Nivolumab or Expectant Observation Following Ipilimumab, Nivolumab, and Surgery in Treating Patients With High Risk Localized, Locoregionally Advanced, or Recurrent Mucosal Melanoma

This randomized phase II trial studies how well nivolumab or expectant observation following ipilimumab, nivolumab, and surgery work in treating patients with high-risk mucosal melanoma that is restricted to the site of origin without evidence of spread, has spread to a local and regional area of the body, or has come back. Monoclonal antibodies, such as nivolumab and ipilimumab, may interfere with the ability of tumor cells to grow and spread. Sometimes the mucosal melanoma may not need more treatment until it progresses. In this case, observation may be sufficient. It is not known if nivolumab or expectant observation following ipilimumab, nivolumab, and surgery may be better in treating patients with mucosal melanoma.

PRIMARY OBJECTIVES:

I. Recurrence free survival (RFS) in patients with mucosal melanoma (MM) treated with neoadjuvant ipilimumab plus nivolumab and surgery followed by adjuvant nivolumab and expectant observation.

SECONDARY OBJECTIVES:

I. Pathologic complete response with neoadjuvant ipilimumab plus nivolumab. II. Distant recurrence-free survival (DRFS) with adjuvant nivolumab and expectant observation.

III. Overall survival (OS) with adjuvant nivolumab and expectant observation. IV. Safety/toxicity as measured by maximum grade adverse event in (a) the neoadjuvant setting, (b) the adjuvant nivolumab cohort after randomization, and (c) the observation cohort after randomization.

V. Rate of delayed primary surgery.

TERTIARY OBJECTIVES:

I. Demonstrate that baseline tumors harboring a higher neoepitope burden have superior median RFS than those who have a lower neoepitope burden in the arm receiving adjuvant nivolumab.

II. Demonstrate that tumors with higher CD8+ infiltration at the tumor invasive margin at surgical resection have superior median RFS than those with lower CD8+ infiltration.

III. Demonstrate that tumors harboring a "T cell inflamed" ribonucleic acid (RNA) expression signature at surgical resection following neoadjuvant nivolumab plus ipilimumab have a superior distant RFS than those harboring a "non-T cell inflamed" signature, both in the overall group and within those who receive adjuvant nivolumab.

IV. Identify recurrent genetic alterations at baseline that are associated with higher CD8+/PD1+ infiltration at baseline and following 1 dose of neoadjuvant nivolumab plus ipilimumab.

V. Tumor response rate will be estimated based on patients whose imaging are captured and submitted during the neo-adjuvant portion of the study (imaging is not required).

OUTLINE:

PART I: Patients receive nivolumab intravenously (IV) over 30 minutes and ipilimumab IV over 30 minutes on day 1. Within 3-6 weeks after receiving nivolumab and ipilimumab, patients undergo surgery per standard of care. Within 84 days of last surgical resection, patients may also undergo adjuvant radiation therapy (RT), if clinically appropriate.

PART II: Within 84 days of last surgical resection, patients are randomized to 1 of 2 arms.

ARM I: Patients undergo active surveillance for 1 year.

ARM II: Patients receive nivolumab IV over 30 minutes once every 2 weeks for 4 doses. Patients then continue to receive nivolumab IV over 30 minutes once every 4 weeks for up to 11 doses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 90 days for 2 years, every 180 days for 3 years or until disease progression, whichever is first, and every 6 months thereafter until a maximum of 5 years following registration.

Eligibility Criteria:
Inclusion Criteria:

* STEP 1 ELIGIBILITY CRITERIA
* Documentation of disease:

  * Histologic documentation: histologically proven mucosal melanoma by local pathology
  * Tumor tissue: tumor tissue from the primary site of disease must be available for PD-L1 testing (stratification factor)
* Disease status

  * Tumors must have NOT been completely resected, or must be locoregionally recurrent if previously resected; tumor must be deemed potentially resectable by local surgeon
  * MM arising from the head/neck, genitourinary, or gastrointestinal tract
  * Disease meets any 1 of 4 characteristics:

    * Regional lymph node (LN) involvement; OR
    * Multifocal/satellite primary disease; OR
    * Single localized, primary disease meeting one of the following site-specific requirements:

      * Head/neck - any primary lesion if sinonasal; pT4a or above for nasal or oral cavity
      * Anorectal - any primary lesion
      * Conjunctiva - any primary lesion T2 or T3 stage by American Joint Committee on Cancer (AJCC)
      * Vaginal/cervical - any primary
      * Vulvar (hair bearing surface, labia majora) - AJCC cutaneous stage IIB or higher
      * Esophageal - any primary
    * Locoregionally recurrent following prior resection
  * No evidence of metastatic disease at the time of registration
* No prior medical therapy (chemotherapy, immunotherapy, biologic or targeted therapy) or radiation therapy for MM, unless locoregionally recurrent; if recurrent, no prior medical or radiation therapy is allowed for the latest recurrence
* No history of the following:

  * Active known or suspected autoimmune disease
  * Human immunodeficiency virus (HIV) with CD4+ count \< 300 or detectable viral load; patients with HIV, undetectable viral load, and CD4+ count \>= 300 are eligible
  * Known active hepatitis B or C

    * Hepatitis B can be defined as:

      * Hepatitis B virus surface antigen (HBsAg) \> 6 months
      * Serum hepatitis B virus (HBV) deoxyribonucleic acid (DNA) 20,000 IU/ml (105 copies/ml), lower values 2,000-20,000 IU/ml (104-105 copies/ml) are often seen in hepatitis B virus e antigen (HBeAg)-negative chronic hepatitis B
      * Persistent or intermittent elevation in alanine aminotransferase (ALT)/aspartate aminotransferase (AST) levels
      * Liver biopsy showing chronic hepatitis with moderate or severe necroinﬂammation
    * Hepatitis C can be defined as:

      * Hepatitis C antibody (AB) positive
      * Presence of hepatitis C virus (HCV) RNA
  * Known active pulmonary disease with hypoxia defined as oxygen saturation \< 85% on room air
* Not pregnant and not nursing

  * For women of childbearing potential only, a negative pregnancy test done =\< 14 days prior to registration is required
* Eastern Cooperative Oncology Group (ECOG) performance status =\< 2
* Absolute neutrophil count (ANC) \>= 1,500/mm\^3
* Platelet count \>= 100,000/mm\^3
* Creatinine clearance \>= 30 mL/min by Modified Diet in Renal Disease (MDRD) equation or Cockcroft-Gault
* Total bilirubin =\< 1.5 x upper limit of normal (ULN)

  * Except in case of Gilbert disease
* AST/ALT =\< 2.5 x upper limit of normal (ULN)
* Thyroid-stimulating hormone (TSH) within normal limits (WNL)

  * Supplementation is acceptable to achieve a TSH WNL; in patients with abnormal TSH if free T4 is normal and patient is clinically euthyroid, patient is eligible
* Concomitant medications

  * No systemic treatment with either corticosteroids (\> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 7 days of registration (inhaled steroids for patients with underlying chronic pulmonary disease is acceptable as long as they meet other eligibility as listed above)
  * No other planned concurrent investigational agents or other tumor directed therapy (chemotherapy, radiation) while on study
* STEP 2 ELIGIBILITY CRITERIA
* Surgical resection of all gross disease

  * This assessment will be made by the local investigator based on review of the operative report, pathology results, and/or radiology reports; microscopically positive margins (e.g. R1 resection) are permitted
* Completion of PD-L1 testing

  * Patients will be stratified as PD-L1 \>= 5% versus (vs) \< 5% OR inevaluable; baseline tumor will be utilized; if this returns inevaluable, efforts should be made to utilize the resected specimen
* Randomization within 112 days of completion of surgical

  * The primary region must be included on cross-sectional imaging (e.g. sinus/neck if arising from sinonasal primary; pelvis if genitourinary); radiographic changes considered nonspecific or possibly due to surgery or radiation are not considered evidence of disease
* No significant immune-related adverse event due to the nivolumab plus ipilimumab dose received in the neoadjuvant setting, as follows:

  * Any grade myocarditis, including an asymptomatic troponin elevation felt to be related to nivolumab plus ipilimumab
  * Any grade neurologic complication (e.g. meningitis, encephalitis, neuropathy); study chair should be contacted if there is any question whether an adverse event (AE) was neurologic in nature
  * Grade 2 or higher pneumonitis
  * Grade 2 colitis
  * Grade 2 or higher anemia (due to drug; unrelated anemia is not exclusionary)
  * Thyroid/adrenal AEs regardless of grade that have stabilized or are clinically asymptomatic are eligible
  * Fatigue, regardless of grade, is not a contraindication to randomization
  * Grade 4 AST or ALT elevation
  * Asymptomatic elevated amylase and lipase, regardless of grade, are not contraindications to randomization
  * Grade 4 rash; grade 3 rash is not a contraindication to randomization; any oropharyngeal lesions or bullous skin lesions that are suggestive of toxic epidermal necrolysis or Stevens-Johnson syndrome are contraindications to randomization regardless of the grade of rash

    * If not specified above, other Common Terminology Criteria for Adverse Events (CTCAE) grade 3 or higher AEs deemed possibly related to the nivolumab plus ipilimumab are exclusions to randomization; AEs that were attributable to surgery or adjuvant RT would not be contraindications to randomization