Biomarkers Clarify Treatment Decisions and Sequencing in Endometrial Cancer

An increased understanding of molecular categorizations in endometrial cancer is steering treatment decisions away from histology-based standards of care (SOCs) and instead driving distinct treatment strategies based on characteristics such as mismatch repair (MMR) status and POLE mutation status, according to Emma L. Barber, MD. 

“Molecular profiling has emerged as an important way to prognosticate between [disease histologies] and maybe even guide treatment decisions,” Barber said in an interview with OncLive^®.

In the interview, Barber discussed the limitations of using disease histology to guide endometrial cancer therapies, the importance of sequencing for POLE mutations, and how a patient’s mutation status influences their subsequent treatment options.

The phase 3 KEYNOTE-775 study (NCT03517449), which evaluated lenvatinib (Lenvima) plus pembrolizumab (Keytruda) vs chemotherapy in patients with previously treated advanced endometrial cancer, showed that patients with MMR-proficient (pMMR) disease who received the combination achieved a median progression-free survival (PFS) of 6.6 months and a median overall survival (OS) of 17.4 months vs 3.8 months and 12.0 months with chemotherapy, respectively.¹ Barber highlighted how these findings established a new second-line SOC for patients with and without MMR expression.

She also emphasized the importance of the ongoing phase 3 PORTEC-4a trial (NCT03469674), which is investigating the role of molecular risk profiles in determining whether patients with endometrial cancer should receive no adjuvant therapy, vaginal brachytherapy, or external beam radiotherapy.²

Barber is an assistant professor of gynecologic oncology at the Northwestern University Feinberg School of Medicine and the director of Robotic Surgery in the Division of Gynecologic Oncology at Northwestern Medicine in Chicago, Illinois.

OncLive^®: What is the importance of molecular profiling in the treatment of patients with endometrial cancer?

Barber: Molecular profiling in endometrial cancer [is important] in the modern era in terms of how we take care of patients. Traditionally, we have looked at the histology of the endometrial cancer to determine treatment. However, there are a variety of outcomes and prognoses for patients with the same histology.

Increasingly, even in the [National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology] for frontline therapy after initial systemic treatment, we’re using molecular categories to determine treatments for patients. For example, [we look to see whether patients have] pMMR or mismatch repair–deficient [dMMR] disease and, [depending on their immunohistochemistry (IHC) results], use the combination of lenvatinib and pembrolizumab vs pembrolizumab or dostarlimab-gxly [Jemperli] or other immune checkpoint inhibitors on their own.

What research has aided in defining the endometrial cancer populations most likely to benefit from immunotherapy?

The [phase 1] GARNET study [NCT02715284] investigated dostarlimab as a single agent for patients with recurrent or metastatic endometrial cancer. This study enrolled 2 cohorts, which were determined by molecular profiling: a pMMR cohort and a dMMR cohort.

GARNET confirmed what we know about the importance of immune checkpoint inhibitors in patients, particularly those with dMMR or microsatellite instability [MSI]–high disease. It showed a 43.5% overall response rate [ORR] in [patients with dMMR or MSI-high disease], compared with around a 14.1% ORR in patients with pMMR disease.

KEYNOTE-775 was an important, large, randomized trial in patients with endometrial cancer, specifically those with pMMR disease, who don’t have great responses to checkpoint inhibitors. This was a trial of recurrent or metastatic endometrial cancer where patients were randomized to receive either [the combination of the] checkpoint inhibitor pembrolizumab plus lenvatinib or physician’s choice of chemotherapy.

This study met its primary end point of improved PFS and OS among patients who received lenvatinib and pembrolizumab. This has revolutionized how we treat all patients with endometrial cancer, not just those with dMMR status. This is important because our normal second-line therapy for patients without a biomarker was chemotherapy, and now it’s this combination. That’s exciting and a huge advance in endometrial cancer.

How do the results of molecular profiling reveal a patient’s specific characteristics and guide their individualized treatments?

[Molecular profiling guides treatment in] several different ways. In going through the algorithm for the molecular profiling of endometrial cancer, the first thing that should be done is sequencing for POLE mutations. Patients with a POLE mutation who have an ultra-mutated phenotype should have a good prognosis.

In general, I still somewhat base my treatment decisions on histology and stage. If a patient has stage III endometrial cancer, even if they have a POLE mutation, I will probably not withhold chemotherapy from them. However, if a patient has stage IB grade 3 endometrial cancer, you might have options with current guidelines to choose either vaginal brachytherapy or whole pelvic radiation. If that patient has a POLE mutation, I might de-escalate their care with vaginal brachytherapy.

If the patient doesn’t have a POLE mutation, the next step is to look at their mismatch repair status, whether they have pMMR or dMMR disease. If the patient has dMMR disease, data from the reanalysis of [the phase 3] PORTEC-3 trial [NCT00411138] indicate that they may be more likely to respond to radiation therapy than chemotherapy. If I’m deciding between treatment modalities, that’s a consideration. If that patient has dMMR disease and has metastatic disease, the first-line therapy is still platinum-based chemotherapy. However, I might be more excited about a trial that adds a checkpoint inhibitor, even a single-agent checkpoint inhibitor, in patients who are too sick to tolerate chemotherapy. That factors into my decision making.

Lastly is that high-risk or copy number–high group that’s characterized by p53 mutation. If patients have no p53 expression on their IHC, I sometimes I use that [information when] considering my next steps for treatment. Patients who are copy number–high or have p53 mutations have a poor prognosis, but may also respond better to chemotherapy, based on the reanalysis of PORTEC-3. In patients with stage IB grade 3 disease or isolated tumor cells in a sentinel lymph node [with either] a p53 mutation or no p53 on their IHC, [I may consider] escalating care, knowing that [those characteristics are] associated with a poor prognosis.

What unmet needs remain in this area, and how might they be addressed going forward?

There are many active trials in this space. Everything I’ve shared so far is retrospective data or reanalyses from PORTEC-3 [and other] clinical trials that were done with other primary study objectives and which sorted patients by their molecular profiles [as secondary objectives]. It’s clear that these molecular profiles are associated with differences in prognosis, and maybe differences in response to treatment. Prospective trials using molecular categorizations to guide treatment and see if that’s associated with improved outcomes is an important future area of study.

What is your main message for colleagues?

The main message is the importance of molecular profiling in endometrial cancer. POLE sequencing is full sequencing, so this is not [a test] we’re routinely doing for every patient with endometrial cancer. It’s expensive and can be cumbersome. [However, testing for] p53 and MMR protein status by IHC has been the SOC in endometrial cancer for a while. It’s important for determining patients’ need for genetic evaluation, as well as for now guiding treatment. Trying to make sure every patient has access to that level of molecular profiling is important.

What ongoing research with molecular testing in endometrial cancer would you like to highlight?

One of the big studies that’s investigating using these molecular categorizations to guide treatment, especially in high- and intermediate-risk endometrial cancer, is PORTEC-4a. That’s a study I’m excited to hear the results of to see how we can incorporate these categories into our treatment paradigms.

Editor's Note: Dr Barber reports being on the scientific advisory board for Merck and research funding to Northwestern Medicine from Eli Lilly.

References

1. Makker V, Colombo N, Casado Herráez A, et al. Lenvatinib plus pembrolizumab for advanced endometrial cancer. N Engl J Med. 2022;386(5):437-448. doi:10.1056/NEJMoa2108330
2. PORTEC-4a: molecular profile-based versus standard adjuvant radiotherapy in endometrial cancer (PORTEC-4a). ClinicalTrials.gov. Updated August 18, 2021. Accessed February 6, 2023. https://clinicaltrials.gov/ct2/show/NCT03469674