To determine the Objective Response Rate (ORR) of immunotherapy with Nivolumab (Group 1) and Nivolumab plus Relatlimab (Group 2) in patients with locally advanced/metastatic squamous cell carcinoma of the skin using Response Criteria in Solid Tumors Version 1.1 (RECIST1.1) per site assessment (Time Frame Group 2: From first dose up to 5 years)

Inclusion Criteria:

1. Men and women, 18 years of age and older on day of signing written informed consent

2. Histologically or cytologically documented locally-advanced and/or metastatic squamous cell carcinoma of the skin (stage III/IV AJCC 2010) that is incurable

3. Archival tumor tissue available for evaluation of PD-L1 and LAG-3 expression

4. Measurable disease based on Response Criteria in Solid Tumors Version 1.1 (RECIST 1.1)

5. Life expectancy of at least 12 weeks

6. Eastern Cooperative Oncology Group (ECOG) Performance status of 0-2

7. Screening laboratory values must meet the following criteria and should be obtained within 14 days prior to registration:

   • WBC ≥ 2000/μl
   • Neutrophils ≥ 1500/μL
   • Platelets ≥ 100 x103/μL
   • Hemoglobin > 9.0 g/dL
   • Serum creatinine ≤ 1.5 x ULN or creatinine clearance (CrCl) ≥ 40 mL/min (if using the Cockcroft-Gault formula below):

   Female CrCl = (140 - age in years) x weight in kg x 0.85/72 x serum creatinine in mg/dL Male CrCl = (140- age in years) x weight in kg x 1.00/72 x serum creatinine in mg/dL

   • AST/ALT ≤ 3 x ULN
   • Total Bilirubin ≤ 1.5 x ULN (except subjects with Gilbert Syndrome, who can have total bilirubin < 3.0 mg/dL)
   • Negative pregnancy test and effective contraception (Pearl-Index <1) for for women of childbearing potential (WOCBP) if the risk of conception exists

8. Prior radiotherapy must have been completed at least 2 weeks prior to study drug administration

9. Prior systemic antibiotic treatment must have been completed at least 30 days prior to stool sample collection

Exclusion Criteria:

1. Patient 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
2. Prior therapy with CTLA-4, PD-1 or LAG-3 antibodies
3. History of myocarditis, regardless of etiology
4. Troponin T (TnT) or I (TnI) > 2× institutional upper limit of normal (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 evaluation and be considered for treatment, based on a favorable benefit/risk assessment by the Investigator. 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 evaluation and be considered for treatment, based on a favorable benefit/risk assessment by the Investigator
5. A condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease
6. Known active central nervous system (CNS) metastases and/or carcinomatous meningitis
7. Known additional malignancy that is progressing or requires active treatment. Patients with chronic lymphocytic leukemia that is stable under active therapy are eligible for inclusion.
8. An active, known or suspected autoimmune disease. Subjects are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger
9. Patients with serious intercurrent illness, requiring hospitalization
10. Other serious illnesses, e.g. serious infections requiring antibiotics
11. Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
12. Pregnancy (absence to be confirmed by ß-HCG urinary test, minimum sensitivity 25 IU/L or equivalent units of HCG)) or lactation period
13. Women of childbearing potential (WOCBP): Refusal or inability to use effective means of contraception (Pearl-Index <1)
14. History of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS)
15. Positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection
16. History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the patient's participation for the full duration of the study, or is not in the best interest of the patient to participate, in the opinion of the treating Investigator
17. Known hypersensitivity reaction to any of the components of study treatment