STEP 0 PRE-REGISTRATION INCLUSION CRITERIA

Patient must be >= 18 years of age

Patient must have active advanced melanoma, defined as unresectable stage IIIB-IV by American Joint Committee on Cancer (AJCC) 8th edition. Patients with mucosal melanoma defined as unresectable stage III or regional/distant metastatic disease are eligible

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. Patients are not required to complete all four induction doses of nivolumab/ipilimumab or pembrolizumab/ipilimumab if they continued to receive anti-PD-1 monotherapy. Weight based anti-PD-1 dosing is permited in place of flat dosing. 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
* Nivolumab 3 mg/kg plus Ipilimumab 1 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
*•Nivolumab 480mg / Relatlimab 160mg FDC IV Q4weeks

STEP 0 PRE-REGISTRATION EXCLUSION CRITERIA

Patient must not be receiving concurrent anti-tumor therapies in addition to the standard of care anti-PD-1 regimens. Patients who are receiving bisphosphonates and RANKL inhibitors for management of bone metastases are eligible

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 baseline brain metastases must have been treated with surgery and/or stereotactic radiosurgery and demonstrate disease control or response. Alternatively, patients with baseline brain metastases primarily treated with systemic therapy must demonstrate ongoing response/disease control. Patients with emergent or progressive brain metastases after start of systemic therapy are not eligible. Brain imaging (magnetic resonance imaging [MRI] with IV contrast preferred; non-contrast MRI or contrast enhanced computed tomography [CT] scan are acceptable) at week 48 (+/- 6 weeks) to confirm disease control/response is required in patients with known brain metastasis history

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 diagnostic restaging scans scans by immune mediated response evaluation criteria in solid tumors (imRECIST) that is maintained on the PET/CT scan 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 FDG 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

Patients must not be pregnant or breast-feeding due to potential harm to an unborn fetus and possible risk for adverse events in nursing infants with the anti-PD-1 regimens being used. All patients of childbearing potential must have a blood test or urine study within 28 days prior to Step 0 pre-registration to rule out pregnancy. A second pregnancy test for patients registered to Arm A may be done as clinically indicated. A patient of childbearing potential is defined as anyone, regardless of sexual orientation or 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 3) 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 must not conceive or father children by using accepted and effective method(s) of contraception or by abstaining from sexual intercourse from the time of study registration and continuing (for patients of childbearing potential) until at least 5 months after the last dose of anti-PD-1 treatment. Patients of childbearing potential must also not donate eggs during this same time period

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

Absolute neutrophil count (ANC) >= 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) and subsequent pathology review performed to determine the presence or absence of viable tumor within 28 days of registration to Step 0
** 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

PRIMARY OBJECTIVE:
I. To determine the 12 month event free survival (EFS) rate following discontinuation of anti-PD-1 therapy in patients with disease control and negative fludeoxyglucose F-18 (FDG)- positron emission tomography (PET)/computed tomography (CT) scan or biopsy for residual disease after 12 months of anti-PD-1 therapy (Arm A).

SECONDARY OBJECTIVES:
I. To determine rates of pathologic response in patients with tumor biopsies where positive hypermetabolic activity was present on FDG-PET/CT scan after 12 months of anti-PD-1 therapy (Arm B).
II. To determine the overall 24 month EFS.
III. To determine overall survival from start of anti-PD-1 therapy.
IV. To determine percentage for patients who remain on treatment beyond 12 months because of positive FDG-PET/CT scan and positive biopsy for residual disease (or unable to obtain a biopsy).
V. To determine incidence rates of treatment-related adverse events beyond 12 months from start of treatment in patients who discontinue anti-PD-1 therapy at 12 months and in patients who continue anti-PD-1 based therapies beyond 12 months (Arm A versus [vs.] Arm B).

EXPLORATORY OBJECTIVES:
I. To assess agreement in determining FDG-PET/CT positivity between the local site read and central review.
II. To determine if metabolic response on serial FDG-PET/CT from pre-therapy to 12 months of anti-PD-1 therapy, as determined centrally by various criteria, is associated with EFS.
III. To determine if metabolic response on serial FDG-PET/CT from 12 to 24 months after start of anti-PD-1 therapy, as determined centrally by various criteria, is associated with EFS.

BIOMARKER OBJECTIVE:
I. To bank tumor samples and peripheral blood for future biomarker studies.

OUTLINE: Patients continue their standard of care anti-PD-1 therapy and are then assigned to 1 of 2 arms.

STANDARD OF CARE: Treatment may consist of the following regimens: 1) nivolumab intravenously (IV) over 30 minutes every 2 weeks (Q2W) or every 4 weeks (Q4W); 2) pembrolizumab IV over 30 minutes every 3 weeks (Q3W) or every 6 weeks (Q6W); 3) nivolumab IV over 30 minutes and ipilimumab IV Q3W for 4 doses followed by nivolumab IV over 30 minutes Q2W or Q4W; or 4) pembrolizumab IV over 30 minutes and ipilimumab IV Q3W for 4 doses followed by pembrolizumab IV over 30 minutes Q3W or Q6W. Treatment continues until 52 weeks from start of standard of care anti-PD-1 therapy in the absence of disease progression or unacceptable toxicity. 

ARM A: Patients with a negative FDG-PET/CT scan or a positive FDG-PET/CT scan but with a negative biopsy for viable tumor discontinue the anti-PD-1 therapy and undergo active surveillance.

ARM B: Patients with a positive FDG-PET/CT scan and positive biopsy for viable tumor or a positive FDG-PET/CT scan and biopsy not performed receive nivolumab IV over 30 minutes Q2W or Q4W, or pembrolizumab IV over 30 minutes Q3W or Q6W for 48 weeks in the absence of disease progression or unacceptable toxicity.

Patients undergo computed tomography (CT) scan, magnetic resonance imaging (MRI), positron emission tomography (PET) scan, tumor biopsy and blood collection throughout the study.