Treatment Landscape for Advanced/Recurrent Endometrial Cancer

Kathleen Moore, MD, Stephenson Cancer Center at The University of Oklahoma Health Sciences, Oklahoma City, Oklahoma, discusses the treatment of advanced or recurrent endometrial cancer, given the recent expanded indication of dostarlimab plus carboplatin and paclitaxel, followed by dostarlimab monotherapy. This approval was based on results from the phase 3 RUBY trial and expanded the previous indication for this regiment from only among patients with mismatch repair deficient (dMMR) or microsatellite instability high (MSI-H) to all primary advanced or recurrent endometrial cancer.

Dr Moore concluded, “For our patients who do have metastatic disease, to have these options really is game-changing. I think we’ll continue to have these conversations after every meeting, with new data presented continuing to improve the options for our patients in this setting.”

Transcript:

My name is Dr Kathleen Moore. I am the deputy director at the Stevenson Cancer Center at OU Health in Oklahoma City, Oklahoma.

What was the treatment landscape like for patients in this population?

As you all likely know by now, endometrial cancer is the only tumor that is increasing in incidence and mortality in the United States and in some other parts of the world as well. And the reasons for this are unknown, but it's been very frustrating for those of us that take care of patients who present with either recurrent or advanced disease.

For well over probably 2 decades, the standard of care has been chemotherapy alone for the treatment of first diagnostic disease. With clinical trials that were done largely sponsored by the National Cancer Institute, we did finally end up on paclitaxel and carboplatin as the superior and best-tolerated regimen for patients who present with first metastatic disease. And this has been the standard of care for about a decade now.

Response rates are in the 60-ish percent range, but they're relatively short-lived. And so, despite maybe an initial response, these were rarely complete responses. And the paradigm for surgery here is very different than ovary. So, patients would finish chemotherapy with disease and roll on to some subsequent line of ineffective chemotherapy. And overall survival was unacceptably short. When I was early in training, in the 2010 range, the likelihood of being alive at 2 years was only about 45%.

The landscape that we're going to talk about today has vastly changed kind of overnight and very recently. Even 5 years ago, this was still where patients were — maybe we were doing a little better, maybe 55% likelihood of being alive at 2 years. And that is just dramatically changed with these new approvals.

How does this dostarlimab regimen fit into this treatment paradigm?

With the presentation of the RUBY trial, along with the presentation of NRG-GY018, both coincidentally presented at the Society of Gynecologic Oncology Meeting in 2023 — this is how recent this is. The landscape changed overnight and expectations for progression-free survival at that time, and now we're seeing data on overall survival also, changed dramatically. With RUBY, as you know, this added the immune checkpoint inhibitor dostarlimab to the standard of care, which is paclitaxel and carboplatin, and then stopped the chemotherapy after 6 cycles, I believe, and went on to a maintenance of an immune checkpoint inhibitor. That’s already 2 innovations in this space that we really hadn't been doing as a practice paradigm.

You're able to induce better responses in some cases with the addition of an immune checkpoint inhibitor, and then discontinue chemotherapy and hold patients stable with their disease with that response for clinically meaningfully long periods of time. Which in and of itself is a great thing, but maybe even more significant, because I think what we're going to see and we'll see over time if this is true, that a patient who hasn't just been continuously exposed to chemotherapy, gets a break from the chemotherapy, and then has to receive subsequent lines of therapy, they’re going to be more fit to be eligible for those subsequent lines of therapy and their tumors may be less resistant. With less exposure to chemotherapy, we may see a delay in the development of chemo-resistance, which may result, in and of itself, in longer overall survival. I think that remains to be seen.

But it is a dramatic change, and that's in all-comers. The primary end point of RUBY was in the intention-to-treat population. It's even more significant when you look at the data by biomarker selection, of course, in the microsatellite instable or mismatch repair deficient tumors. Quite frankly, I think we may have cured some patients. We'll see, overtime. Both of these haven’t been followed long enough yet to say that.

But the disease-free survival curves for the microsatellite instable or the mismatch repair deficient tumors, you do see a drop-off. That first year, there are a proportion of patients, not the majority but some, who do progress in that first year. But once you get through that first year, that curve is flat. And when you look at the overall survival curves in that same population, it's very flat. There is this sense that in that biomarker-selected population, there's going to be a not small fraction of patients who may not recur, which is amazing when you think about the fact that all of these patients were at very high-risk for early progression and early death.

The microsatellite instability/mismatch repair deficiency is not a prognostic marker at all. These patients, just like microsatellite stable or mismatch repair proficient, with chemotherapy alone would have the same pretty dismal outcomes. And now we've flipped some of them into potentially cure, if not longer term survival. That is one of the, to use the term “miracle,” it's kind of a miracle, honestly, and it's exciting.

In the mismatch repair proficient subset, which is the majority, a majority of our patients have mismatch repair proficient tumors, I think the benefit of the dostarlimab is clinically relevant in the impact on progression-free survival, but it's more modest. I don't think we're necessarily moving more of those patients to cure, but we are improving their progression-free survival and, as I said earlier, allowing them a break from chemotherapy by maintaining them on an active medication that may serve them well in how they respond to subsequent lines of therapy. And given the fact that we're now developing more active second- and third-line therapies, mainly in the form of antibody drug conjugates in this space, I anticipate that our expectations for survival are going to increase markedly with this as sort of the anchor regimen at first recurrence, and then having subsequent lines of therapy that actually work.

It’s a very different outlook than it was even 3 years ago.

What is the safety profile of dostarlimab plus carboplatin-paclitaxel?

The addition of immune checkpoint inhibitors, in this case dostarlimab, to paclitaxel and carboplatin in the treatment of first-line metastatic disease, has a lot of benefits and appropriately has become the standard of care for mismatch repair deficient tumors and a standard of care for mismatch repair proficient. I 100% agree with that.

It does come with a cost, meaning, certainly there's a financial cost, but a cost in terms of adverse effects. Fortunately, though, because immune checkpoint inhibitors combined with a variety of chemotherapies have been the standard of care across many solid tumors for many years, we’re talking over a decade, I think it's just a vastly different world than when we were first developing immune checkpoint inhibitors and the somewhat unexpected, then, autoimmune side effects could be missed or there could be delayed appropriate treatment because people really didn't understand what they were seeing. Those days, I think, are over.

We're all very well educated on the most common and the rarer side effects that can be seen with immune checkpoint inhibitors, that we’re on the lookout for them for all of our patients who we are treating with these medications so that when they're recognized, they are, in a majority of cases, recognized early, treated, and then appropriate decisions are made regarding the continuation or discontinuation of the medication.

The safety profile really doesn’t differ from any other solid tumor that’s using this class of medications. We don’t see any increase in a certain type of toxicity when we use this type of medication in endometrial cancer, for example. There was some concern with that, maybe the same concern we had when we added immune checkpoint inhibitors to the first-line metastatic setting in cervical cancer, where you have patients that might have had prior pelvic radiation, for example. There were concerns that maybe we would see more severe colitis or diarrhea, as one example, and we just didn't see that. It didn’t come to fruition in any trial to date. We see immune-related toxicities at the same kind of rate and severity as we see at any other solid tumor. Those toxicities need to be anticipated, so that they can be recognized and mitigated as quickly as possible. But they have been largely that: mitigatable, so that patients were able to receive these therapies without a significant signal of severe toxicity that would limit the ability to obtain benefit from the medications.

Is there anything else pertaining to this approval or the study findings that you would like to add?

I'm really excited to have been asked to do this short interview today. It's really fun to talk about endometrial cancer now, because we've just come so far in such a short period of time. Again as recently as 3 or 4 years ago, we still were just using paclitaxel and carboplatin, and we had fortunately in the second-line lenvatinib and pembrolizumab as an active second-line regimen. We will forever be grateful for that, but after that, we had just monotherapy chemotherapy, which has an anticipated response rate from phase 3 clinical trials of only 15%. So our patients just did not live very long, and that's just the sad truth. And that had been the sad truth for as long as I've been a GY oncologist.

And then just overnight with the development of, well, immune checkpoint inhibitors were not developed overnight, but overnight with the presentation of the RUBY study and also in NR-GGY018, and we've had subsequent studies even in the last year, the whole landscape changed. And at the same time, the development across hematologic and solid tumors of antibody drug conjugates (ADCs) and the recognition that endometrial cancers present a lot of these tumor-associated antigens that are the targets of some of these ADCs, has brought those into clinical trials and now even an approval, in the form of trastuzumab deruxtecan in HER2/3-plus expressing tumors, which we find in endometrial cancer. We have that particular drug already for a biomarker-selected group and others entering large phase 3 clinical trials, to hopefully show efficacy and tolerability and move into practice as well.

There’s just a pipeline of other small molecules, bispecifics, all being developed with endometrial in mind. And a lot of them won't make it, but some of them will. And this is really, I think, going to continue to transform expectations for outcome for our patients, which is just quite remarkable. We had no movement for a long, long, long time. And then all of a sudden, a lot of movement really to the benefit of a patient population who is long overdue for attention. I think it's just an exciting time.

I guess I should say, first of all, I want to make sure that we are continuing to develop interventions that prevent patients from having first metastatic disease, so we can even just eliminate this as a thing is a first priority. But for our patients who do have metastatic disease, to have these options really is game-changing. I think we’ll continue to have these conversations after every meeting, with new data presented continuing to improve the options for our patients in this setting.

This is an exciting time to be practicing.

Source:

Powell MA, Biorge L, Willmott L, et al. Overall survival in patients with endometrial cancer treated with dostarlimab plus carboplatin–paclitaxel in the randomized ENGOT-EN6/GOG-3031/RUBY trial. Ann Oncol. Published online: June 9, 2024. doi: 10.1016/j.annonc.2024.05.546

FDA expands endometrial cancer indication for dostarlimab-gxly with chemotherapy.Published online: August 1, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-expands-endometrial-cancer-indication-dostarlimab-gxly-chemotherapy