ALPINE: Maintenance Letrozole/Abemaciclib Vs Pembrolizumab

Inclusion Criteria:

• Participants must have histologically confirmed either i) endometrioid endometrialcancer or ii) endometrial carcinosarcoma with endometrioid epithelial component.

• Participants must have ER-positive disease, defined as ≥ 1 percent of tumor cellnuclei being immunoreactive by immunohistochemistry (IHC). If multiple analyses havebeen performed, judgment should be based on the most recent biopsy or pathologyspecimen analyzed in a CLIA (Clinical Laboratory Improvement Amendments)-certifiedlaboratory.

• Tumor must be TP53 wild-type as determined by immunohistochemistry (IHC) or viaCLIA-certified targeted Next-Generation Sequencing (NGS); IHC assessment of p53status is included in the NCCN guidelines of uterine neoplasms for the molecularanalysis of endometrial carcinoma.

• Participants must have mismatch repair proficient (MMRP) endometrial cancer asdetermined by immunohistochemistry (IHC) or polymerase chain reaction (PCR) or anyCLIA-certified next generation sequencing assay.

• No known tumor mutational burden ≥ 10 mutations/megabase (Mb).

• Participants must have completed a minimum of 4 cycles and a maximum of 10 cycles ofcombination carboplatin, paclitaxel, and pembrolizumab.

• Participants must be considered appropriate to proceed with maintenancepembrolizumab monotherapy.

• Participants must have had measurable stage III, measurable stage IVA, stage IVB (with or without measurable disease) or recurrent (with or without measurabledisease) endometrial cancer.

• Participants are permitted to have received:

• a. Prior adjuvant chemotherapy (e.g., paclitaxel/carboplatin alone or as acomponent of concurrent chemotherapy and radiation therapy [with or withoutcisplatin])

• b. Prior radiation therapy for treatment of endometrial cancer. Prior radiationtherapy may have included pelvic radiation therapy, extended fieldpelvic/paraaortic radiation therapy, intravaginal brachytherapy, and/orpalliative radiation therapy. All radiation therapy must have been completed atleast 4 weeks prior to registration.

• c. Prior hormonal therapy for treatment of endometrial cancer.

• Must be able to initiate study drug between 3 to 8 weeks (or 21 to 56 days) aftercompletion of their final dose of chemotherapy and pembrolizumab.

• Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 (see Appendix A)

• Age ≥ 18 years

• Participants must have normal organ and bone marrow function within 2 weeks beforestarting protocol therapy as defined below:

• System Laboratory Value

• Hematologic

• ANC ≥1.5 × 109 /L

• Platelets ≥100 × 109 /L

• Hemoglobin ≥8 g/dL Patients may receive erythrocyte transfusions toachieve this hemoglobin level at the discretion of the investigator.Initial treatment must not begin earlier than the day after theerythrocyte transfusion.

• Hepatic

• Total bilirubin ≤1.5 × ULN Patients with Gilbert's syndrome with a totalbilirubin ≤2.0 times ULN and direct bilirubin within normal limits arepermitted.

• ALT and AST ≤3 × ULN

• Creatinine ≤ 1.5 × institutional ULN, OR

• Creatinine clearance ≥ 60 mL/min/1.73 m2 for participants with creatininelevels above 1.5 x institutional ULN.

• Abbreviations: ALT = alanine aminotransferase; ANC = absolute neutrophilcount; AST = aspartate aminotransferase; ULN = upper limit of normal.

• Ability to understand and the willingness to sign a written informed consentdocument.

• Ability to swallow and retain oral medication.

• Participants must have archival tissue available for analysis in the form of aformalinfixed paraffin embedded (FFPE) block or unstained slides. Note: confirmationof availability of archival tissue is the only requirement for eligibility, archivaltissue does not need to be received by the study team prior to enrollment.

Exclusion Criteria:

• Participants who have received previous treatment with CDK4/6 inhibitors, includingbut not limited to previous abemaciclib therapy.

• Any gastrointestinal dysfunctions that could interfere with the absorption of studydrugs (e.g., bowel obstruction, inability to swallow tablets, malabsorptionsyndrome, unresolved nausea, vomiting, diarrhea CTCAE v 5.0 > grade 1).

• Patients who received chemotherapy must have recovered (Common Terminology Criteriafor Adverse Events [CTCAE] Grade ≤1) from the acute effects of chemotherapy exceptfor residual alopecia or Grade 2 peripheral neuropathy prior to randomization.

• The patient has active systemic bacterial infection (requiring intravenous [IV]antibiotics at time of initiating study treatment), fungal infection, or detectableviral infection (such as known human immunodeficiency virus positivity or with knownactive hepatitis B or C [for example, hepatitis B surface antigen positive].Screening is not required for enrollment.

• Major injuries or surgery within 14 days prior to randomization and/or planned majorsurgery during the on-treatment study period. Patients who received radiotherapymust have completed and fully recovered from the acute effects of radiotherapy. Awashout period of at least 14 days is required between end of radiotherapy andrandomization.

• Other malignant disease with disease-free ≤ 3 years except: curatively treatedcarcinoma in situ of the cervix, basal cell carcinoma of the skin, or ductalcarcinoma in situ (DCIS) of the breast or any other cancer deemed by theinvestigator to be at low risk for recurrence of that malignancy.

• Active brain metastases (e.g., stable for < 8 weeks, no adequate previous treatmentwith radiotherapy and/or surgery, symptomatic, requiring treatment withanti-convulsant therapy. Corticoid therapy is allowed if administered as stable dosefor at least 1 month before randomization).

• Females who are pregnant or lactating. The effects of the study agents on thedeveloping human fetus are unknown. For this reason, women of child-bearingpotential must agree to use a medically approved contraceptive method during thetreatment period and for 3 months following the last dose of study agent.Contraceptive methods may include an intrauterine device (IUD) or barrier method. Ifcondoms are used as a barrier method, a spermicidal agent should be added as adouble barrier protection. Should a woman become pregnant or suspect she is pregnantwhile she is participating in this study, she should inform her treating physicianimmediately. A negative serum pregnancy test is required for study entry from womenof childbearing potential.

• The patient has serious and/or uncontrolled preexisting medical condition(s) that,in the judgment of the investigator, would preclude participation in this study (forexample, interstitial lung disease/pneumonitis, severe dyspnea at rest or requiringoxygen therapy, severe renal impairment [e.g. estimated creatinine clearance <30ml/min], history of major surgical resection involving the stomach or smallbowel, or preexisting Crohn's disease or ulcerative colitis or a preexisting chroniccondition resulting in baseline Grade 2 or higher diarrhea).

• Participants who at the time of study enrollment are known to require concomitanttherapy with strong CYP3A4 inducers, or strong inhibitors of CYP3A4. Due topotential drug interactions, concomitant use of these medications is not permittedfor the duration of treatment on trial. Participants are eligible for study entry ifan appropriate substitution is made prior to the first dose of study medication.

• Participants with personal history of any of the following conditions: syncope ofcardiovascular etiology, ventricular arrhythmia of pathological origin (including,but not limited to, ventricular tachycardia and ventricular fibrillation), or suddencardiac arrest.

• Individuals with a history of a different malignancy are ineligible with thefollowing exceptions: individuals who have been treated and are disease-free for aminimum of 3 years prior to study enrollment, or individuals who are deemed by thetreating investigator to be at low risk for disease recurrence.