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

Patient must not be pregnant or breast-feeding due to the potential harm to an unborn fetus and possible risk for adverse events in nursing infants with the treatment regimens being used. All patients of childbearing potential must have a blood test or urine study with a minimum sensitivity of 25 IU/L or equivalent units of Bacille Calmette-Guerin (BCG), within 14 days prior to randomization to rule out pregnancy. A patient of childbearing potential is defined as anyone, regardless of whether they have undergone tubal ligation, who meets the following criteria: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months).

Patients of childbearing potential must not expect to conceive children by using accepted and effective method(s) of contraception or to abstain from sexual intercourse for at least one week prior to the start of treatment, and continue for 5 months after the last dose of protocol treatment

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

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

Hemoglobin (Hgb) >= 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

Patient must not have had previous use of systemic chemotherapy or other investigational drugs for the treatment of inoperable recurrent or metastatic anal cancer (previous use of radiotherapy or chemoradiotherapy in this setting is not an exclusion criterion if: 1) non-irradiated target tumor lesions are present at randomization for the purpose of tumor response assessment or 2) in the absence of non-irradiated target tumor lesions, progression of the irradiated tumor lesions according to the RECIST criteria version 1.1 is documented)

Patient must not have current or recent (within 30 days prior to randomization) treatment with another investigational drug or participation in another investigational study

Patient must not have had prior immunotherapy

Patient must not have a history of known hypersensitivity reaction to any platinum or taxane-based chemotherapy or monoclonal antibody

Patient must not have active autoimmune disease or history of autoimmune disease that might recur, which may affect vital organ function or require immune suppressive treatment including chronic prolonged systemic corticosteroids (defined as corticosteroid use of duration one month or greater). These include but are not limited to patients with a history of immune related neurologic disease, multiple sclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome, myasthenia gravis; systemic autoimmune disease such as systemic lupus erythematosus (SLE), connective tissue diseases, scleroderma, inflammatory bowel disease (IBD), Crohn’s, ulcerative colitis, and patients with a history of toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, or anti-phospholipid syndrome. Patients with any of these are ineligible because of the risk of recurrence or exacerbation of autoimmune disease

Patient must not have a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of randomization. Inhaled or topical steroids and adrenal replacement doses < 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease. Patients are permitted to use topical, ocular, intra-articular, intranasal, and inhalational corticosteroids (with minimal systemic absorption). Physiologic replacement doses of systemic corticosteroids are permitted, even if < 10 mg/day prednisone equivalents. A brief course of corticosteroids for prophylaxis (e.g., contrast dye allergy) or for treatment of non-autoimmune conditions (e.g., delayed-type hypersensitivity reaction caused by contact allergen) is permitted

Patient must not have had major surgery performed =< 28 days prior to randomization

Patient must not have a history of interstitial lung disease (e.g., pneumonitis or pulmonary fibrosis) or evidence of interstitial lung disease on baseline chest computed tomography (CT) scan

Patient must not have a serious active infection requiring IV antibiotics at time of randomization

Patient must not have other primary malignancy within the last 3 years, except for adequately treated carcinoma in situ of the cervix or squamous carcinoma of the skin, or adequately controlled limited basal cell skin cancer, or any other cancer from which the patient has been disease-free for at least 3 years

Patient must not have known peripheral neuropathy > grade 1 at the time of randomization (absence of deep tendon reflexes as the sole neurological abnormality does not render the patient ineligible)

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

PRIMARY OBJECTIVE:
I. To demonstrate that anti-PD-1 therapy in combination with carboplatin/weekly paclitaxel results in improved progression-free survival (PFS) versus systemic chemotherapy alone.

SECONDARY OBJECTIVES:
I. To demonstrate that anti-PD-1 therapy in combination with carboplatin/weekly paclitaxel results in improved overall survival (OS) versus systemic chemotherapy alone.
II. To demonstrate that anti-PD-1 therapy in combination with carboplatin/weekly paclitaxel results in improved objective response using Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 versus systemic chemotherapy alone.
III. To evaluate toxicity profiles of the two regimens.
IV. To elucidate the role of the human papillomavirus (HPV) circulating cell-free deoxyribonucleic acid (cfDNA) viral load on PFS with the hypothesis that longer PFS will be associated with viral load.

OUTLINE: Patients are randomized to 1 of 2 arms. Randomization will be 2:1 favoring the experimental regimen, Arm B.

ARM A: Patients receive paclitaxel intravenously (IV) on days 1, 8, and 15 of each cycle, and carboplatin IV on day 1 of each cycle. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.

ARM B: Patients receive nivolumab IV over 30 minutes on days 1 and 15 of cycle 1 and then on day 1 only of subsequent cycles, paclitaxel IV on days 1, 8, and 15 of each cycle, and carboplatin on day 1 of each cycle. Treatment repeats every 28 days for up to 6 cycles for carboplatin and paclitaxel, and up to 2 years for nivolumab in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 1 month, then every 3 months for 2 years.