The purpose of this research study is to see if it is feasible to combine a fixed dose of pembrolizumab and a daily dose of oral lenvatinib, along with daily treatments of an abbreviated course of pelvic external beam radiation therapy, to support cancer cells in multiplying and spreading to other body sites.

Inclusion Criteria:

1. Biopsy-proven recurrent pMMR EC following surgery alone or de novo unresectable pMMR EC for whom External beam radiation therapy (EBRT) has been determined as an appropriate therapeutic approach. Eligible tumor histologies include the following: endometrioid adenocarcinoma, adenocarcinoma with squamous differentiation, mucinous, mixed carcinoma, undifferentiated carcinoma, clear cell adenocarcinoma, and serous adenocarcinoma histologies as determined by tissue from an archival sample or newly obtained core or excisional biopsy of a tumor lesion. For patients with recurrent disease greater than six months (>6 months), a fresh biopsy must be obtained.

2. Measurable disease of at least 1.0 cm in size defined by RECIST 1.1 on imaging studies with at least one (1) site located in the pelvis and/or vagina without any foci of extra-pelvic disease (including the para-aortic region or inguinal-femoral lymph nodes).13

3. Patients must have Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 (Karnofsky score ≥50).

4. Patients must have pMMR tumor subtype(s).

5. Patients must have normal organ and marrow function as defined below:

   1. Absolute neutrophil count (ANC) ≥1,500 cells/mm³
   2. Platelets ≥100,000 cells/mm³
   3. Hemoglobin ≥9.0 g/dL
   4. Serum creatinine or Measured or calculated a creatinine clearance glomerular filtration rate (GFR) can also be used in place of creatinine or creatinine clearance (CrCl) ≤ 1.5 x upper limit of normal (ULN) or CrCl ≥ 40 mL/min
   5. Serum total bilirubin <1.0 ULN
   6. Aspartate aminotransferase (AST) serum glutamic-oxaloacetic transaminase (SGOT) and alanine transaminase (ALT) serum glutamic-pyruvic transaminase (SGPT) Aminotransferase (AST and ALT) ≤ 2.5 x ULN or 5 X ULN for patients with liver metastases
   7. Albumin ≥2.5 mg/dL

   CrCl should be calculated per institutional standard.

6. Female participants of childbearing potential (those who have not been surgically sterilized or have not been without menses for >1 year) should be willing to use 2 methods of birth control at the same time or be surgically sterile or abstain from heterosexual activity for the course of the study and for at least 120 days after the last study dose.

7. Ability to understand and the willingness to sign a written informed consent document.

8. Women age ≥18 years old.

Exclusion Criteria:

1. Patients who are currently in or have participated in a study of an investigational agent or used an investigational device within 4 weeks of the first dose of study treatment.

2. Patients with Mismatch repair deficient (dMMR) and endometrial carcinomas.

3. Patients with dMMR and uterine carcinosarcomas.

4. Patients with known active central nervous system (CNS) metastases and/or carcinomatous meningitis.

   EXCEPTION: Patients with previously treated brain metastases, including receiving prior brain irradiation, may participate provided they are stable (without evidence of progression by imaging for at least 3 months prior to the first dose of study treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, are not using steroids for at least 28 days prior to study treatment, and have not received prior cranial irradiation for at least 3 months prior to study treatment.

5. Patients with a known additional malignancy that is progressing or requires active treatment.

   EXCEPTIONS include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy.

6. Prior treatment with lenvatinib, anti-programmed cell death-1(PD)-1, anti-PD-L1, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways.

7. Patients who are planned to receive vaginal brachytherapy as their pelvic boost course of radiation as determined by their treating physician(s).

8. No prior radiation therapy to the vagina, pelvis, or abdomen will be allowed.

9. Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or other serious medical condition or social situations that in the judgement of the Investigator(s) would interfere or limit compliance with study requirements/treatments.

10. Receiving systemic steroid therapy or any other form of immunosuppressive therapy within 21 days prior to the first dose of study treatment.

    Note: Patients with active autoimmune disease that has required systemic treatment in the past 2 years (i.e., with use of disease-modifying agents, corticosteroids or immunosuppressive drugs) and/or requiring replacement therapy (i.e., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.

11. Evidence of interstitial lung disease or active, non-infectious pneumonitis.

12. Evidence of uncontrolled hypertension as documented in the patient's medical record.

13. Known psychiatric illness/condition or substance abuse disorders that in the judgement of the Investigator(s) would interfere with cooperation with requirements of the study.

14. Is pregnant or breastfeeding or expecting to conceive within the projected duration of the study, starting with the pre-screening or screening visit through 120 days after the last dose of study treatment.

15. Patients with uncontrolled human immunodeficiency virus (HIV) infection, which is defined as follows:

    1. Antiviral therapy treatment for <4 weeks AND
    2. Have an HIV viral load ≥400 copies/mL prior to enrollment.

16. Patients with uncontrolled hepatitis B virus (HBV) infection or who are chronic carriers of hepatitis B infection, which is defined as:

    1. Hepatitis B surface antigen reactive (HbsAg-positive), undetectable or low HBV DNA, and with normal ALT levels who are not on HBV therapy
    2. Individuals who have serologic evidence of a resolved prior HBV infection (ie, HBSAg-negative and anti-core hepatitis B antibody positive (anti-Hepatitis B core -positive)

17. Patients with active, untreated hepatitis C virus (HCV) infection or who have not completed their HCV antiviral regimen. Patients with a history of HCV infection may participate in this study if their HCV ribonucleic acid (RNA) level is below the limit of quantification.

18. Received live vaccine within 30 days prior to the first dose of study treatment.

19. Patient has active Mycobacterium tuberculosis infection (tuberculosis or TB).

20. A QT interval corrected for heart rate using Bazett's formula (QTcB) ≥ 480msec.

21. Patient receiving concurrent additional biologic therapy.

22. Patients with impaired decision-making capacity.

23. Patients who have not recovered from major surgery.