Pembrolizumab in Ultramutated and Hypermutated Endometrial Cancer

Inclusion Criteria: 1. Patients must have histologically confirmed endometrial cancer that is recurrent or progressive following at least one prior chemotherapy regimen. 2. Patients with the following histologic epithelial cell types are eligible: Endometrioid adenocarcinoma, serous adenocarcinoma, clear cell carcinoma, undifferentiated carcinoma, mixed epithelial carcinoma, carcinosarcoma, and adenocarcinoma not otherwise specified (N.O.S.). 3. Tumors must demonstrate ultramutation (POLE/POLD1-mutation) and/or hyper-mutation (due to MMR gene defect) in a representative primary or metastatic tumor site by next generation sequencing (NGS) and Comprehensive Genomic Profiling (CGP) testing, and/or standard PCR-based DNA microsatellite instability (MSI) and immunohistochemistry (IHC). 4. All patients must have measurable disease by RECIST 1.1. 5. Patients must have a ECOG performance status of 0 or 1. 6. Women of childbearing potential must have a negative urine and serum pregnancy test within 72 hours prior to receiving first dose and must be willing to use contraceptive through 120 days of last dose of Pembrolizumab. 7. Patients must have recovered from effects of recent surgery, radiotherapy, or chemotherapy. Patients with ≥ Grade 2 neuropathy are eligible. 8. Patients may have received prior radiation therapy for treatment of endometrial cancer. Prior radiation therapy may have included pelvic radiation therapy, extended field pelvic/para-aortic radiation therapy, intravaginal brachytherapy and/or palliative radiation therapy. All radiation therapy must be completed at least 4 weeks prior to the first date of study therapy. 9. Patients may have received prior hormonal therapy for treatment of endometrial carcinoma. All hormonal therapy must be discontinued at least one week prior to the first date of study therapy. 10. Patients may have received prior therapy (including chemotherapy, biologic/targeted therapy and immunotherapy) for treatment of endometrial cancer. All therapy must be discontinued at least 3 weeks prior to the first date of study therapy. Any investigational agent must be discontinued at least 30 days prior to the first date of study therapy. 11. Chemotherapy administered in conjunction with primary radiation as a radio-sensitizer WILL be counted as a systemic chemotherapy regimen. 12. Patients are allowed to receive, but not required to receive, up to 4 additional lines of therapy. 13. At least 4 weeks must have elapsed since the patient underwent any major surgery (e.g., major: laparotomy, laparoscopy) There is no delay in treatment for minor procedures (e.g., tumor FNA or core biopsy, venous access device placement). 14. Have demonstrated adequate organ function. All screen labs should be performed within 14 days of treatment initiation 15. Patients must have signed an approved informed consent and authorization permitting release of personal health information. 16. Patients must be 18 years or older Exclusion Criteria: 1. Patients who have had prior therapy with nivolumab, pembrolizumab or with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or immune check point pathways. 2. History of severe hypersensitivity reaction to any monoclonal antibody. 3. Patients with uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure and unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. 4. Patients who are pregnant or nursing. The effects of pembrolizumab on the developing human fetus are unknown. For this reason, women of child-bearing potential (WOCBP) must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. WOCBP should use an adequate method to avoid pregnancy for 23 weeks after the last dose of investigational drug. WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IV/L or equivalent units of HCG) within 24 hours prior to the start of pembrolizumab. Women must not be breastfeeding. 5. Women who are not of childbearing potential (i.e., who are postmenopausal or surgically sterile or have undergone definitive radiation) do not require contraception. 6. Patients with known brain metastases or leptomeningeal metastases are excluded unless the following conditions are met: Metastases have been treated and there is no evidence of progression by CT scan or magnetic resonance imaging (MRI) prior to the first dose of pembrolizumab administration). There must also be no requirement for immunosuppressive doses of systemic corticosteroids (\>10 mg/day prednisone equivalents) for at least 1 week prior to study drug administration. 7. Patients should be excluded if they have known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS). Patients should be excluded if they have a positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection (e.g., HCV RNA \[qualitative\] is detected). 8. Patients with active autoimmune disease or history of autoimmune disease that might recur, which may affect vital organ function or require immune suppressive treatment including systemic corticosteroids, should be excluded. These include but are not limited to patients with a history of immune related neurologic disease, multiple sclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome, myasthenia gravis; systemic autoimmune disease such as SLE, connective tissue diseases, scleroderma, inflammatory bowel disease (IRB), Crohn's, ulcerative colitis, hepatitis; and patients with a history of toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, or phospholipid syndrome should be excluded because of the risk of recurrence or exacerbation of disease. Patient with vitiligo, endocrine deficiencies including thyroiditis managed with replacement hormones including physiologic corticosteroids are eligible. Patients with rheumatoid arthritis and other arthropathies, Sjogren's syndrome and psoriasis controlled with topical medication and patients with positive serology, such as antinuclear antibodies (ANA), anti-thyroid antibodies should be evaluated for the presence of target organ involvement and potential need for systemic treatment but should otherwise be eligible. NOTE: Patients are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger (precipitating event). 9. Patients should be excluded if they have a condition requiring systemic treatment with either corticosteroids (\>10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses \<10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease. Patients are permitted to use topical, ocular, intra-articular, intranasal, and inhalational corticosteroids (with minimal systemic absorption). Physiologic replacement doses of systemic corticosteroids are permitted, even if \<10 mg/day prednisone equivalents. A brief course of corticosteroids for prophylaxis (e.g., contrast dye allergy) or for treatment of non-autoimmune conditions (e.g., delayed-type hypersensitivity reaction caused by contact allergen) is permitted. 10. Patients who have had evidence of active or acute diverticulitis, intra-abdominal abscess, abdominal/pelvic fistula, gastrointestinal perforation, GI obstruction and/or who require parenteral hydration and/or nutrition.. 11. Has a known history of active TB (Bacillus Tuberculosis) 12. Hypersensitivity to pembrolizumab or any of its excipients. 13. Prior invasive malignancy (except non-melanomatous skin cancer such as basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer) unless disease free for a minimum of 3 years. 14. Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis. 15. Has an active infection requiring intravenous systemic therapy. 16. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator. 17. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial. 18. Has not recovered from adverse events to \<Grade 1 or prior treatment level due to a previously administered agent. Subjects with Grade \<2 neuropathy or alopecia of any grade are an exception to this criterion and may qualify for the study. 19. Has a known additional malignancy that progressed or required active treatment within the last five years. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer. 20. Is pregnant or breastfeeding, or expecting to conceive children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment. 21. Patients should not have used investigational agents or device within 4 weeks prior to first dose. 22. Has received a live vaccine within 30 days of planned start of study therapy. Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed.