CE / CME
ABIM MOC: maximum of 1.00 Medical Knowledge MOC point
Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™
Released: September 07, 2023
Expiration: September 06, 2024
Endometrial Cancer: Overview
Endometrial cancer (or uterine or corpus cancer) is the most common gynecologic malignancy in the United States and developed nations. Each year, approximately 66,000 women will be diagnosed with endometrial cancer, and more than 13,000 will die of this disease.1 The average age at diagnosis is approximately 63 years.
Unlike most other malignancies, endometrial cancer is being diagnosed more frequently, with an incidence that has increased approximately 1% annually since the mid-2000s among women aged 50 years and older.1,2 There are notable healthcare disparities in both incidence and mortality related to this disease, with non‑Hispanic Black women having a 2-fold higher likelihood of dying from endometrial cancer compared with non‑Hispanic White women.
Management of Newly Diagnosed or Relapsed/Recurrent Endometrial Cancer
This schematic provides a nice overview of the management options for newly diagnosed early‑stage through advanced‑stage disease, as well as first- and later‑line recurrent disease. This module will focus on the management of advanced‑stage disease that is newly diagnosed or recurrent in the first‑line setting.
TCGA Molecular Classification and Outcomes
Historically, endometrial cancer was divided into endometrioid and nonendometrioid subtypes. However, molecular classification data from The Cancer Genome Atlas project in 2013 demonstrated that endometrial cancer is a heterogeneous disease with 4 clinically important molecular subtypes conferring different prognoses.3 These subgroups include:
Patients with POLE-ultramutated tumors have the best prognosis, followed by those with copy number–low disease, MSI-H disease, and, lastly, copy number high–disease.5
Recommendations for Molecular Testing to Inform Treatment Decisions in Endometrial Cancer
Most endometrial cancers are the result of sporadic or somatic mutations. However, germline mutations associated with Lynch syndrome account for approximately 3% of cases.6 Molecular characterization of endometrial cancer is important not only to inform treatment decisions, but also to guide genetic testing. Screening the tumor for loss of MMR proteins using IHC and/or for MSI-H status can be used to identify patients who should undergo genetic testing.7 Tumors that have MLH1 protein loss should be further evaluated for MLH1 promoter hypermethylation, which suggests an epigenetic process rather than a germline etiology.
HER2/neu Testing in Endometrial Cancer
Approximately 30% of uterine serous carcinomas overexpress HER2/neu, a receptor tyrosine kinase critical to cancer signaling, growth, survival, and proliferation.8,9 HER2 overexpression and/or gene amplification appear to be poor prognostic factors in uterine serous carcinoma. Thus, guidelines recommend evaluation of HER2 overexpression in uterine serous carcinomas, carcinosarcomas, and any endometrial cancers harboring TP53 aberrations.7 The NCCN recommends HER2 IHC testing and HER2 fluorescence in situ hybridization reflex testing for samples that demonstrate equivocal IHC.
HER2 status in endometrial cancer is associated with response to carboplatin/paclitaxel combined with the anti-HER2 antibody trastuzumab.9 This combination is the SoC for stage III/IV or recurrent HER2‑positive endometrial cancers.7
Standard of Care for Advanced or Recurrent Endometrial Cancer
Supportive data for this standard approach in HER2-positive advanced or recurrent endometrial cancer come from a multisite phase II study of 61 patients, which reported significant improvement in PFS in a preliminary analysis.10 An update observed a 5.2-month improvement in median OS with the addition of trastuzumab, yielding an HR of 0.58 (90% CI: 0.34-0.99; P = .046).9
Until early 2023, the SoC for advanced or recurrent endometrial cancer without HER2 overexpression was carboplatin/paclitaxel. This combination became the standard after the GOG0209 study established the noninferiority of carboplatin/paclitaxel vs doxorubicin/cisplatin/paclitaxel.11 The median OS with carboplatin/paclitaxel was 37 months vs 41 months for doxorubicin/cisplatin/paclitaxel, yielding a stratified HR of 1.002 (90% CI: 0.895-1.121).
ENGOT-EN6/GOG-3031/RUBY: Dostarlimab Plus Chemotherapy in Primary Advanced or Recurrent Endometrial Cancer
In 2023, data from 2 clinical trials revolutionized the SoC for systemic treatment of primary advanced or recurrent endometrial cancer. First, we will discuss the ENGOT‑EN6/GOG‑3031/RUBY trial; then we will move on to the NRG GY018 trial.12,13
RUBY was a phase III trial comparing the addition of dostarlimab, an anti–PD-1 antibody, or placebo to standard carboplatin/paclitaxel, followed by maintenance with dostarlimab or placebo.12 Patients with primary advanced or recurrent endometrial cancer of any histologic subtype were eligible to enroll. This included carcinosarcoma, which was the histologic subtype in 17.8% of the total population.
The primary endpoints are PFS in the dMMR/MSI-H subgroup and PFS and OS in the total patient population.
ENGOT-EN6/GOG-3031/RUBY: PFS
After a median follow-up of 25.4 months, there was a PFS benefit observed with the addition of dostarlimab in the overall population, those with dMMR/MSI-H disease, and those with pMMR/MSS disease.12 The greatest magnitude of benefit was seen in the dMMR subgroup, with a 2‑year PFS rate of 61.4% in the dostarlimab arm vs 15.7% in the placebo arm. The HR for progression or death was 0.28 (95% CI: 0.16-0.50; P <.001).
ENGOT-EN6/GOG-3031/RUBY: OS in dMMR/MSI-H and pMMR/MSS
Before discussing the OS results, it is important to note that RUBY was designed to hierarchically test first PFS in the dMMR population, then PFS in the overall population, and then OS in the overall population.12 Although the addition of dostarlimab improved OS in the overall population, yielding an HR for death of 0.64 (95% CI: 0.46-0.87; P = .0021), this did not meet the level of significance set as the stopping rule, which required P = .00177.
In the dMMR/MSI-H group, the addition of dostarlimab improved the 2‑year OS rate to 83.3% vs 58.7% with placebo and yielded an HR of 0.30 (95% CI: 0.13-0.70). There was a numerical improvement in OS favoring dostarlimab plus chemotherapy vs placebo plus chemotherapy in the MSS group, but this was not significant.
ENGOT-EN6/GOG-3031/RUBY: Investigator-Assessed Response
In the dMMR group, adding dostarlimab also improved the overall response rate (ORR) to 77.6% vs 30.6% with the addition of placebo to chemotherapy.12 The median duration of response has not yet been reached in the dostarlimab arm of the dMMR group, whereas the placebo arm had a median duration of response of 5.4 months.
NRG GY018: Pembrolizumab Plus Chemotherapy in Primary Advanced or Recurrent Endometrial Cancer
The second study that changed the management of newly diagnosed advanced and recurrent endometrial cancer is the phase III NRG GY018 trial.13,14 This was an international, double‑blind phase III trial that randomized patients to receive the addition of either pembrolizumab, an anti–PD-1 antibody, or placebo to standard carboplatin/paclitaxel, followed by maintenance with pembrolizumab or placebo. Randomization was stratified by MMR status, Eastern Cooperative Oncology Group performance status, and prior adjuvant chemotherapy.
NRG GY018 enrolled patients with measurable stage III/IVA, stage IVB, or recurrent endometrial cancer. In contrast to RUBY, patients with carcinosarcoma were excluded.
The primary endpoints are investigator-assessed PFS per RECIST v1.1 in the pMMR and dMMR populations. Secondary endpoints assessed in each population include safety, ORR, duration of response, and OS, as well as patient‑reported outcomes and quality of life in the pMMR population.
NRG GY018: PFS (per RECIST v1.1) in dMMR and pMMR Cohorts
At the time of analysis, the median follow-up was 12 months for the dMMR population and 7.9 months for the pMMR population.13 The addition of pembrolizumab to SoC chemotherapy followed by pembrolizumab maintenance significantly reduced the risk of disease progression or death in patients with dMMR or pMMR disease. In the dMMR population, the median PFS was not yet reached vs 7.6 months with the addition of placebo (HR: 0.30; 95% CI: 0.19-0.48; P <.001). In the pMMR population, the median PFS was 13.1 vs 8.7 months, respectively (HR: 0.54; 95% CI: 0.41-0.71; P <.001).
OS data have not yet been reported.
RUBY and NRG GY018: Clinical Implications
This has been an exciting year for endometrial cancer. We now have 2 trials supporting the use of immunotherapy in the frontline setting, along with updated NCCN recommendations and a new approval from the FDA. In July 2023, the FDA approved dostarlimab plus carboplatin/paclitaxel followed by single-agent dostarlimab for patients with primary advanced or recurrent endometrial cancer that is dMMR or MSI-H.15
Regardless of MMR status, the NCCN recommends dostarlimab plus carboplatin/paclitaxel or pembrolizumab plus carboplatin/paclitaxel for primary treatment of stage III-IV disease or first-line treatment of recurrent disease.7 The pembrolizumab-based regimen is not recommended for carcinosarcoma, as that histology was excluded from the NRG GY018 trial.
Should we use immunotherapy in patients with pMMR disease? I am somewhat surprised that the FDA did not approve dostarlimab plus carboplatin/paclitaxel for all comers, because there was such a profound PFS benefit in that population in the RUBY trial.12 There was no significant difference in OS for the pMMR group, but there was still a noteworthy trend toward improvement.
Given these data showing clinical benefit in both dMMR and pMMR populations, I would advocate for consideration of immunotherapy plus carboplatin/paclitaxel regardless of MMR status.
Management of Progressive Disease After Frontline Immunotherapy Plus Chemotherapy
As more patients receive immunotherapy in the frontline setting, we face questions about what treatment options to use when disease progresses. Can other immunotherapies be used after frontline immunotherapy?
We will briefly address some nonimmunotherapy treatment options for recurrent disease. We can use molecular profiling of the tumor to guide treatment selection. For example, hormonal therapy can be used as a single agent or combined with mTOR inhibition. The data supporting use of everolimus and letrozole for endometrial cancer come from a phase II trial published in 2022.16 Single‑agent chemotherapy, as well as other targeted therapies (eg, bevacizumab), or mTOR inhibitors (eg, temsirolimus), are options.7
The question of whether clinical benefit can be obtained by sequencing immunotherapy after immunotherapy remains to be addressed. I might consider additional immunotherapy if a patient had a long benefit with frontline immunotherapy before progression, but we currently lack trial data to support that approach.
Hormonal Therapies
Current guidelines also include the use of hormonal therapies for the management of metastatic or recurrent endometrial cancer.7 Of note, hormonal options remain a viable and relatively nontoxic option for many patients with advanced recurrent endometrial cancer. I would consider hormonal therapy for a patient who has expression of the estrogen receptor and/or progesterone receptor on their tumor, who has multiple medical comorbidities, and/or who has toxicities from other therapies. Hormonal therapy is a reasonable option for patients who want to mitigate the risk of and/or lingering toxicities from chemotherapy.
Single-Agent Immunotherapies in Recurrent Endometrial Cancer
We will now move on to discussion of single‑agent immunotherapy. Both pembrolizumab and dostarlimab are approved by the FDA and endorsed by NCCN guidelines for treatment of MSI-H or dMMR endometrial cancer that progressed after systemic therapy.7,15,17 There are slight differences in the indications between these agents. Dostarlimab is specifically approved in this setting for disease that is recurrent or advanced, has progressed on or after a platinum-based therapy in any setting, and where the patient is ineligible for curative surgery or radiation. Pembrolizumab is approved in this setting for advanced disease with progression after prior systemic therapy in any setting and where the patient is ineligible for curative surgery or radiation.
The benefit of pembrolizumab was initially reported in an analysis of 2 cohorts enrolling patients with endometrial cancer on the nonrandomized, multicohort phase II KEYNOTE‑158 trial.18 More than one half of the 79 patients with endometrial cancer had ≥2 previous therapies, yet there were 11 complete responses, and ORR was 48%. The median duration of response was not yet reached.
Dostarlimab was evaluated in the large, nonrandomized, multicohort phase I GARNET trial, which included a cohort with dMMR/MSI-H endometrial cancer and another cohort with pMMR/MSS endometrial cancer.19 Among those with endometrial cancer, the ORR was higher in the dMMR cohort (43.4%), with 11 complete responses. Again, the median duration of response was not yet reached. Although we saw some benefit in the pMMR cohort, the magnitude of benefit was small, with an ORR of only 13%.
Based on these data and the FDA approvals, single-agent immunotherapy with pembrolizumab or dostarlimab would be the next optimal treatment for patients who have dMMR tumors and who progress on or after platinum‑based chemotherapy.
Study 309/KEYNOTE-775: Lenvatinib Plus Pembrolizumab After Platinum in Advanced Endometrial Cancer
For patients with endometrial cancer that is pMMR or MSS, who progressed after systemic therapy in any setting and who are ineligible for curative surgery or radiation, the SoC is combination therapy with lenvatinib, an oral multikinase inhibitor that targets VEGFR1-3, and pembrolizumab.
Lenvatinib/pembrolizumab received regular FDA approval in this setting based on Study 309/KEYNOTE-775.20,21 This was a confirmatory, randomized, open‑label phase III trial that enrolled patients with both pMMR disease (n = 697) and dMMR disease (n = 130). All patients had advanced metastatic or recurrent endometrial cancer with measurable disease after 1 previous platinum‑based chemotherapy and were randomized to receive lenvatinib/pembrolizumab vs physician’s choice of chemotherapy. The initial stratification was by MMR status; the pMMR group was further stratified by geographic region, Eastern Cooperative Oncology Group performance status, and prior pelvic radiation.
The primary endpoints were PFS by blinded independent central review and OS. Secondary endpoints included ORR, health‑related quality of life, pharmacokinetics, and safety.
Study 309/KEYNOTE-775: PFS and OS
Shown here are data on PFS and OS among patients with pMMR disease and all comers. We can see that in patients with pMMR disease, lenvatinib/pembrolizumab prolonged median PFS vs standard chemotherapy (6.7 vs 3.8 months, respectively), yielding an HR of 0.60 (95% CI: 0.50-0.72).20,21 Median OS was also improved in this group to 18.0 months vs 12.2 months, respectively, with an HR of 0.70 (95% CI: 0.58-0.83).
Among all patients, the median PFS with lenvatinib/pembrolizumab was 7.3 months vs 3.8 months with chemotherapy, for an HR of 0.56 (95% CI: 0.48-0.66). The median OS was 18.7 months vs 11.9 months, respectively, with an HR of 0.65 (95% CI: 0.55-0.77).
Study 309/KEYNOTE-775 Post Hoc Analysis: PFS by Tumor Histology (pMMR Subgroup)
A post hoc analysis of KEYNOTE-775 reported PFS benefit with lenvatinib/pembrolizumab across multiple histologic subtypes in the pMMR population, including those with endometrioid, serous, or clear-cell histology.22 The HR for mixed-cell histology was 0.90 (95% CI: 0.35-2.29), although there were very few patients in this category, and I would caution against extrapolating too much from this underpowered post hoc analysis. However, this lack of benefit also may reflect the challenge of treating mixed-cell disease.
CCO Decision Support Tool: Expert Recommendations on Management of Advanced or Recurrent Endometrial Cancer
As we have discussed, the optimal management of advanced or recurrent endometrial cancer is rapidly evolving. Clinical Care Options has worked with a panel of experts, including myself, to update a free interactive algorithm tool to help healthcare professionals quickly access case-specific recommendations for management of unique patient scenarios based on specific prior therapies, response to prior therapy, biomarkers, and disease histology. Please visit this link to access the current version of this decision support tool.
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