Pembrolizumab and Lenvatinib in Mismatch Repair Proficient Recurrent Endometrial Cancer After Progression on or Following First-Line Immunotherapy Maintenance

Inclusion Criteria:

1. Histologically confirmed recurrent endometrial carcinoma, including serous, endometrioid, carcinosarcoma, clear cell subtypes, with measurable disease per RECIST 1.1 criteria.
2. Mismatch repair (MMR) proficient status confirmed by immunohistochemistry (IHC) or molecular testing.
3. Patients must have progressed on or after first-line maintenance immunotherapy that was started while on carboplatin-based doublet chemotherapy and continued following chemotherapy until completion (prior chemotherapy for this disease administered before the most recent line is permitted).
4. Prior radiation is permitted but not required.
5. Patient must have completed next-generation sequencing on either primary or recurrent tumor.
6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 - 3.
7. Age ≥ 18 years.
8. Female participants must be of non-childbearing potential or for females of child bearing potential (FOCBPs), must agree to use contraception as described in protocol. FOCBPs must not be pregnant or breastfeeding.
9. At least one measurable lesion according to RECIST 1.1.
10. Adequate organ function, including:

    * Hemoglobin ≥ 8 g/dL (blood transfusions are permitted)
    * Absolute neutrophil count ≥ 1000
    * Platelet count ≥ 100 x 10⁹/L
    * Glomerular filtration rate (GFR) ≥ 30 mL/min
    * Bilirubin ≤ 1.5 x ULN (upper limit of normal)
11. Written informed consent obtained from the patient.
12. At least 3 weeks must have elapsed from any prior therapy

Exclusion Criteria:

1. Uterine sarcoma
2. Active central nervous system metastases or leptomeningeal disease.
3. History of severe allergic reactions to pembrolizumab, lenvatinib, or any components of the formulations.
4. Active autoimmune disease requiring chronic systemic steroids for \> 3 months in the last 6 months prior to enrollment.
5. Pregnancy or breastfeeding at the time of enrollment.
6. Previous treatment with lenvatinib or other VEGFR inhibitors.
7. Concurrent treatment with other investigational drugs or anti-cancer therapies except for adjuvant hormonal therapy for breast cancer.
8. Uncontrolled concurrent illness, such as active infections that could interfere with study participation.
9. Blood pressure \>160 systolic or \>110 diastolic averaged over last 3 documented measurements.
10. History of significant cardiovascular events within 12 months prior to enrollment, including myocardial infarction, unstable angina, or congestive heart failure (NYHA Class III or IV).
11. History of organ transplant or immune suppressive therapy that would interfere with the efficacy or safety of the investigational drugs.
12. Other malignancies within the past 2 years except for non-melanoma skin cancer.
13. Patients that have received more than one prior line of immunotherapy.