Immunotherapy Approvals Signal a Need for Molecular Testing in Endometrial Cancer

The FDA approvals of pembrolizumab (Keytruda) and dostarlimab-gxly (Jemperli) emphasize the need to test for microsatellite instability–high (MSI-H), mismatch repair deficient (dMMR), and tumor mutational burden–high (TMB-H) tumors in endometrial cancer, said Sarah Lee, MD, MBA, who added that testing for these molecular features will ensure immunotherapy is tailored to appropriate patients.

“The alphabet soup [of these disease features] could be very confusing [for patients]; it is certainly confusing for me as well. What is important for patients is that they look beyond just the histology of their cancers and get as much information as they can so that they are able to get therapies they are eligible for based on some of these biomarkers,” Lee explained.

In an interview with OncLive^® during the SGO 2022 Winter Meeting, Lee, a first-year fellow in the Department of Obstetrics and Gynecology at NYU Langone Health, discussed the use of checkpoint inhibitors in endometrial cancer, research regarding the association between MSI-H, dMMR, and TMB-H disease, and the importance of broad molecular testing to ensure all eligible patients are appropriately matched to immunotherapeutic options.

OncLive^®: How has immunotherapy changed the landscape of endometrial cancer management?

Lee: Several FDA indications [have been granted] for patients with endometrial cancer. For pembrolizumab, there was an FDA approval in 2017 for patients with MSI-H or dMMR disease. Then in 2020, [another indication was granted to pembrolizumab] for TMB-H [solid tumors]. Then, the results of the GARNET trial [NCT02715284] came out, which brought forth dostarlimab, another checkpoint inhibitor, which was approved for patients with dMMR disease in April of 2021.

We are excited about all these expanding indications for endometrial cancer, but we really want to know what the overlap of [MSI-H, dMMR, and TMB-H] is and their associations so that we can maximize our patients who qualify for immunotherapy

During the SGO 2022 Winter Meeting, you presented findings from a study looking at the association between MSI-H, dMMR, and TMB-H disease features in endometrial cancer. What was the rationale to evaluate this topic in the context of these FDA approvals?

The main goal of our study was to determine the association between TMB-H and MSI-H/dMMR; 16% of our patient cohort had all 3 [markers]. When we looked closer at the patients who were not MSI-H/dMMR, 5% were found to be TMB-H alone. These patients would have been missed if we just did MSI and MMR testing alone.

We wanted to hit home that patients are likely getting a mixture of testing that is institutional and provider dependent. If we don’t [test for all potentially relevant markers] and get the tumor molecularly profiled, we have the potential to miss a subset of patients, mainly the TMB-H patients, who would otherwise be eligible for immunotherapy.

Did you find any of these results particularly surprising?

The findings that were interesting to us [were] when we looked specifically at the 6 patients who were found to be TMB-H without being MSI-H/dMMR. That is a cohort that would have been missed with just MSI/MMR testing alone. We found that in this subgroup of patients, 5 of the 6 were non-Whites and 5 of the 6 had non-endometrioid, high-risk histologies. This is in comparison to the group who met all 3 criteria of [having] TMB-H, MSI-H, and dMMR disease. In that group, only 12% of patients had non-endometrioid histologies.

Yes, our n is small, but perhaps the signals that the group of patients who are TMB-H alone [had are] different [from those in a] subset of patients with cancer characteristics that are associated with a worse prognosis.

What other aspects of the SGO 2022 Winter Meeting were intriguing to you that you could bring back to your practice? What research needs to be done with molecular subtyping in endometrial cancer?

It’s been inspiring to be here at the SGO 2022 Winter Meeting. In the uterine section, there was a lot of talk about type 1 and type 2 endometrial cancers. Really diving deeper into the molecular subtypes as evidenced by TCGA [(The Cancer Genome Atlas) is exciting].

There is a lot of movement in the field [of endometrial cancer] to decipher what it means to have one of these clinical molecular subtypes at the patient level. Our data are very small and limited to a single-institute case series, so we need to validate it. We plan to do that with a multi-institutional endometrial cancer consortium moving forward to see what the associations are between these 3 entities and take a closer look at these patients who are TMB-high alone to see if we can validate our findings.

What other patient populations could this research affect?

One of the important findings is that if we just limit ourselves to certain types of testing, like MMR testing, we are missing large [populations] of patients. This is important for Lynch syndrome because MMR testing is not 100% [effective] for diagnosing Lynch syndrome. This has important implications for patients, but also for their families in terms of cascade testing. It is important to molecularly sequence our patients so that we can maximize their chances of being eligible for some of these exciting immunotherapies.