Frontline Immunotherapy Combined with Radiation and Chemotherapy in High Risk Endometrial Cancer, FIERCE Study

Inclusion Criteria

• All patients must have undergone hysterectomy. Bilateral salpingo-oophorectomy is strongly encouraged but not mandatory
• Pelvic and para-aortic lymphadenectomy are optional, but strongly encouraged. Peritoneal washing are optional. The hysterectomy may be performed as per the surgeon’s preference including vaginally, laparoscopically, robotic, or open. A specific number of lymph nodes removed will not be utilized for eligibility, but the operative report should reflect what procedure was performed
• If either a bilateral salpingo-oophorectomy (BSO) or nodal sampling was not performed, post-operative pre-treatment computed tomography (CT)/magnetic resonance imaging (MRI) is required and must not demonstrate evidence suggestive of metastatic disease (adnexa, nodes, intraperitoneal disease). Post-operative, pre-treatment CT/MRI must be performed if a BSO and/or lymph node sampling was not performed
• Tissue from an archival sample or newly obtained core or excisional biopsy of a tumor lesion within 10 weeks confirming diagnosis. Immunohistochemistry for mismatch proteins will be run on all specimens as a part of standard of care work up
• All patients will be staged according to the Federation of Gynecology and Obstetrics (FIGO) 2009 staging system and with endometrial carcinoma (endometrioid types) confined to the corpus uteri or with endocervical glandular involvement fitting one of the following high-intermediate risk factor categories: * Age >= 18 years with 3 risk factors * Risk factors: ** Grade 2 or 3 tumor, (+) lymphovascular space invasion, outer 1/2 myometrial invasion. Patients with these risk criteria may be enrolled with either positive or negative cytology ** Patients with stage II endometrial carcinoma (any histology) with cervical stromal invasion (occult or gross involvement), with or without high-intermediate risk factors ** Patients with serous or clear cell histology (with or without other high-intermediate risk factors) are eligible provided the disease is stage I or II (with or without cervical stromal invasion or endocervical glandular involvement). Eligibility for clear cell and serous histology is not based on presence of lymphovascular space invasion or depth of invasion
• Patients must have Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
• The participant (or legally acceptable representative if applicable) provides written informed consent for the trial and authorization permitting release of personal health information
• Neuropathy (sensory and motor) =< CTCAE v5.0 grade 1
• Absolute neutrophil count (ANC) >= 1500/uL
• Platelets >= 100,000/uL
• Hemoglobin >= 9.0 g/dL or >= 5.6 mmol/L * Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) transfusion within last 2 weeks
• Creatinine =< 1.5 x upper limit of normal (ULN) OR measured or calculated creatinine clearance >= 30 mL/min for participant with creatinine levels > 1.5 x institutional ULN (glomerular filtration rate [GFR] can also be used in place of creatinine or CrCl) * Creatinine clearance (CrCl) should be calculated per institutional standard
• Total bilirubin =< 1.5 x ULN OR direct bilirubin =< ULN for participants with total bilirubin levels > 1.5 x ULN
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 2.5 x ULN (=< 5 x ULN for participants with liver metastases)
• International normalized ratio (INR) OR prothrombin time (PT) =< 1.5 x ULN unless participant is receiving anticoagulant therapy as long as PT or activated partial thromboplastin time (aPTT) is within therapeutic range of intended use of anticoagulants
• Activated partial thromboplastin time (aPTT) =< 1.5 x ULN unless participant is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants

Exclusion Criteria

• Patients with recurrent disease
• Greater than 12 weeks elapsed from surgery to enrollment
• Patients have prior pelvic or abdominal radiation therapy
• Known hypersensitivity to any component of study treatments that resulted in drug discontinuation
• Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4, OX-40, CD137)
• Has received prior systemic anti-cancer therapy including investigational agents within 4 weeks (could consider shorter interval for kinase inhibitors or other short half-life drugs) prior to allocation * Note: Participants must have recovered from all adverse events (AEs) due to previous therapies to =< grade 1 or baseline. Participants with =< grade 2 neuropathy may be eligible * Note: If participant received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting study treatment
• Has received prior radiotherapy within 2 weeks of start of study treatment. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (=< 2 weeks of radiotherapy) to non-central nervous system (CNS) disease
• Has received a live vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette–Guerin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist) are live attenuated vaccines and are not allowed
• Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment * Note: Participants who have entered the follow-up phase of an investigational study may participate as long as it has been 4 weeks after the last dose of the previous investigational agent
• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug
• Has a known additional malignancy that is progressing or has required active treatment within the past 3 years * Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (e.g. breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy are not excluded
• Has known active CNS metastases and/or carcinomatous meningitis
• Has severe hypersensitivity (>= grade 3) to pembrolizumab and/or any of its excipients
• Has 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). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment
• Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis
• Has an active infection requiring systemic therapy. This excludes grade 2 urinary tract infections or grade 1-2 skin infections
• Has a known history of human immunodeficiency virus (HIV)
• Has a known history of hepatitis B (defined as hepatitis B surface antigen [HBsAg] reactive) or known active hepatitis C virus (defined as hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected) infection
• Has a known history of active TB (Bacillus tuberculosis)
• Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject’s participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating investigator
• Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
• Is pregnant or breastfeeding