Induction Pembrolizumab and Chemotherapy Followed by Pembrolizumab Before Chemoradiation and Pembrolizumab Maintenance Compared to Standard Chemoradiation With Pembrolizumab Followed by Pembrolizumab Maintenance in High-Risk Cervical Cancer

Inclusion Criteria:

• Patients must have pathologically confirmed newly diagnosed cervical cancer. Eligible pathologic types: squamous cell carcinoma, adenocarcinoma, adenosquamous cell carcinoma

• Patients must have locally advanced cervical cancer (LACC) with T3 or T4 disease with or without lymph node involvement:

• IIIA (T3aN0M0)

• IIIB (T3bN0M0)

• IIIC1(T3aN1M0, T3bN1M0)

• IIIC2 (T3aN2M0, T3bN2M0)

• IVA (T4aN0M0, T4aN1M0, T4aN2M0) No prior hysterectomy defined as removal of the entire uterus.

• NOTE: prior partial/subtotal hysterectomy for reasons other than cervical cancer are eligible to participate in the study. No plan to perform a hysterectomy as part of initial cervical cancer therapy.

No paraaortic lymph node (PALN) metastases above the T12/L1 interspace.

• Note: Nodal status can be confirmed by imaging (CT, MRI, or PET/CT), fine needle aspirate/core biopsy, extra peritoneal biopsy, laparoscopic biopsy, or lymphadenectomy.

Radiologic definition of lymph node staging:

• N1:

• One or more pelvic lymph nodes with short axis diameter of ≥ 15 mm (axial plane) by CT or MRI, and/or

• One or more pelvic lymph nodes with short axis diameter of ≥ 10 mm and standardized uptake value maximum (SUVmax) ≥ 2.5 by fludeoxyglucose (FDG)-PET

• N2:

• One or more para-aortic lymph node with short axis diameter of ≥ 15 mm (axial plane) by CT or MRI, and/or

• One or more para-aortic lymph node with short axis diameter of ≥ 10 mm and SUVmax ≥ 2.5 by FDG-PET

• No prior definitive surgical, radiation, or systemic therapy for cervical cancer

• No prior immunotherapy

• No prior pelvic radiation therapy for any disease

• Age ≥ 18

• Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2

• Not pregnant and not nursing

• Absolute neutrophil count (ANC) ≥ 1,500 cells/mm^3

• Platelets ≥ 100,000 cells/mm^3

• Hemoglobin ≥ 8 g/dl (Note: The use of transfusion or other intervention to achieve hemoglobulin [Hgb] ≥ 8 g/dl is acceptable)

• Creatinine clearance (CrCL) of ≥ 50 mL/min by the Cockcroft-Gault formula

• Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) (patients with known Gilbert's disease who have bilirubin level ≤ 3 x institutional ULN may be enrolled)

• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 x institutional ULN

• Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better

• No active infection requiring parenteral antibiotics

• No live vaccine within 30 days prior to registration. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacille Calmette Guerin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines are live attenuated vaccines and are not allowed

• No 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 registration

• No active autoimmune disease that has required systemic treatment in 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) is not considered a form of systemic treatment and is allowed

• No history of (non-infectious) pneumonitis that required steroids, or current pneumonitis

• No history of allergic reaction to the study agent(s) or compounds of similar chemical or biologic composition to the study agent(s) (or any of its excipients)