Testing the Addition of the Immunotherapy Drug, Pembrolizumab, to the Usual Radiation Treatment for Newly Diagnosed Early Stage High Intermediate Risk Endometrial Cancer

PRIMARY OBJECTIVE: I. To compare the 3-year recurrence-free survival of women with high intermediate risk (HIR) stage I/II mismatch repair deficient (dMMR) endometrioid endometrial cancer treated with radiation and pembrolizumab (MK-3475) versus radiation alone. SECONDARY OBJECTIVES: I. To describe the safety and tolerability of concurrent pembrolizumab (MK-3475) and radiation compared to radiation alone in patients with MMR deficient high intermediate risk endometrial cancer (HIR EC). II. To describe the recurrence patterns in each group. III. To measure recurrence free survival at 5 years in each group. IV. To estimate disease specific overall survival in each group. V. To determine whether the addition of pembrolizumab (MK-3475) to radiation, compared with radiation alone is associated with decreased quality of life at 6- and 24-weeks, as measured with the Functional Assessment of Cancer Therapy (FACT)-Endometrial (En) Trial Outcome Index (TOI), increased gastrointestinal (GI) symptoms as measured with the GI subscale, and increased fatigue as measured with the Patient Reported Outcomes Measurement Information System (PROMIS)-Fatigue scale (short form). VI. To validate the Functional Assessment of Cancer Therapy-Immune Checkpoint Modulator (FACT-ICM) subscale, which assesses in cancer patients on immunotherapy. VII. To evaluate the ability of ctDNA to predict outcomes in the experimental and control groups. CORRELATIVE/TERTIARY OBJECTIVES: I. To explore the baseline tumor genetic and microenvironment parameters predictive of clinical benefit or resistance to immunotherapy. II. To determine whether the addition of pembrolizumab (MK-3475) to radiation, compared with radiation alone, is associated with decreased quality of life as measured with the Functional Assessment of Cancer Therapy-Immune Checkpoint Modulator (FACT-ICM subscale) and more self-reported bother from side effects as measured with a single item GP5 "I am bothered by side effects," a question from the FACT-En TOI. OUTLINE: Patients are randomized to 1 of 2 arms. ARM I: Patients undergo pelvic external beam radiation therapy (EBRT) daily for 5-6 weeks and vaginal brachytherapy completed within 7 days after completion of EBRT in the absence of disease progression or unacceptable toxicity. ARM II: Patients undergo EBRT and brachytherapy as in Arm I. Within 7 days prior to the start of radiation therapy, patients also receive pembrolizumab intravenously (IV) over 30 minutes on day 1. Treatment with pembrolizumab repeats every 6 weeks for up to 1 year (9 cycles) in the absence of disease progression or unacceptable toxicity. Patients in both arms also undergo collection of blood samples and computed tomography (CT) scans, magnetic resonance imaging (MRI) scans, or x-ray imaging throughout the trial. After completion of study treatment, patients are followed up every 3 months for 2 years and then every 6 months for 3 years.