• Age ≥12 years on the date of providing informed consent

• Patients with histologically confirmed unresectable Stage III and Stage IV (metastatic) melanoma (AJCC, 8th revised edition) who have not received prior systemic therapy for advanced unresectable disease

‣ Patients who received adjuvant and/or neoadjuvant systemic therapies are eligible if they did not have evidence of progression or recurrence of disease and/or discontinued due to occurrence of unmanageable imAEs ≥ grade 3 (with the exclusion of endocrinopathies which are fully controlled by hormone replacement) while on such therapies. Also, patients must have had a treatment-free and disease-free interval of \>6 months. Accrual of these patients is limited to approximately 10% of the total population enrolled.

⁃ Patients with acral and mucosal melanomas are eligible. Accrual will be limited to 10% of the total population.

• Measurable disease per RECIST v1.1

‣ Previously irradiated lesions can only be counted as target lesions if they have been demonstrated to progress and no other target lesion is available

⁃ Cutaneous lesions should be evaluated as non-target lesions

• Performance status:

‣ For adult patients: Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1

⁃ For pediatric patients: Karnofsky performance status ≥70 (patients ≥16 years) or Lansky performance status ≥70 (patients ≤16 years)

• Anticipated life expectancy of at least 3 months