Pilot Study of the Safety/Efficacy of Combination Checkpoint Blockade + External Beam Radiotherapy in Stage IV Melanoma

Inclusion Criteria: 1. Histologic diagnosis of Stage IV metastatic melanoma, with 1 melanoma lesion that could be safely irradiated and, in the opinion of the radiation oncologist, was of benefit to the subject to irradiate (note: subjects with primary ocular and mucosal melanoma were permitted). Lesions may have included, but were not limited to: 1. Symptomatic lymphadenopathy; 2. Bothersome cutaneous disease; 3. Hepatic metastases; 4. Pulmonary metastases. 2. Excluding the lesion intended to undergo radiation, subjects must have had at least 1 unresectable, non-bony lesion that was measurable radiographically (based on Response Evaluation Criteria in Solid Tumors \[RECIST\] 1.1). 3. Any number of prior therapies (including none). For subjects who had received prior systemic treatment with cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), programmed cell death-1 (PD-1), and/or programmed cell death ligand-1 (PD-L1) therapy, the last monoclonal antibody administration should have been no less than 4 weeks prior to start of this protocol therapy and all prior side effects must have resolved to grade 1 or less by the time of the start of this protocol therapy. 4. Subjects must have: * Completed investigational therapy, other immunotherapy, or prior RT at least 28 days before administration of the first dose of study drug(s) * Completed chemotherapy or targeted therapy at least 14 days before administration of the first dose of study drug(s) * Sufficiently recovered from prior surgery as determined by the treating Investigator. Clinically significant toxicity or pharmacodynamic effects experienced during any prior therapy must have been resolved or stabilized before the first dose of study drug(s). 5. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1. 6. Life expectancy ≥ 4 months. 7. Screening laboratory parameters: 1. White blood cell count ≥ 2000/μL; 2. Absolute neutrophil count ≥ 1500/μL; 3. Platelets ≥ 100,000/μL; 4. Hemoglobin ≥ 9 g/dL; 5. Aspartate aminotransferase and alanine aminotransferase ≤ 3 × upper limit of normal (ULN); 6. Total bilirubin ≤ 1.5 × ULN (\< 3 mg/dL for subjects with Gilbert's disease); 7. 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 = \[(140 - age in years) x weight in kg x 1.00\] / \[72 x serum creatinine in mg/dL\]. 8. Age ≥ 18 years. 9. Able and willing to give valid written informed consent. Exclusion Criteria: 1. Unresolved immune-related AEs following prior biological therapy. Subjects with asymptomatic endocrinopathy may have enrolled. 2. Active autoimmune disease or any condition requiring systemic treatment with either corticosteroids (\>10 mg daily of 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 were permitted in the absence of active autoimmune disease. 3. History of motor neuropathy considered to be of autoimmune origin (e.g., Guillain-Barre Syndrome, Myasthenia Gravis). 4. Other active, concurrent malignancy that required ongoing systemic treatment or interfered with radiographic assessment of melanoma response as determined by the Investigator. 5. Active brain metastases or leptomeningeal metastases. Subjects with brain metastases were eligible if metastases had been treated and there was no magnetic resonance imaging (MRI) evidence of progression for 4 weeks or more after treatment was completed and within 28 days prior to the first dose of nivolumab administration. There must also have been no requirement for immunosuppressive doses of systemic corticosteroids (\> 10 mg/day prednisone equivalents) for at least 2 weeks prior to study drug administration. 6. Known immunodeficiency or human immunodeficiency virus, Hepatitis B, or Hepatitis C positivity. Antibody to Hepatitis B or C without evidence of active infection may have been allowed. 7. History of severe allergic reactions to any unknown allergens or any components of the study drugs. 8. Other serious illnesses (e.g., serious infections requiring antibiotics, bleeding disorders). 9. Requirement of RT to treat brain metastases or receipt of any non-study systemic therapy for cancer or any other experimental/investigational treatment. 10. Mental impairment that may have compromised the ability to give informed consent and comply with the requirements of the study. 11. Lack of availability for immunological and clinical assessments or post-study follow-up contact to determine relapse and survival. 12. Women who were breastfeeding or who were pregnant as evidenced by a positive serum pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin) performed within 14 days of the first dose of study drug and by a urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin) within 24 hours of the first dose of study drug(s). 13. Females of childbearing potential who were sexually active with a nonsterilized male partner must have used 2 methods of effective contraception from screening, and must have agreed to continue using such precautions for 23 weeks after the final dose of investigational product; cessation of birth control after this point should have been discussed with a responsible physician. Periodic abstinence, the rhythm method, and the withdrawal method were not acceptable methods of birth control. \[Females of childbearing potential were defined as those who were not surgically sterile (i.e., bilateral tubal ligation, bilateral oophorectomy, or complete hysterectomy) or postmenopausal (defined as 12 months with no menses without an alternative medical cause).\] Nonsterilized males who were sexually active with a female partner of childbearing potential must have used 2 acceptable methods of effective contraception from Day 1 and for 31 weeks after receipt of the final dose of investigational product. 14. Any condition that, in the clinical judgment of the treating physician, was likely to interfere with the interpretability of the data or prevent the subject from complying with any aspect of the protocol or that may have put the subject at unacceptable risk.