Key Biomarkers Driving Treatment of Endometrial Cancer

Eirwen M. Miller, MD

Immunotherapies like pembrolizumab (Keytruda) and dostarlimab (Jemperli) used alone or in combination with chemotherapy recently emerged as standards of care for mismatch repair deficient (dMMR) or microsatellite instability-high (MSI-H) primary advanced or recurrent endometrial cancer. The approval of these therapies underscores the relevance of dMMR as a biomarker, according to Eirwen M. Miller, MD.

Another biomarker showing promise in the endometrial cancer space is p53 wild-type, and several studies of patients with endometrial cancer and p53 wild-type are underway.

“The landscape of targeted therapy across those gynecologic malignancies is expanding rapidly. I think that we'll continue to see additional targets come to be studied and come to the market over the next 5 to 10 years,” said Miller, gynecologic oncologist at Allegheny Health Network, in an interview with Targeted Oncology™.

In the interview, Miller, discussed the endometrial cancer landscape and future projections.

TARGETED ONCOLOGY: What do you currently have in the toolbox for endometrial cancer?

Miller: The treatment of endometrial cancer today probably [is] astronomically more complicated than it was 3 or 4 years ago. The most recent publication publications came to us at SGO in March this year. The NRG-GY018 [NCT03914612] and RUBY [NCT03981796] studies were presented and simultaneously published, evaluating the role of immunotherapy in combination with chemotherapy followed by immunotherapy maintenance for patients with advanced-stage endometrial cancer. Each study had slightly different inclusion criteria and slightly different designs, but both demonstrated a progression-free survival benefit with the addition of immunotherapy.

The most profound [results were] what was seen in the patients that had mismatch repair deficient endometrial cancers, and that certainly will change our standard of care for that subgroup of patients. There is also a benefit, though more modest in the mismatch repair patient population, in the intention-to-treat populations of those studies. That certainly will change the way we treat upfront endometrial cancer, giving thought to the addition of maintenance therapy. What is the role now of radiation therapy for [the] upfront management of advanced endometrial cancer?

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What novel biomarkers will be important for endometrial cancer in the future?

In endometrial cancer, we're seeing some interesting in targeted therapies. I mentioned the MMR pathway, which is definitely a target that has some FDA approvals at this time. Both pembrolizumab and dostarlimab are FDA-approved for patients with dMMR endometrial cancers, either as a treatment or in combination with chemotherapy.

In terms of future targets that we're looking at, we have 2 phase 3 clinical trials right now, enrolling for a p53 wild-type population. One of the drugs, Selinexor [Xpovio], has demonstrated a progression-free survival benefit in a p53 wild-type subgroup in a prior study. We are really exploring that subgroup of patients. I think those are probably the 2 biggest targets that we're looking at at the moment. The landscape of targeted therapy across those gynecologic malignancies is expanding rapidly. I think that we'll continue to see additional targets come to be studied and come to the market over the next 5 to 10 years.

What are your hopes and expectations from future endometrial cancer research?

We've seen immunotherapy change the landscape in dMMR tumors. We're looking to find some headway in the MMR proficient tumors. The Cancer Genome Atlas essentially reclassified endometrial cancers according to a molecular profile. What we don't know yet is what that has on treatment implications. Certainly, that molecular classification is prognostic, but we don't know how it necessarily affects our treatment yet.

When we're looking at future directions and unmet needs, I think it's largely looking at those subgroups of patients according to their molecular subtype and understanding how they're best going to respond to different targeted therapies. Whether it's immunotherapy in the dMMR population or in the p53 wildtype population, which is largely measured by copy number variants in the Cancer Genome Atlas, some of those patients have HER2 overexpression and can be targeted with [trastuzumab; Herceptin] in a largely a serous carcinosarcoma histology. But how do we change management based on that molecular profile and the targets? I think there is a lot more to come as we're learning.