The Future of Endometrial Cancer Treatment Based on Practice-Changing SGO Abstracts

John Nakayama, MD

Adding immunotherapy to chemotherapy continues to be the standard treatment method for patients with endometrial cancer, regardless of disease stage, according to John Nakayama, MD. Recent data presented at the Society of Gynecologic Oncology (SGO) Annual Meeting may bring additional combinations to the armamentarium.

The phase 3 NRG-GY018 study (NCT03914612) and the phase 3 RUBY trial (NCT03981796) have both recently had reports of positive results in endometrial cancer subgroups.

“These 2 trials have kind of [determined] how we're going to deal with endometrial cancer. One of the things with these trials are that they both had recurrent patients in them, and they made a decent subset of the patients up. When you're looking at the Kaplan Meier curves and when you're looking at the hazard ratios, it's important to keep in mind that these aren’t just frontline patients. These are recurrent patients and frontline patients,” Nakayama, gynecologic oncologist at Allegheny Health Network told Targeted Oncology^TM, in an interview.

In the NRG-GY018 study of pembrolizumab (Keytruda) in combination with carboplatin and paclitaxel, a statistically significant and clinically meaningful improvement in progression-free survival (PFS) was achieved in patients with stage III-IV or recurrent endometrial carcinoma regardless of mismatch repair (MMR) status. The median PFS shown with pembrolizumab plus chemotherapy in the MMR deficient (dMMR) population was not reached vs 7.6 months in the placebo arm (HR, 0.30; 95% CI, 0.19-0.48; P < .00001). In the MMR proficient (pMMR) population, the median PFS was 13.1 months with the pembrolizumab combination vs 8.7 months in the placebo arm (HR, 0.54; 95% CI, 0.41-0.71; P < .00001).¹

Treatment in the NRG-GY018 was associated with adverse events (AEs) in 15% of patients. According to data presented at the SGO Annual Meeting, the frequency of grade 3 or 4 Aes were similar in both MMR populations. AEs of interest, like immune-related etiologies, occurred more frequently with pembrolizumab.

Then, in the RUBY study, which investigated dostarlimab (Jemperli) plus carboplatin and paclitaxel in patients with dMMR, microsatellite instability–high (MSI-H) tumors, the agent demonstrated a significant PFS improvement vs placebo.²

The estimated PFS rate at 24 months was 61.4% (95% CI, 46.3%-73.4%) in the dMMR/MSI-H population treated with dostarlimab, and chemotherapy compared with 15.7% (95% CI, 7.2%-27.0%) in the placebo group (HR, 0.28; 95% CI, 0.16-0.50; P < .001). In the pMMR population, the estimated 24-month PFS was 28.4% with dostarlimab vs 18.8% with placebo, for an estimated HR of 0.76 (95% CI, 0.59-0.98).

In the study, serious treatment-emergent adverse events (TEAEs) were observed in 37.8% of patients in the dostarlimab arm compared with 27.6% in the placebo arm.

“The FDA obviously hasn't given its final blessing yet, said Nakayama, “but I think a lot of people are excited and foresee this as changing the practice. We will probably be incorporating these agents in the frontline and recurrent settings.”

In the interview, Nakayama discussed the 2 recently reported, practice-changing studies in endometrial cancer, and where the field is heading.

Targeted Oncology: What has the evolution of endometrial cancer treatment looked like in recent years?

Nakayama: Endometrial cancer has kind of been stuck since the GOG 209 study showed that are carboplatin and paclitaxel were active agents and changed the standard of care. Since then, there have been marginal changes in what we've done. Then along came immunotherapy.

Immunotherapy is kind of a broad term. What I think most people think about when we talk about that are the checkpoint inhibitors. The most recent trials are looking at the targeting the PD-L1 pathway. Basically, the way I like to think of it, which is kind of simplistic, is it takes the patient’s immune system, and it turns off. What it does is it turns it up to 11 like the old amplifiers, where you turn it up to 10, at the immune system just goes all the way to 11 and just attacks. That's really what's changed recently.

When you think about it, which population is likely to respond to that? What they've done in the past is they looked at the recurrent setting. They looked MMR status, mismatch repair status, or MSI status, and they're kind of measuring similar things. But if your MMR deficient or you are MSI-high, the idea was that you are more likely to respond to a checkpoint inhibitor. Now, what's happened recently is there has been the introduction of these checkpoint inhibitors in the frontline setting. Those are the trials that came out just in the last couple of weeks.

Can you discuss the significance of the NRG GY018 in endometrial cancer?

GY018 was reported recently. This is a trial that looked at patients with both recurrent and frontline endometrial cancer. It used the combination of carboplatin and paclitaxel along with pembrolizumab with pembrolizumab monotherapy as maintenance therapy. What it showed was that there was a significant progression-free survival in the patients that were treated on the pembrolizumab arm, and this was despite MMR or MSI status, while the patients that had an MMR deficiency had a longer improvement than those with a proficient status.

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There were also important results on dostarlimab in the in the RUBY study. What are your thoughts on those data?

The RUBY study looked at a similar population. There were some key differences between the groups. The RUBY study required patients to only be recurrent 6 months out as opposed to 12 in the NRG GY018 study. It looked, again, at the combination of carboplatin and paclitaxel along with the dostarlimab, followed by the dostarlimab maintenance. Similarly, it looked at recurrent vs patients that had advanced stage disease in the frontline setting. This showed that the MMR deficient and the MMR proficient groups had significantly improved progression-free survival.

What do both of these studies say about the role of chemotherapy in endometrial cancer? Do you see this role changing anytime soon?

These 2 trials have [determined] how we're going to deal with endometrial cancer. One of the issues with these trials are that they both had recurrent patients in them, and they made a very decent subset of the patients up. When you're looking at the Kaplan Meier curves and when you're looking at the hazard ratios, it's important to keep in mind that this isn't just frontline patients, this is recurrent patients and frontline patients. In the RUBY trial, approximately 50% of the patients were recurrent patients, as opposed to frontline. I think that's something that we're going to have to tease out very carefully in the following months.

The FDA obviously hasn't given its final blessing yet, but I think a lot of people are very excited and foresee this as changing the practice, and we will probably be incorporating these agents in the frontline and recurrent settings.

I think it’s important that oncologists test for MMR or their MSI status very early in diagnosis because it will change how they potentially think about some of these patients. For example, in GY018, the hazard ratio for those who were MMR deficient was 0.3 while for those that were MMR proficient, it was 0.57. There’s a fairly decent change there. Now, are you going to use it in all people? I think that's going to be something that we talk about and figure out is the risk/benefit, and we’ll try to figure out the difference in the median progression-free survival, and if this is something that's new worthwhile.

The other thing that's going to be challenging is that immunotherapy has become something that most patients with recurrent endometrial cancer are already getting. If the patient is MMR deficient, then odds are they are going to get pembrolizumab at some point in the recurrent setting. If the patient is MMR proficient, the odds are that they are going to get pembrolizumab plus lenvatinib [Lenvima] at some point. Obviously, there are caveats to that, but that is something that a lot of people are getting. Now we're talking about moving pembrolizumab or dostarlimab into the frontline setting. What does this do in the recurrent setting? Not only are we talking about how frontline is going to change, we have to think about the downstream effects.

Which endometrial cancer groups still have poor outcomes and limited therapies?

I think this goes back to what we were talking about before, what does this mean for the recurrent setting? I was happy when all these checkpoint inhibitors started coming out in the recurrent setting, because it gave me viable options of what to do in the recurrent setting. It’s now becoming more of a frontline thing. What are we going to do in the recurrent setting? What are our options at that point? That's going to be a major challenge in the future.

I also think with the introductions to the changes in the staging, we're going to start to be talking about those more, and it's going to be very important that we keep in mind the importance of categorizing patients with endometrial cancer and testing them early, so that we can put those patients in the appropriate category to maximize the benefit of targeted agents.

_REFERENCES:

_{1. Eskander RN, Sill MW, Beffa L, et al. Pembrolizumab versus placebo in addition to carboplatin and paclitaxel for measurable stage III or IVA, stage IVB, or recurrent endometrial cancer: the phase 3, NRG GY018 study. Presented at: 2023 Society of Gynecologic Oncology Annual Meeting on Women’s Cancer; March 25-28, 2023; Tampa, FL.}

_{2. Mirza M, Chase D, Slomovitz, et al. Dostarlimab in combination with chemotherapy for the treatment of primary advanced or recurrent endometrial cancer: a placebo-controlled randomized phase 3 trial (ENGOT-EN6-NSGO/GOG-3031/RUBY). Presented at: 2023 SGO Annual Meeting on Women’s Cancer; March 25-28, 2023; Tampa, Florida.}