Novel Strategies in Development for EC Management

David M. O’Malley, MD: One thing with uterine cancer is that we’re finally starting to get some trials. We actually have agents out there. We have opportunities for new agents, and there are a lot of exciting new agents. I have never been more excited for uterine cancer developmental therapeutics than I am today. There are 21 large-phase trials ongoing. That’s more ongoing right now than we’ve had in probably the previous 50 years. Immune agents are at the center of this.

We’re trying to find ways to move the immunotherapy from a recurrent setting into the up-front setting. We look at the RUBY and AtTEnd trials. We look at GOG-18. What are those trials? Backbone of carboplatin-paclitaxel plus or minus I/O [immuno-oncology] agent. That’s advanced or recurrent disease. Some people would argue noncurative. What are we doing now? We’re taking patients with curative intent. My partner Dr Floortje Backes is PI-GYN-20, which is looking at patients who have intermediate-risk uterine cancer to whom you’re going to give either whole pelvic radiation or vaginal cuff brachytherapy. They’re MMR [mismatch repair] deficient or MSI [microsatellite instability] high, and they’re randomizing them to I/O [immuno-oncology], in this case pembrolizumab, or not, placebo controlled.

We’re trying to increase the curative intent with those patients who we know will have a decent chance of recurrence. Looking at KEYNOTE-B21 again—patients with curative intent. In these patients, it’s a carboplatin-paclitaxel backbone and once again looking at pembrolizumab, but more a higher-risk population of patients: advanced disease, higher risk, serous cancers. In addition, we’re now allowing radiation in that trial to see how those patients do, and that’s physicians’ choice. We’re allowing them to also utilize an agent that some of us believe may help.

What else? We’re looking at lenvatinib-pembrolizumab. I can’t believe they did this: They went head-to-head to chemotherapy backbone, carboplatin-paclitaxel in the first-line setting. We already know from a recent press release that in the recurrent or advanced up-front setting with the prior therapies—as I said, the progressive setting—lenvatinib-pembrolizumab beat physicians’ choice. We already have a press release saying that this is positive.

Now we’re waiting to see if lenvatinib-pembrolizumab beat carboplatin-paclitaxel. That is going to turn the world on its head if that’s positive. It’s a pretty big bar, but at the very least we’re going to see how they compare. The AtTEnd trial is also looking at patients with curative intent. We have the MITO END-03 trial, in which Italian colleagues are looking at patients with curative intent. We have 21 trials. What else do we have? We have better drugs—antibody-drug conjugates—targeting HER2 [human epidermal growth factor receptor 2]/neu. A couple of trials are looking at patients who would use trastuzumab and whether to either add to that, or in the recurrent setting.

There’s also combining some antivascular therapy, pan TKIs [tyrosine kinase inhibitors], and I/O therapies. So there are different ways. Looking at potentially PARP inhibitors in patients who act more like ovarian cancer, HR deficiency—homologous recombination deficiency—not mismatched repair deficiency. Seeing if bringing PARP inhibitors plus other agents is going to improve the outcomes of those patients.

Remember what I said at the beginning as we started talking: There was nothing for second line just a few years ago. Once we get beyond these agents that we’re talking about, pembrolizumab plus or minus lenvatinib, depending on the patient population, the options are really limited. We are going to have the options for those patients or, most important, a potentially higher chance of curative intent at the first line of therapy.

I almost forgot 1 of the biggest trials, the RUBY trial, which is probably going to be done with enrollment shortly. Once again, this trial is looking at carboplatin-paclitaxel plus or minus dostarlimab in these patients in the first-line setting. All these options are going to improve the outcomes of our patients, but let’s try to get them on clinical trial.

Kathleen Moore, MD: It’s amazing that we have 2 regimens: monotherapy immunotherapy as well as the lenvatinib-pembrolizumab combination for patients in the recurrent setting. Those are game changers for our patients. We do have some complete responses. Time will tell how long those complete responses hold. That’s pretty exciting to think about as well. But patients who have partial responses for long periods of time will, unfortunately, eventually progress and will need another line of therapy. The nice thing is coming off these studies with responses, they actually feel better enough that they can get another line of therapy, which is a change from our prior options.

It’s exciting to know that there are a number of very promising agents in the pipeline that are entering larger clinical trials. I’m going to highlight 2 of them. The first has been led by my good friend Dr Joyce Liu from Dana-Farber Cancer Institute. This uses the WEE1 kinase inhibitor adavosertib in women with recurrent uterine serous carcinoma. This is a group of patients we talked about earlier in this session who have loss of TP53 and very poor prognosis based on that. There may be some benefit from chemotherapy but very high risk for recurrence. Fortunately, as I just mentioned, they do tend to respond well to pembrolizumab and lenvatinib, so that would definitely be my first choice. But we have emerging data with adavosertib that this is also a compelling agent in this setting.

Dr Liu ran a single-site phase 2 trial that has 34 patients with recurrent uterine serous carcinoma. Several of them have had many lines of therapy. This isn’t a group of patients who came up 1 line and then onto adavosertib. They are very heavily pretreated. The median number of prior lines was 3. This is a different world from when I was training. You had a response rate of 30%, which is quite high when you think about it in this heavily pretreated population. Six-month progression-free survival was almost 60%. Even if they didn’t respond, you had 60% of women not progressing at the 6-month mark, which is a nice signal for clinical efficacy.

If you add the adverse events that we know well, for WEE1 kinase inhibition with neutropenia, in about 30% of patients;these are grade 3 toxicities. Patients with anemia are at about 20%, and then about 25% have grade 3 or higher fatigue. We still need to work on the dosing of this plus the population. This has moved into a larger multisite single arm, so everyone will get adavosertib. But it is moving into what will be hopefully an accelerated approval strategy to get this agent approved and available for patients with recurrent uterine serous carcinoma.

Encouragingly, there is a lot of biomarker work being done in Dr Liu’s study, which should be coming out in the press very shortly. Then there’s the upcoming study looking at CCNE1 amplification as potentially a biomarker for patients who will respond even better to this than the whole intent-to-treat group. It doesn’t identify the patients who only respond, so it’s not an eligibility criteria, but keep an eye out for CCNE1 as an emerging biomarker for several diseases—especially surrounding use of this class of agents. This is an exciting advance. The study is just launching, so hopefully several of you will be opening it. I think it will open and close fairly quickly given the excitement surrounding this agent.

Switching gears a little away from immunotherapies to tyrosine kinase inhibitors and kinase inhibitors, focusing on hormonal interventions and other strategies. We’ve been talking about endometrial cancer and loss of TP53 and different subtypes, but a lot of our patients with endometrial cancer have endometrioid types. They have estrogen receptor–positive tumors, and we’ve been using hormonal modulation with pretty good efficacy for a long time. Can we improve on that?

There’s a lot of interest coming from our colleagues in breast cancer about using CDK4/6 inhibitors. As you know, CDK4/6 inhibitors, such as abemaciclib, palbociclib, and ribociclib, are used with aromatase inhibitors in patients with hormone receptor–positive HER2-negative breast cancer in the front line. There are a lot of data in this hormone receptor–positive breast cancer population with not only progression-free but overall survival data. Would that translate to hormone receptor–positive endometrial cancer as well?

Dr Mansoor Mirza and the ENGOT [European Network for Gynaecological Oncological Trial] group presented this at ESGO [European Society of Gynaecological Oncology International Meeting]. It’s also been published. This is the ENGOT-en3 study. This is a randomized double-blind phase 2 study in patients with recurrent endometrial cancer, and they were randomized to the CDK4/6 inhibitor palbociclib plus letrozole, compared with letrozole. Letrozole is probably not the first choice of any of us for hormonal management in an endometrial patient. We probably would be using medroxyprogesterone with or without tamoxifen. That’s 1 weakness of the study, but it is cleaner to look at it vs letrozole. I do think the control arm is something we have to think about it.

But be that as it may, it was a randomized phase 2, really well-designed blinded study, and they looked at progression-free survival as an end point. They had 77 patients enrolled, so it was a nice-size study. What you saw was that the use of palbociclib and letrozole significantly improved the progression-free survival compared with letrozole and placebo. The median progression-free survivals were 8.3 vs 3 months, respectively, and the hazard ratio was 0.56. Even though I don’t love the letrozole as a control, I don’t know that medroxyprogesterone would have been that much better. It may have been a little better, maybe 4 or 5 months, but the combination would have still won.

These are really compelling early data. You did see the traditional adverse effects. We know these well from breast cancer, with palbociclib. Neutropenia is the big thing. Grade 3/4 neutropenia is 42% with palbociclib vs none in the letrozole arm. That’s well known from the breast cancer literature. It’s 1 of the known adverse events with CDK4/6 inhibition. These are compelling early data. There are planned studies that are just launching in the United States, a bit of a me-too design, but just trying to confirm this. I’m guessing this regimen will get some sort of an NCCN [National Comprehensive Cancer Network] listing at some point. Then we’ll have to see where it fits in the lineup of options for patients with recurrent disease.

We have data from Dr Brian Slomovitz’s work with everolimus and letrozole in the recurrent, but also in the untreated population of patients with hormone receptor–positive endometrial cancer. That looked very compelling instead of chemotherapy. I know I’m probably not alone: There are some patients with recurrent advanced disease that I start on everolimus-letrozole, but I used to start them on medroxyprogesterone-tamoxifen, and you would get years on that. I’m interested in how this story plays out and how I would sequence this particular regimen in individual patients based on their presentation, performance status, and expectations of efficacy. These are very compelling data. Time will tell where it ends up in the sequencing of things, but it’s definitely something to keep an eye on.

Transcript Edited for Clarity