Immunotherapy Redefines Standard of Care for Frontline Advanced Endometrial Cancer

The addition of immunotherapy into chemotherapy regimens has transformed the frontline treatment paradigm for advanced endometrial cancer, according to Monica H. Vetter, MD, who highlighted the importance of patient selection and guideline-based decisions in this evolving landscape.

“A majority of us would now consider the addition of immunotherapy to chemotherapy, followed by immunotherapy maintenance, as standard of care for most of our patients with advanced endometrial cancer,” Vetter said. “We know that the magnitude of benefit is greater for our patients with mismatch repair–deficient [(dMMR) disease], but the data also support its use in patients with mismatch repair–proficient [(pMMR) disease].”

In an interview with OncLive®, Vetter detailed the distinctions between the phase 3 RUBY (NCT03981796)and the KEYNOTE-868 (NCT03914612) trials that led to the FDA approvals of dostarlimab-gxly (Jemperli) plus chemotherapy and pembrolizumab (Keytruda) plus chemotherapy for patients with primary advanced or recurrent endometrial cancer.1,2 She expanded on how these regimens have affected the treatment paradigm and factors to consider when selecting a treatment.

Vetter is a gynecologic oncologist with Norton Cancer Institute in Louisville, Kentucky.

OncLive: When looking at the KEYNOTE-868 and RUBY trials that supported the respective FDA approvals of pembrolizumab/chemotherapy and dostarlimab/chemotherapy in endometrial cancer, how important is patient selection for these immunotherapy-based regimens?

Vetter: The difference in the inclusion criteria is important because it explains some of the differences in terms of the magnitude of benefit that we saw, particularly in the pMMR groups. It's also important to note those differences in inclusion criteria because from a practical standpoint, those [criteria] are included in the National Comprehensive Cancer Network [NCCN] Guidelines and have impacted some of the insurance approvals that we have for our patients in terms of whether they're able to get pembrolizumab vs dostarlimab.

When you look at the NCCN Guidelines, they [include information] about dostarlimab usage for patients with uterine carcinosarcomas. It's also important to note that for both the indications for pembrolizumab and dostarlimab, [the NCCN Guidelines include] footer information that goes along with it, listing the criteria from the KEYNOTE-868 and RUBY trials. We have found that some insurance companies are sticking to the true inclusion criteria and may be rejecting [coverage of] pembrolizumab for patients who didn't meet the true inclusion criteria for KEYNOTE-868; but we have been able to get coverage for dostarlimab.

What updated data are important to note with each regimen?

The updated overall survival [OS] data, particularly in the dMMR groups, are outstanding for both drugs. Any time that you can get a study that demonstrates an improvement in OS, that's fantastic. [Generating an improvement in OS] can be challenging to do, particularly in the gynecologic oncology space.

For the RUBY trial, I would point to the updated OS data that were presented at the 2024 Society of Gynecologic Oncology Annual Meeting. Although the OS data [for dostarlimab plus chemotherapy] did not meet statistical significance in pMMR group, there was still a 7-month difference between the [dostarlimab regimen and the placebo regimen]. Although that [OS difference] may not be statistically significant, that could be clinically significant for our patients [with pMMR disease] who otherwise have a poor prognosis.

What factors do you consider when selecting a treatment regimen for a patient with dMMR disease?

In order to make it simpler for my staff, I personally have chosen to go specifically for the dostarlimab regimen for my [patients with] frontline endometrial cancers because it has the widest indication. Essentially, there are patients who are going to be candidates for dostarlimab who are not candidates for pembrolizumab, but not vice versa. For the efficiency and safety of my [practice], I've personally elected to go to dostarlimab-containing regimen for all frontline endometrial cancers.

Which treatment regimen would you consider most appropriate for a patient with pMMR disease?

I also go with the dostarlimab regimen, partially because I appreciate that [the NCCN Guidelines] included uterine carcinosarcomas and the higher-risk patients with stage 3C1 [disease] without measurable disease, because that's what we find the majority of our [patients with] high-grade endometrial cancer fall under. With endometrial cancer, because it's mostly surgically staged, it's somewhat rare to get a patient with true stage 3C1 [disease, meaning] a patient with positive pelvic lodes with residual disease—that would be incredibly uncommon.

What should be known about the safety profiles of these chemoimmunotherapy regimens in endometrial cancer?

It's reassuring that we did not see our differences or notable safety signals [with these immunotherapy-based regimens compared with] our previous experience with the different immunotherapies that we use, both in endometrial cancer and other disease sites. [Immunotherapies] have an acceptable, anticipated toxicity profile that gynecologic oncologists are becoming increasingly more comfortable managing.

Are there any other key considerations when selecting a frontline chemoimmunotherapy regimen in endometrial cancer?

If you have a patient who is a candidate for both [dostarlimab plus chemotherapy and pembrolizumab plus chemotherapy], I always tell people to use the regimen that you're most comfortable with. The [adverse] effects and the toxicity profiles should be similar between [the 2 regimens]. However, especially with all of the new advances we always have, if you've got options that are fairly comparable, I always recommend sticking with the 1 that you're most comfortable with.

References

1. FDA expands endometrial cancer indication for dostarlimab-gxly with chemotherapy. FDA. August 1, 2024. Accessed December 4, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-expands-endometrial-cancer-indication-dostarlimab-gxly-chemotherapy
2. FDA approves pembrolizumab with chemotherapy for primary advanced or recurrent endometrial carcinoma. FDA. June 17, 2024. Accessed December 4, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-chemotherapy-primary-advanced-or-recurrent-endometrial-carcinoma