The purpose of this pilot study is to determine the safety and feasibility of giving a single dose of Nivolumab with Ipilimumab or Relatlimab in participants with brain metastases from melanoma who can undergo surgery for removal of their brain metastases 7- 10 days after receiving the study drug.

Inclusion Criteria:

• Age 18 years old or older on day of signing the informed consent.
• Histological confirmation of systemic cancer from melanoma.
• Surgery for metastatic brain lesions (i.e., MBM) is needed but not imminent. Imminent defined as requiring emergent intervention. A multidisciplinary team will determine the appropriateness for resection via craniotomy and level of urgency for surgery of the MBM.
• Resectable metastatic brain lesions (i.e., MBM) in whom surgical resection is a reasonable therapeutic option. A resectable metastatic brain lesion is defined as a lesion that is ≥10 mm in size of longest diameter and in a location outside of the brainstem. (Other target lesions, i.e. those that are not resected but are followed for response, can be ≥5 mm). A multidisciplinary team will determine the appropriateness for resection via craniotomy and level of urgency for surgery of the MBM.
• Patient is on ≤4 mg/day dexamethasone or equivalent/day over pre-op period.
• Patients treated with prior monotherapy with PD-1/PD-L1 are permitted.
• Treatment with BRAF MEK inhibitors (BRAF MEKi) (for example, dabrafenib / trametinib) is permitted as long as has been at least five half-lives or one week prior to study treatment, whichever is shorter.
• MRI with enhancing metastatic brain lesions (i.e., MBM) amenable to resection of contrast-enhancing tumor (determined by neurosurgeon). A multidisciplinary team will determine the appropriateness for resection via craniotomy and level of urgency for surgery of the MBM.
• Patient willing to undergo craniotomy and resection.
• Patient eligible for surgery in the 7-10 days after initial treatment.
• Patients who had prior surgical resection of MBM are eligible to enroll.
• Usual acceptable lab parameters, demonstrating adequate organ function as defined in protocol. All screening labs should be performed within 21 days of treatment initiation.
• Resting baseline O2 saturation by pulse oximetry of 92% or higher at rest.
• Be willing and able to provide written informed consent for the trial.
• Willing to provide tissue and blood samples for correlative research purposes.
• Has ECOG Performance Status (PS) of 0, 1 or 2.
• Prior whole Brain radiation therapy (WBRT), single fraction radiation therapy (e.g., SRS), or multiple fraction radiation therapy (e.g., fSRT) to the brain is permitted.
• A negative serum pregnancy test must be documented at the screening visit. Additionally, female patients must exhibit a negative urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 72 hours prior to the start of study drug, therefore the screening pregnancy test may need to be repeated prior to the start of study drug dosing. A urine pregnancy test can be used for this. A pre-dosing urine pregnancy test must be performed prior to each dose during study phase. A urine pregnancy test will also be conducted at End of Treatment Visit.
• Female patients of childbearing potential must be willing to use an adequate method of contraception as outlined in Section 13.1.2 Contraception Guidance for Female Participants of Child Bearing Potential. Contraception, for the duration of treatment and an additional 5 months after the last dose of the study drug. Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the patient.
• Male patients of childbearing potential who are sexually active with Women of Child Bearing Potential do not require contraception.

Exclusion Criteria:

• Has a metastatic brain lesion (or all brain lesions) that is (are) unresectable. Unresectable defined as located in the brainstem or measuring <10 mm in longest diameter. Note, patients with multiple metastatic brain lesions that include non-targetable lesions of <10 mm are allowed to enroll in the study as long as they have at least 1 lesion that is ≥10 mm in size of longest diameter.
• Has clear evidence of leptomeningeal disease.
• Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment or five half-lives, whichever is shorter, or has not recovered (i.e., ≤ Grade 1 or at baseline) from AEs due to a previously administered agent.
• Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment. Physiologic doses of steroid therapy (≤ 3 mg/day dexamethasone equivalents) by the time of first dose of treatment are allowed.
• Has a known history of active Bacillus Tuberculosis.
• Hypersensitivity to either Nivolumab, Ipilimumab, or Relatlimab or any of its excipients.
• Has had 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 AEs due to a previously administered agent. Note: Patients with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for the study. Note: If patient received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.
• Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer.
• Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with the 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. Patients with vitiligo or resolved childhood asthma/atopy would be an exception to this rule. Patients that require intermittent use of bronchodilators or local steroid injections would not be excluded from the study. Patients with hypothyroidism stable on hormone replacement or Sjogren's syndrome will not be excluded from the study.
• Has a prior history of life-threatening toxicity related to prior immune therapy (i.e., anti-CTLA-4 or anti- PD-1/PD-L1 treatment or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways) except those that are unlikely to re-occur with standard countermeasures (i.e., hormone replacement after adrenal crisis).
• Has prior treatment with Relatlimab or any other LAG-3 targeted agent or CTLA-4 targeted agent within 3 months prior to day 1 of treatment.
• Other than the medications explicitly stated in the exclusion criteria or elsewhere in the protocol, other medications or prior treatments are allowed.
• Has known history of, or any evidence of active, interstitial lung disease or noninfectious pneumonitis requiring corticosteroid therapy.
• Has history of myocarditis
• Has documented LVEF <50% within 6 months prior to start of study treatment and unable to be re-assessed with an LVEF >50%.
• Has an active infection requiring systemic therapy.
• Had major surgical procedure, open biopsy, or significant traumatic injury within 21 days prior to day 1 of treatment on study.
• Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the patient's participation for the full duration of the trial, or is not in the best interest of the patient to participate, in the opinion of the treating investigator.
• Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
• Is pregnant, breastfeeding, or expecting to conceive children within the projected duration of the trial, starting with the pre-screening or screening visit through 5 months after the last dose of study drug. Patients must not have a positive pregnancy test at enrollment or prior to administration of study medication. Male patients of childbearing potential who are sexually active with Women of Child Bearing Potential do not require contraception.
• Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, or anti-LAG-3 agent within 6 months prior to day 1 of treatment on study.
• Patients with prior focal radiation to the lesion planned for resection will be excluded from the study, as distinguishing radiation necrosis from progression cannot be definitely performed until after surgery.
• Has a known history of a positive test for Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies), or known acquired immunodeficiency syndrome (AIDS). NOTE: Testing for HIV must be performed at sites where mandated locally.
• Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected). Patients must not have any positive test result for hepatitis B virus or hepatitis C virus indicating presence of virus, eg, Hepatitis B surface antigen (HBsAg, Australia antigen) positive, or Hepatitis C antibody (anti-HCV) positive (except if HCV-RNA negative).
• Has received a live / attenuated vaccine within 30 days of first treatment. Inactivated vaccines are permitted.
• Has received treatment with botanical preparations (e.g., herbal supplements or traditional Chinese medicines) intended for general health support or to treat the disease under study within 2 weeks prior to treatment.
• Participants must not be prisoners or involuntarily incarcerated.
• Participants must not be compulsorily detained for treatment of either a psychiatric or physical (e.g., infectious disease) illness.