that we can do weekly video visits, let’s get them on the phone, on the video weekly, and talk about the symptoms they’re having to keep on top of it.

 In the state of Arizona, it’s the law that they have to reimburse for that, so we’re able to keep our doors open. The other thing we’ve learned is they have to stop the lenvatinib if the blood pressure is too high, so it’s not the medication or the antihypertensive. We tell outpatients to stop if they get somewhere between 160 and 170; 160 begins to make me nervous.

They’ll go fairly quickly, and then suddenly they’re in trouble. You’re right. With the short half-life, it will get better all the time. But I like them to have that prescription in their hand.

 That’s a great idea. Brilliant as usual.

Drs Bradley Monk and David O’Malley explain dose reduction in endometrial carcinoma treatment based on clinical trial data.

Dose Reduction in Endometrial Carcinoma Treatment

 Hello, my name is Krish Tewari. I’m a professor and division director of gynecologic oncology at UC Irvine [the University of California, Irvine]. I’m joined by Dr Bradley Monk from the University of Creighton and the University of Arizona College of Medicine in Phoenix. I’m also joined by my good friend Dr David O’Malley from The Ohio State University Comprehensive Cancer Center. We’re going to be talking about endometrial cancer.

I’m going to start with an interesting patient. I have a 55-year-old with a medical history that’s notable for high blood pressure, hypercholesterolemia, and type 2 diabetes. She was diagnosed after surgery with a FIGO [International Federation of Obstetrics and Gynecology] stage IIIC1 endometrioid adenocarcinoma of the uterus. She had undergone robotic hysterectomy, bilateral salpingo-oophorectomy, and sentinel lymphatic mapping. Interestingly, her pathology indicated that the tumor was MSI [microsatellite instability] stable, and postoperative imaging was negative for metastatic disease. Of course, this was done once we found out that she had a nodal metastasis. The patient was counseled accordingly and started adjuvant systemic therapy with a platinum and paclitaxel, carboplatin specifically. David, what are your initial impressions? This is the type of patient many of us see every month.

 My first question, Krish, is why didn’t you get her on protocol, the GOG-3053 trial or the KEYNOTE-B21 trial? It’s a perfect opportunity. She’s MSI stable and MMR [mismatch repair] proficient, but as we look at these patients, clearly the carboplatin-paclitaxel backbone is important. Can we do better with loco-regional disease? The biggest question for me is, do you add radiation? Do you add the whole pelvic radiation? As I’m going through this, I’m thinking about the PORTEC-3 trial, both the molecular and clinical outcomes. The recent report in 

] shows there’s some survival advantage when we bring chemotherapy onto radiation backbone. The biggest question always on my mind for these patients is, how much more am I adding with regard to the radiation compared with the balance of the long-term toxicities? It’s a 55-year-old woman; she has 30 years to live in the long-term implications of radiations. What do you guys think?

 Brad, do you want to take that and frame it in the context of the subgroup analysis of stage III patients in the GOG-0258 trial?

 I love seeing you guys. I love hearing you guys. That study you’re referring to, Dave, is called KEYNOTE-B21. It takes the global standard of carboplatin-paclitaxel and randomizes them to pembrolizumab or placebo. I love that study. That’s what would have happened at my center.

 Do they need to have measurable disease for that study?

 They don’t. It’s an adjuvant study, so we have 2 buckets. We have the adjuvant patient, which could be uterine serous cancer with no metastatic disease or this patient with stage IIIC1. The other bucket is stage IV recurrent. All the phase 3 trials we’re doing are stage IV recurrent except for that 1 adjuvant study, which is a massive study. GOG-0258 was a randomized phase 3 trial published in the 

, standard chemotherapy vs adding radiation, and it was negative. It was published in the 

 to teach people to stop doing the wrong thing—adding radiation to chemotherapy—because it was a negative study. The subset analysis suggests there might be subsets. I don’t care; it’s negative. You shouldn’t do radiation in this setting.

 GOG-99 was a negative study, but for patients with early stage, high-risk endometrial cancer, we follow the subset analysis in GOG-99.

 Our audience doesn’t know these numbers. GOG-99 was adjuvant therapy: you had a hysterectomy, you got radiation or not, and there was maybe a benefit in patients who had deeper invasion in higher-risk tumors. That created the current study, which is now the standard, pelvic radiation vs chemotherapy radiation, which is called GOG-0249. There’s no benefit of dual-modality therapy. The reason radiation is the standard in those patients is because the lymph nodes are negative. You have a patient, you do the nodes, and you assess the risk. Even if the nodes are negative, such as a serous cancer or an adjuvant chemotherapy, and if the risk is high because the nodes are positive, then you give her chemotherapy. The role of radiation is undefined.

 I can’t argue. When we look at survival advantage, until the PORTEC-3 trial, we didn’t have a survival advantage by adding radiation. You could argue the survival advantage wasn’t the radiation. It was chemotherapy added to the radiation. You still don’t have survival advantage, right?

 What was the control arm of the PORTEC-3 trial? Radiation.

 Yes, as the roll-on control arm. It’s another irrelevant study, and I don’t know why we talk about it.

We have to look at the loco­-regional recurrence in GOG-0258. We know the percentage of these patients who get salvage if they have a regional lymph node metastasis; it’s very low. If I have that subset with the metastatic lymph node, it’s very reasonable to have the conversation with her about radiation. Debating you to say you clearly should add radiation to chemotherapy, I’m not going to win, but if you’re going to treat with 1 modality, treat with chemotherapy.

 Krish, if you’re going to add radiation to chemotherapy, how do you do that? Do you give the radiation first, do you sandwich it, or do you give it at the end of the chemotherapy because the chemotherapy is the dominant modality?

I don’t give radiation for advanced-stage cases. We all have plenty of examples of patients who had nodal metastases only, and they’ve been salvaged with chemotherapy. For intraperitoneal metastases plus nodal metastases, with or without nodal metastases, it’s very difficult to save those people.

 That’s the other bucket: stage IV recurrent. Dr O’Malley, it’s 2 to 1. You’re outvoted.

I told you I wasn’t going to win this, Krish, but it’s a reasonable alternative. How would the molecular components to these tumors potentially change? Are you checking 

 I was going to move on to biomarkers, so let’s talk about that next.

Oncologists describe a typical presentation of endometrial carcinoma and debate the implications of radiation treatment.

David O’Malley, MD

Articles

Sequencing Therapy for MSI-High and MMR-Proficient Endometrial Carcinomas

Endometrial Carcinoma: Clinical Case Scenario 3

Endometrial Carcinoma: Clinical Case Scenario 2

Dose Reduction in Endometrial Carcinoma Treatment

Endometrial Carcinoma: Clinical Scenario 1