A Randomized Phase III Study of Immune Checkpoint Inhibition With Chemotherapy in Treatment-Naive Metastatic Anal Cancer Patients

• Patient must have inoperable, recurrent, or metastatic disease not amenable to curative therapy

• Patient must have histological or cytological confirmation of anal squamous cell carcinoma (includes basaloid and cloacogenic lesions) from the primary tumor or a newly diagnosed recurrent/metastatic lesion

• Patient must be \>= 18 years of age

• Patient must have Eastern Cooperative Oncology Group (ECOG) performance status =\< 0-1

• Patients must have measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria version 1.1 and based on radiologic assessment performed \< 4 weeks prior to randomization

• Patient receiving palliative (limited-field) radiation therapy is allowed, as long as the lesion treated for palliation is not a target lesion and is \> 7 days from completion from palliative radiation

• Patients with brain metastasis are eligible if patient is asymptomatic and if treatment ended \> 3 months prior to randomization. Patients with treated brain metastases are eligible if follow-up brain imaging after central nervous system (CNS)-directed therapy shows no evidence of progression within 4 weeks prior to randomization

• Absolute neutrophil count \>= 1,500/mcL (obtained \< 14 days prior to randomization)

• Platelets \>= 100,000/mcL (obtained \< 14 days prior to randomization)

• Hemoglobin (Hb) \>= 9 g/dL for males and \>= 9 g/dL for females (obtained \< 14 days prior to randomization)

• Total bilirubin =\< 1.5 x institutional upper limit of normal (ULN) (obtained \< 14 days prior to randomization)

• Aspartate transaminase (AST)(serum glutamic-oxaloacetic transaminase \[SGOT\]) /alanine transferase (ALT)(serum glutamate pyruvate transaminase \[SGPT\]) =\< 5 x institutional ULN (obtained \< 14 days prior to randomization)

• Creatinine =\< 1.5 x institutional ULN OR creatinine clearance (CrCl) \>= 50 mL/min (if using the Cockcroft-Gault formula) (obtained \< 14 days prior to randomization)

• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy (ART) with CD4 count \>= 200 or have a CD4 count \< 200 but an undetectable viral load are eligible

‣ All HIV+ patients should be under the care of an infectious diseases specialist. If a relationship with an infectious diseases specialist is not established, an infectious disease specialist should be consulted. Records of all viral counts and peripheral T-cell counts should be documented in order to follow these values over the course of treatment

⁃ All patients must be willing to undergo testing for HIV testing if not tested within the past 12 months

• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable or on suppressive therapy (if indicated)

• Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load

• Patients with known history or current symptoms of cardiac disease, 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. Patients with a history of congestive heart failure (CHF) or who are at risk because of underlying cardiovascular disease or exposure to cardiotoxic drugs must be willing to undergo evaluation of cardiac function including electrocardiogram (EKG) and echocardiogram (ECHO) as clinically indicated

• Patient must have the ability to understand and the willingness to sign a written informed consent document. Patients with impaired decision-making capacity (IDMC) who have a legally authorized representative (LAR) or caregiver and/or family member available will also be considered eligible

• Patients must agree to not receive live vaccines while on this study