This is a multicenter, phase II trial of relatlimab (rela), nivolumab (nivo), and ipilimumab (ipi) in patients with asymptomatic and symptomatic melanoma brain metastases.

Inclusion Criteria:

1. Histologically confirmed non-uveal melanoma that has metastasized to the brain. At least 1 measurable intracranial target lesion (5-40mm) which was not previously treated with local therapy (no prior SRS to this lesion). Prior surgery for a brain metastasis is allowed but this lesion cannot be a target lesion.

   a. Growth or change in a lesion previously irradiated will not be considered measurable. Regrowth in cavity of previously excised lesion will not be considered measurable.

2. Age ≥ 18 years

3. Eastern Cooperative Oncology Group (ECOG) performance status 0-1 for Cohort A (asymptomatic), ECOG performance status 0-2 for Cohort B (symptomatic)

4. No prior anti-CTLA-4, anti-PD-1, or anti-LAG-3 therapy for unresectable stage III/IV melanoma. Prior CTLA-4, PD-1, and/or LAG-3 therapy in the neoadjuvant or adjuvant setting is acceptable if >6 months since last treatment. Participants may have had prior BRAF+MEK inhibitors for adjuvant therapy and/or unresectable/metastatic melanoma if >2 weeks have elapsed since last treatment.

5. Adequate organ function as assessed by the following parameters:

   1. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 times the upper limit of normal (≤ 3 ×ULN); patients with liver metastasis ≤ 5 × ULN
   2. Estimated creatinine clearance (eCrCl) ≥ 30 mL/min using the Cockcroft-Gault formula at Screening
   3. Total bilirubin ≤ 1.5x ULN OR direct bilirubin ≤ ULN for participants with total bilirubin levels >1.5x ULN

6. Patients must have recovered from all prior anti-cancer therapy-related adverse events (AEs) to ≤ Grade 1 (per Common Terminology Criteria for Adverse Events [CTCAE] v 5.0), except for alopecia, vitiligo, thyroid dysfunction, hypophysitis, or adrenal insufficiency, prior to enrollment.

7. Cohort A (asymptomatic): participants must be free of neurologic signs and symptoms related to metastatic brain lesions and must not have required or received systemic corticosteroid therapy greater than physiologic replacement (>10 mg of prednisone/day or equivalent) in the 10 days prior to beginning protocol therapy. Cohort B (symptomatic): participants may be on steroids with doses no higher than a total daily dose of 4 mg of dexamethasone or equivalent that is stable or tapering within 10 days prior to treatment. Patients who are symptomatic and are not being treated with steroids are also eligible.

8. Participants with known human immunodeficiency virus (HIV)-infection are eligible providing they are on effective anti-retroviral therapy and have undetectable viral load at their most recent viral load test and within 90 days prior to treatment.

9. Participants with a known history of hepatitis B virus (HBV) or hepatitis C virus (HCV) infection must have been treated and cured. Participants with HBV or HCV infection who are currently on treatment must have an undetectable HCV viral load prior to treatment.

10. Representative formalin-fixed paraffin-embedded (FFPE) tumor specimens in paraffin blocks (blocks are preferred) OR at least 4 unstained slides, with an associated pathology report, for testing of tumor PD-L1 expression:

    1. Tumor tissue should be of good quality based on total and viable tumor content.
    2. Patients who do not have tissue specimens may undergo a biopsy during the screening period. Acceptable samples include core-needle biopsies for deep tumor tissue or excisional, incisional, punch, or forceps biopsies for cutaneous, subcutaneous, or mucosal lesions. Fine Needle Aspirations (FNA) will not be considered acceptable for tissue procurement.
    3. Tumor tissue from bone metastases is not evaluable for PD-L1 expression and is therefore not acceptable.
    4. However, if repeat biopsy is not feasible, and no archival tissue available patient still may be enrolled.

11. Any radiation treatment or excision of non-target brain lesions must have occurred ≥ 1 weeks before the start of dosing for this study. NOTE: The radiation field must not have included the brain index lesion(s).

12. Radiation to non-CNS lesions is allowed and does not require a washout period for treatment initiation. Any radiation-related toxicity must have recovered to ≤ Grade 1 (per Common Terminology Criteria for Adverse Events [CTCAE] v 5.0).

13. Women of child-bearing potential (WOCBP) must not be breastfeeding and must have a negative pregnancy test within 3 days prior to initiation of dosing. WOCBP (or female partners of male participants) must agree to use an acceptable method of birth control from the time of the negative pregnancy test, through the duration of treatment with the study combination and for 12 months after their last dose of any study component medication.

    NOTE: A female participant is eligible to participate if she is not a woman of childbearing potential.

    Approved methods of birth control are as follows:

    Combined (estrogen and progesterone containing) hormonal birth control associated with inhibition of ovulation: oral, intravaginal, transdermal Progesterone-only hormonal birth control associated with inhibition of ovulation: oral, injectable, implantable Intrauterine device (IUD) Intrauterine hormone-releasing system (IUS) Bilateral tubal occlusion Vasectomized partner True sexual abstinence when this is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (eg, calendar ovulation, symptothermal, post-ovulation methods) is not acceptable

14. Patients (or legally authorized representative) must have the ability to understand the requirements of the study, have provided written informed consent as evidenced by signature on an ICF approved by an Institutional Review Board/Independent Ethics Committee (IRB/IEC) and agree to abide by the study restrictions and return to the site for the required assessments.

Exclusion Criteria

1. Another primary malignancy within the previous 3 years (with the exception of carcinoma in situ of the breast, cervix, or bladder; localized prostate cancer; and non-melanoma skin cancer that has been adequately treated).
2. Active medical illness(es) that would pose increased risk for study participation, including: active systemic infections (including COVID-19), coagulation disorders, or other major active medical illnesses of the cardiovascular, respiratory, or immune systems.
3. Active autoimmune disease that has required systemic therapy with corticosteroids or other immunosuppressive agents within the past 3 years (excluding immune-related adverse events from immunotherapy as described above.
4. Implanted device that precludes the use of MRI.
5. Prior Grade 4 treatment-related AE with immune checkpoint inhibitor treatment.
6. History of leptomeningeal metastasis determined by imaging or lumbar puncture.
7. Prior whole brain radiation therapy (WBRT)
8. Women who are breast-feeding or pregnant
9. History of clinically significant cardiac disease or congestive heart failure > New York Heart Association (NYHA) class 2. Subjects must not have unstable angina (anginal symptoms at rest) or new-onset angina within the last 3 months or myocardial infarction within the past 6 months or a history of myocarditis
10. Troponin T (TnT) or I (TnI) > 2 × institutional ULN. Participants with TnT or TnI levels between > 1 to 2 × ULN will be permitted if repeat levels within 24 hours are ≤ 1 ULN. If TnT or TnI levels are between >1 to 2 × ULN within 24 hours, the participant may undergo a cardiac consultation and be considered for treatment, following cardiologist recommendation. When repeat levels within 24 hours are not available, a repeat test should be conducted as soon as possible. If TnT or TnI repeat levels beyond 24 hours are < 2 × ULN, the participant may undergo a cardiac consultation and be considered for treatment, following cardiologist recommendation. Notification of the decision to enroll the participant following cardiologist recommendation has to be made to the principal investigator.
11. Investigational drug use within 14 days (or 5 half-lives, whichever is longer) of the first dose of study treatment.
12. Dexamethasone use > 4mg/day (or equivalent)