Background: Understanding the bifunctional role that the immune system plays in tumor eradication vs growth promotion is critical in the design and timing of tumoricidal and immunologic therapies for sarcomas. Hypothesis: Immune checkpoint inhibitors that promote sustained T cell activation would be most effective when given as first line therapy, together with a tumoricidal agent. Methods: Eligible patients for this Phase 2 study are males or females ≥ 18 years of age with locally advanced unresectable or metastatic soft tissue sarcoma, previously untreated, with measurable disease by RECIST v1.1. Treatment protocol: (I) mg/kg i.v. q 12 wks, (N) 3 mg/kg i.v. q 2 wks, (T) 1.2 mg/m2 CIV q 3 wks. Treatment Outcome Parameters: (1) Best objective response rate by RECIST v1.1, (2) Progression-free survival (PFS), (3) Overall survival (OS), and (4) Incidence of treatment-related adverse events. Results: Ninety-nine patients were enrolled. Efficacy analysis (n = 88): There were 8CR (1 surgical CR), 11PR, 58SD, 11PD. Overall response rate was 21.6%, Disease Control Rate, 87.5%. The median PFS was 7 (range:1-44) months, median OS, 14 (range: 1-46) months. Grade 3 TRAEs include fatigue (n = 8), adrenal insufficiency (n = 1), dehydration (n = 1), hyponatremia (n = 2), increased AST (n = 8), increased ALT (n = 24), increased ALP (n = 2), port site infection (n = 2), psoriasis exacerbation (n = 1), anemia (n = 9), thrombocytopenia (n = 2), and neutropenia (n = 5). Grade 4 TRAES include anemia (n = 1), neutropenia (n = 1), thrombocytopenia (n = 2), increased AST (n = 2), increased ALT (n = 2), and increased CPK (n = 2). Grade 5 TRAES include rhabdomyolysis (n = 1). There was no incidence of alopecia nor cardiac toxicity reported. Conclusions: Taken together, these data indicate that first-line combinatorial therapy with Ipilimumab, Nivolumab, and Trabectedin (1) may be more effective than standard first line therapy (doxorubicin/ifosfamide/mesna), and (2) is safer than standard first line therapy for advanced soft tissue sarcoma. Clinical trial information: NCT03138161.