Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Phase II Randomized Study of Adjuvant Versus NeoAdjuvant Pembrolizumab (MK-3475) for Clinically Detectable Stage III-IV High-Risk Melanoma
Brief Summary: This phase II trial studies how pembrolizumab works before and after surgery in treating patients with stage III-IV high-risk melanoma. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving pembrolizumab before and after surgery may work better compared to after surgery alone in treating melanoma.


Options:
A: Inclusion Criteria:

* STEP 1 REGISTRATION (RANDOMIZATION): Patients must have clinically detectable stage III (clinically detectable N1b, N1c, N2b, N2c, N3b and N3c) or stage IV resectable melanoma. Patients with melanoma of mucosal or acral origin are eligible. Patients with melanoma of uveal origin are not eligible. Patients with a history of brain metastases are not eligible. Clinically detectable is defined as disease that is apparent and measurable via physical examination or radiographic imaging.
* STEP 1 REGISTRATION (RANDOMIZATION): Patients are eligible for this trial either at initial presentation of their melanoma or at the time of the first detected nodal, satellite/in-transit, distant metastases, or recurrent disease in prior lymphadenectomy basin or distant site. Nodal, satellite/in-transit metastasis, distant metastases or disease in a prior complete lymphadenectomy basin must have been confirmed histologically by hematoxylin (H) \& eosin (E) stained slides.
* STEP 1 REGISTRATION (RANDOMIZATION): Patients with multiple regional nodal basin involvement are eligible. Gross or microscopic extracapsular nodal extension is permitted.
* STEP 1 REGISTRATION (RANDOMIZATION): Patients must have histologically proven stage IIIB or higher. This would entail pathologic confirmation beyond the primary or initial diagnosis of melanoma involving fine needle aspiration cytology or biopsy confirmation of any N-category or M-category resectable site.
* STEP 1 REGISTRATION (RANDOMIZATION): Patients must not have received previous neoadjuvant treatment for their melanoma. Patients may have received prior non-immunotherapy adjuvant therapy. Patients must not have had prior immunotherapy including, but not limited to ipilimumab, interferon alfa-2b, high dose interleukin (IL)-2, pegylated-interferon (PEG-IFN), anti-PD-1, anti-PD-L1 intra-tumoral, or vaccine therapies. Patients must not be planning to receive any of the prohibited therapies during treatment phases on the study.
* STEP 1 REGISTRATION (RANDOMIZATION): Patients must not be planning to receive concomitant other biologic therapy, hormonal therapy, other chemotherapy, surgery, while on protocol therapy.
* STEP 1 REGISTRATION (RANDOMIZATION): Patients may have received prior radiation therapy, including after prior surgical resection. All adverse events associated with prior surgery and radiation therapy must have resolved to =\< grade 1 prior to randomization.
* STEP 1 REGISTRATION (RANDOMIZATION): Patients must be \>= 18 years of age
* STEP 1 REGISTRATION (RANDOMIZATION): All patients must have disease status documented by a complete physical examination and imaging studies within 42 days prior to randomization. Imaging studies must include a CT of the chest, abdomen and pelvis with intravenous contrast (unless contraindicated). For patients with melanoma arising from the head and neck, dedicated neck imaging (CT with intravenous contrast is required. If the patient has unknown primary with disease in the axilla, neck imaging is required CT imaging must be done with intravenous contrast if there are no contraindications for it. Extremity melanomas must be imaged using CT with intravenous contrast or MRI with and without gadolinium

  * Note: PET-CT scans are NOT acceptable to establish eligibility. Non-iodinated CT scans that are part of common PET-CT imaging protocols do not provide contrast for difficult to ascertain areas such as the neck and liver, and do not provide enough CT detail to perform appropriate RECIST 1.1 measurements. As such, a PET-CT with non-contrast CT or non-diagnostic quality CT images is considered insufficient for the detection of melanoma.
* STEP 1 REGISTRATION (RANDOMIZATION): All patients must have a CT or magnetic resonance imaging (MRI) of the brain within 42 days prior to randomization. The brain CT or MRI should be performed with intravenous contrast (unless contraindicated).
* STEP 1 REGISTRATION (RANDOMIZATION): Absolute neutrophil count (ANC) \>= 1,500/microliter (mcL) (within 42 days prior to randomization).
* STEP 1 REGISTRATION (RANDOMIZATION): Platelets \>= 100,000/mcL (within 42 days prior to randomization).
* STEP 1 REGISTRATION (RANDOMIZATION): Hemoglobin \>= 10 g/dL (within 42 days prior to randomization).
* STEP 1 REGISTRATION (RANDOMIZATION): Total bilirubin =\< 1.5 x institutional upper limit of normal (IULN) (except patients with Gilbert's syndrome, who must have a total bilirubin \< 3.0 mg/dL) (within 42 days prior to randomization).
* STEP 1 REGISTRATION (RANDOMIZATION): Serum glutamic-oxaloacetic transaminase (SGOT) (aspartate aminotransferase \[AST\]) and serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase \[ALT\]) =\< 2 x IULN (within 42 days prior to randomization).
* STEP 1 REGISTRATION (RANDOMIZATION): Alkaline phosphatase =\< 2 x IULN (within 42 days prior to randomization).
* STEP 1 REGISTRATION (RANDOMIZATION): Patients must have lactate dehydrogenase (LDH) performed within 42 days prior to randomization.
* STEP 1 REGISTRATION (RANDOMIZATION): Patients must have adequate renal function as evidenced by calculated creatinine clearance \> 30 mL/min. The creatinine level (mg/dL) used in the calculation must be obtained within 42 days prior to randomization.
* STEP 1 REGISTRATION (RANDOMIZATION): Patients must have Zubrod performance status =\< 2.
* STEP 1 REGISTRATION (RANDOMIZATION): Patients must not have a history of (non-infectious) pneumonitis that required steroids or current pneumonitis.
* STEP 1 REGISTRATION (RANDOMIZATION): Patients must not have an active infection requiring systemic therapy.
* STEP 1 REGISTRATION (RANDOMIZATION): Patients must not have active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
* STEP 1 REGISTRATION (RANDOMIZATION): Patients must not have received live vaccines within 42 days prior to randomization. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, chicken pox, shingles, yellow fever, rabies, Bacillus Calmette-Guerin (BCG), and typhoid (oral) vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., Flu-Mist) are live attenuated vaccines, and are not allowed.

  * NOTE: The COVID-19 vaccines (currently available and those in the pipeline for FDA emergency use authorization or FDA approval) do not contain live virus, and therefore, COVID-19 vaccination does not affect or preclude eligibility for the S1801 trial. For patients who have undergone lymphadenectomy, vaccines should be delivered to a limb with an intact lymph node basin (Sentinel lymph node biopsy in a limb is acceptable). The vaccine should not be administered in a limb that has undergone lymphadenectomy.
* STEP 1 REGISTRATION (RANDOMIZATION): Patients known to be human immunodeficiency virus (HIV) positive are eligible if they meet the following criteria within 30 days prior to randomization: stable and adequate CD4 counts (\>= 350 mm\^3), and serum HIV viral load of \< 25,000 IU/ml. Patients may be on or off anti-viral therapy so long as they meet the CD4 count criteria.
* STEP 1 REGISTRATION (RANDOMIZATION): Patients must not have known active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection prior to randomization. Note: No testing for hepatitis B and hepatitis C is required unless mandated by local health authority.
* STEP 1 REGISTRATION (RANDOMIZATION): Prior malignancy is allowed providing it does not require concurrent therapy.
* STEP 1 REGISTRATION (RANDOMIZATION): Women of childbearing potential must have a negative urine or serum pregnancy test within 28 days prior to randomization. Women/men of reproductive potential must have agreed to use an effective contraceptive method for the course of the study through 120 days after the last dose of study medication. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. A woman is considered to be of "reproductive potential" if she has had menses at any time in the preceding 12 consecutive months. In addition to routine contraceptive methods, "effective contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy, or bilateral tubal ligation. However, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures. Patients must not be pregnant or nursing due to unknown teratogenic side effects.
* STEP 1 REGISTRATION (RANDOMIZATION): Patients must be deemed medically fit to undergo surgery by the treating medical/surgical team.
* STEP 1 REGISTRATION (RANDOMIZATION): Patients must be willing to submit the following surgical specimens: either all tissue blocks from the surgical specimen or two slides per block (\[1\] hematoxylin and eosin \[H\&E\] slide and \[1\] unstained slide OR \[2\] unstained slides if H\&E stained slides cannot be provided).
* STEP 1 REGISTRATION (RANDOMIZATION): Patients must be offered the opportunity to participate in specimen banking.
* STEP 1 REGISTRATION (RANDOMIZATION): Patients must be informed of the investigational nature of this study and must sign and give written informed consent for this protocol in accordance with institutional and federal guidelines.
* STEP 1 REGISTRATION (RANDOMIZATION): As a part of the Oncology Patient Enrollment Network (OPEN) randomization process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system.
* STEP 2 REGISTRATION (SURGERY): Patients randomized to arm 2 (neoadjuvant arm) must be willing to submit tissue to determine pathologic response regardless of number of pre-operative doses of pembrolizumab (MK-3475) received. Determination of pathologic response cannot be done on less than the full surgical specimen.
* STEP 2 REGISTRATION (SURGERY): Patients must have disease assessments by CT chest/abdomen/pelvis with IV contrast, and neck CT with IV contrast if primary head and neck melanoma, performed within 42 days (and no more than 49 days) before the planned date of surgery. MRI combined with non-contrast CT is an acceptable alternative for patients with CT contrast allergy, but imaging must encompass total body.
* STEP 2 REGISTRATION (SURGERY): Patients must register to step 2 within 17 days prior to planned date of surgery.
* STEP 3 REGISTRATION (ADJUVANT THERAPY): Patients must have undergone surgery prior to Step 3 registration. The Step 2 surgery must have completely resected their melanoma.

  * Patients with gross positive residual disease following surgery do not qualify as having disease-free status, and, therefore, such patients are not eligible to register for adjuvant therapy.
  * Patients with microscopic residual disease (i.e., positive margins) can be treated with re-excision or radiation, per site discretion, to render the patient disease-free prior to registration of adjuvant therapy.
  * Disease-free status must be documented by a complete physical examination and radiographic imaging studies within 42 days prior to Step 3 registration. Imaging studies must include a CT of the chest, abdomen, and pelvis (unless contraindicated). Extremity melanomas must be imaged using CT with intravenous contrast or MRI with and without gadolinium. CT imaging must be done with intravenous contrast if there are no contraindications for it.
  * For patients with melanoma arising from the head and neck, dedicated neck imaging (CT with IV contrast, unless contraindicated) is required.
  * If the patient has had unknown primary with disease in the axilla, neck imaging is required to assure the region is clear of cancer.
  * Any other clinically indicated imaging studies if performed (e.g., bone scan) must show no evidence of disease.
* STEP 3 REGISTRATION (ADJUVANT THERAPY): Patients must be registered to step 3 no more than 84 days after date of surgery.
* STEP 3 REGISTRATION (ADJUVANT THERAPY): Patients with R0 or R1 resections must have disease-free status documented by a complete physical examination and imaging studies within 42 days prior to step 3 registration. These patients must have disease assessments by CT chest/abdomen/pelvis with IV contrast, and neck CT with IV contrast if primary head and neck melanoma. MRI combined with non-contrast CT is an acceptable alternative for patients with CT contrast allergy, but imaging must encompass total body.
* STEP 3 REGISTRATION (ADJUVANT THERAPY): Patients with R2 resections are not eligible for step 3 and must be removed from study treatment
B: Inclusion Criteria:

* written informed consent for the study
* ≥ 18 years of age
* histologically or cytologically confirmed diagnosis of cutaneous or unknown primary melanoma (excluding uveal/choroidal and mucosal melanoma; although acral melanoma is included) belonging to one of the following AJCC 8th edition TNM stages:

  1. Tx or T1-4 AND
  2. N1b, or N1c, or N2b, or N2c, or N3b, or N3c AND/OR
  3. M1a or M1b

Patients are eligible for this trial either at presentation for primary melanoma with concurrent regional nodal and/or in-transit metastasis and/or oligometastasis; AND/OR at the time of clinical detected nodal and/or in-transit and/or oligometastatic recurrence; and may belong to any of the following groups:

Primary melanoma with clinically apparent regional lymph node metastases; Clinically detected recurrent melanoma at the proximal regional lymph node(s) basin; Clinically detected primary melanoma involving multiple regional nodal groups; Clinical detected nodal melanoma (if single site) arising from an unknown primary; In-transit and/or satellite metastases with or without regional lymph node involvement; Distant skin and/or in-transit and/or satellite metastases with or without regional lymph node involvement; Oligometastatic lung disease with or without regional lymph node involved permitted if deemed resectable at baseline NOTE: Determination of resectability must be made at baseline to be eligible for this neoadjuvant study.

* measurable disease based on RECIST 1.1
* must provide tumor tissue from a newly obtained core, punch, incisional or excisional tumor biopsy
* 0 or 1 on the ECOG Performance Scale
* Demonstrate adequate organ function on screening labs obtained within 14 days of registration
* negative serum pregnancy test (females of childbearing potential)
* females of non-childbearing potential must be ≥45 years of age and has not had menses for \>1 year; if amenorrhoeic for \<2 years without history of a hysterectomy and oophorectomy must have an FSH value in the postmenopausal range; post-hysterectomy, post-bilateral oophorectomy, or post-tubal ligation (documented hysterectomy or oophorectomy)
* male subjects should agree to use an adequate method of contraception

Exclusion Criteria:

* Patients with uveal and/or mucosal melanoma histology are excluded (Patients with melanoma of unknown histology are permitted to enroll after discussion with Principal Investigator)
* Is currently participating in or has participated in a study of an investigational agent or using an investigational device within 4 weeks of the first dose of treatment.
* Is receiving systemic immunosuppression with either corticosteroids (\>10mg daily prednisone equivalent) or other immunosuppressive medications) for active autoimmune disease: history of active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids (\>10mg daily prednisone or equivalent) or systemic immunosuppressive agents
* ≥ CTCAE grade 3 immune-related AE (irAE) experienced with prior immunotherapy (except, non-clinically significant lab abnormalities (elevations in lipase, amylase not associated with clinically significant disease etc.) even if ≥ CTCAE grade 3 may enroll if resolved at this time, or, development of autoimmune disorders of Grade ≤ 3 may enroll if the disorder has resolved to Grade ≤ 1)
* received prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent (except ≤ Grade 2 neuropathy)
* autoimmune disorders of Grade 4 while on prior immunotherapy
* active (i.e., symptomatic or growing) central nervous system (CNS) and/or leptomeningeal metastases (CNS lesions that are treated and deemed stable (repeat imaging study done at least 2 weeks prior to first dose of study treatment) are NOT permitted to enroll even if other inclusion criteria are met and patients are neurologically asymptomatic)
* known additional malignancy that is progressing or requires active treatment (except, basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy)
* invasive cancer diagnosed and treated less than 2 years prior to current presentation (other indolent malignancies that are not progressing and/or deemed to require active therapy are not exclusionary)
* evidence of interstitial lung disease or active, non-infectious pneumonitis
* active infection requiring systemic therapy
* history or current evidence of any condition, therapy, or laboratory abnormality determined to be significant, in the opinion of the treating investigator
* known psychiatric or substance abuse disorders that would interfere with study compliance
* is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial
* had a live vaccine within 30 days of initiating protocol therapy
* received prior therapy with an IDO inhibitor, anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137 and/or combination (including nivolumab, pembrolizumab or ipilimumab/nivolumab). Prior treatment with ipilimumab or interferon alfa is allowed.
* history of allergic or hypersensitivity reaction to components or excipients of Dostarlimab (TSR-042) and TSR-022, interferon alfa or ipilimumab
* known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
* known history of or screening test that is positive for hepatitis B virus (HBV; eg, HBsAg reactive or HBV DNA detected) or hepatitis C virus (HCV; HCV antibody positive and/or HCV RNA quantitative is detected). Hepatitis C antibody - positive subjects who received and completed treatment for hepatitis C that was intended to eradicate the virus may participate if hepatitis C RNA levels are undetectable. Hepatitis B positive subjects who received and completed treatment for hepatitis B that was intended to eradicate the virus may participate if hepatitis B DNA levels are undetectable.
C: Inclusion Criteria:

* Participants with histologically confirmed melanoma, either unresectable stage IIIc or stage IV metastatic melanoma, as defined by the American Joint Committee on Cancer 7th edition. Unresectability of stage IIIc disease must have confirmation from a surgical oncologist
* Participants must be naïve to treatment for locally advanced unresectable or metastatic disease (ie, no prior systemic anti-cancer therapy for advanced disease; stage IIIc and IV). Prior adjuvant immunotherapy (including ipilimumab) is allowed
* Documentation of BRAF V600 mutation-positive status in melanoma tumor tissue (archival or newly obtained tumor samples) using the cobas 4800 BRAF V600 mutation test
* Measurable disease per RECIST v1.1
* Eastern Clinical Oncology Group performance status of 0 or 1
* Consent to provide archival for biomarker analyses
* Consent to undergo tumor biopsies for biomarker analyses
* Life expectancy greater than or equal to (≥) 12 weeks
* Adequate hematologic and end organ function

Exclusion Criteria:

* History of prior rapidly accelerated fibrosarcoma or mitogen-activated protein kinase pathway inhibitor treatment
* Palliative radiotherapy within 14 days prior to the first dose of study treatment
* Major surgery or traumatic injury within 14 days prior to first dose of study treatment
* Active malignancy other than melanoma that could potentially interfere with the interpretation of efficacy measures. Participants with a previous malignancy within the past 3 years are excluded except for participants with resected basal cell carcinoma or squamous cell carcinoma of the skin, melanoma in-situ, carcinoma in-situ of the cervix, and carcinoma in-situ of the breast
* History of or evidence of retinal pathology on ophthalmological examination that is considered a risk factor for neurosensory retinal detachment, retinal vein occlusion, or neovascular macular degeneration
* Uncontrolled glaucoma with intraocular pressure
* Serum cholesterol ≥ Grade 2
* Hypertriglyceridemia ≥ Grade 2
* Hyperglycemia (fasting) ≥ Grade 2
* History of clinically significant cardiac dysfunction
* Participants with active central nervous system (CNS) lesions (including carcinomatous meningitis) are excluded. However, participants are eligible if:

  1. All known CNS lesions have been treated with stereotactic therapy or surgery, AND
  2. There has been no evidence of clinical and radiographic disease progression in the CNS for ≥ 3 weeks after radiotherapy or surgery
* Current severe, uncontrolled systemic disease
* History of malabsorption or other condition that would interfere with absorption of study drugs
* Pregnant, lactating, or breast feeding women
D: Key Inclusion Criteria:

* \>= 18 years of age
* Stage IIIc or Stage IV BRAF V600E/K cutaneous melanoma
* Measurable disease according to RECIST 1.1
* Women of childbearing potential with negative serum pregnancy test prior to randomisation
* Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1
* Adequate baseline organ function

Key Exclusion Criteria:

* Any prior use of a BRAF or MEK inhibitor
* Prior systemic anti-cancer treatment in the advanced or metastatic setting; prior systemic treatment in the adjuvant setting is allowed
* History of another malignancy (except subjects who have been disease free for 3 years or with a history of completely resected non-melanoma skin cancer)
* Known HIV, HBV, HCV infection (except chronic or cleared HBV and HCV infection which will be allowed)
* Brain metastases (except if all known lesions were previously treated with surgery or stereotactic radiosurgery and lesions, if still present, are confirmed stable for \>= 12 weeks prior to randomisation or if no longer present are confirmed no evidence of disease for \>= 12 weeks, and are asymptomatic with no corticosteroid requirements for \>= 4 weeks prior to randomisation, and no enzyme inducing anticonvulsants for \>= 4 weeks prior to randomisation
* History or evidence of cardiovascular risk (LVEF \< LLN; QTcB \>= 480 msec; blood pressure or systolic \>=140 mmHg or diastolic \>= 90 mmHg which cannot be controlled by anti-hypertensive therapy)
* History or current evidence/risk of retinal vein occlusion (RVO) or central serous retinopathy (CSR)

Answer: A