• STEP 0 PRE-REGISTRATION INCLUSION CRITERIA

• Patient must have active advanced melanoma, defined as unresectable stage IIIB-IV by American Joint Committee on Cancer (AJCC) 8th edition

• Patient must have melanoma originating from cutaneous, acral-lentiginous, or mucosal primary sites. Patients with melanoma of unknown primary site are eligible. Patients must not have melanoma from an ocular primary site

• Patient must have had measurable disease by immune related Response Evaluation Criteria in Solid Tumors (imRECIST) prior to start of initial anti-PD-1 therapy

• Patient must be actively receiving standard of care anti-PD-1 therapy, currently be 52 weeks (+/- 2 weeks) from start of anti-PD-1 therapy, and have not experienced a toxicity that prevents them from continuing on therapy. Permitted systemic anti-PD-1 therapy regimens include:

‣ Nivolumab 240 mg IV every (Q)2weeks or 480 mg IV Q4weeks

⁃ Pembrolizumab 200 mg IV Q3weeks or 400 mg IV Q6weeks

⁃ Nivolumab 1 mg/kg plus ipilimumab 3 mg/kg IV Q3weeks induction x 4 doses, followed by nivolumab 240 mg IV Q2weeks or 480 mg IV Q4weeks maintenance

⁃ Pembrolizumab 2 mg/kg (or 200 mg flat dose) plus Ipilimumab 1 mg/kg IV Q3weeks induction x 4 doses, followed by pembrolizumab 200 mg IV Q3weeks or 400 mg IV Q6weeks maintenance

• Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2

• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial. Patients with detectable viral loads are excluded as it is unclear if these patients have a low risk of melanoma progression off anti-PD-1 treatment

• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable 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 a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial

• 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

• Patient must have experienced complete response, partial response, or stable disease on restaging CT scans by imRECIST that is maintained on restaging scans obtained at week 52 (+/- 2 weeks) from start of initial anti-PD-1 therapy

• Patient must have completed an FDG-PET/CT scan at week 52 (+/- 2 weeks) from start of initial anti-PD-1 therapy

‣ Patients with PET/CT positive for hypermetabolic lesions: If a core needle, punch or excisional biopsy and pathological review of a representative lesion was not performed prior to pre-registration (Step 0) must either:

• Be amenable to undergo a biopsy. Patient must not be on anticoagulation therapy or, if on anti-coagulation therapy, patient must be able to hold treatment for a biopsy procedure (core needle, punch or excisional biopsy). Anti-coagulation therapy is defined as low molecular weight heparin, warfarin, factor Xa inhibitor, or direct thrombin inhibitor

∙ Have documentation of inability to perform the biopsy due to feasibility or safety concerns

• Leukocytes \>= 3,000/mcL (obtained =\< 4 weeks prior to protocol registration)

• Absolute neutrophil count \>= 1,500/mcL (obtained =\< 4 weeks prior to protocol registration)

• Platelets \>= 100,000/mcL (obtained =\< 4 weeks prior to protocol registration)

• Total bilirubin =\< institutional upper limit of normal (ULN) (patients with history of Gilbert's syndrome are permitted to have a total bilirubin \> 1.5 x institutional ULN) (obtained =\< 4 weeks prior to protocol registration)

• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase \[SGPT\]) =\< 2.5 x institutional ULN (obtained =\< 4 weeks prior to protocol registration)

• Creatinine =\< 1.5 x institutional ULN (obtained =\< 4 weeks prior to protocol registration)

• STEP 1 REGISTRATION INCLUSION CRITERIA

• Patient met all eligibility criteria outlined above

• Patient must register to Step 1 within 4 weeks of registration to Step 0

• Patients must meet one of the following criteria:

‣ Patient had no positive hypermetabolic lesions on the week 52 FDG-PET/CT.

⁃ Patients with positive hypermetabolic lesion(s) on the week 52 FDG-PET/CT (positive hypermetabolic = standard uptake volume \[SUV\] \> pooled mediastinal blood), one of the following must have occurred:

• A representative lesion was biopsied (core needle, punch or excisional biopsy) within 14 days of registration to Step 0 and subsequent pathology review performed to determine the presence or absence of viable tumor

∙ Documentation is present that the patient is not able to undergo biopsy of a hypermetabolic lesion due to feasibility or safety concerns, i.e., the lesion location that is not amenable to biopsy