Background: Bispecific antibodies have shown activity in hematologic (heme) but not solid tumors. ImmTAC molecules are unique TCR–anti-CD3 bispecifics that redirect T cells against intracellular antigens. IMCgp100, an ImmTAC targeted against melanocyte-associated lineage antigen gp100, has shown monotherapy responses in advanced melanoma with associated immune changes. IMCgp100 causes rash and cytokine-mediated AEs, hypothesized to be on-target (gp100) or effector (CD3) mediated. We explored clinical and biological characteristics of pts associated with treatment benefit. Methods: 84 HLA-A2 positive advanced melanoma pts received IMCgp100 on study IMCgp100-01 in 13 dose escalation cohorts. Efficacy was assessed by Kaplan–Meier survival and treatment related AEs (TRAE) reported by CTCAE v4.0. Serum samples evaluated changes in cytokines. A multivariate analysis investigated the relationship between efficacy and safety variables. Results: Demographics: 73% cutaneous (CM), 23% uveal (UM) primaries; 51% LDH > ULN; 25% received prior anti-PD(L)1. 83 (99%) pts had ≥1 TRAE; most commonly in skin (rash 82%, pruritus 69%) or cytokine-mediated (pyrexia 57%); the majority were Grade 1–2 and occurred and resolved within first 3 doses. The 2 most frequent Grade ≥3 TRAEs were rash (26%) and lymphopenia (13%). IMCgp100 induced transient increases in peripheral cytokines (peaking Day 1–2) that attenuated with subsequent doses; cytokine-mediated AE had similar kinetics.1-yr OS was 65% (95% CI: 48–78). In multivariate analysis, longer OS was associated with: LDH ≤ULN (p = 0.002) and any-grade rash occurring within 21 days (p = 0.003); melanoma primary site and prior anti-PD-(L)1 did not significantly affect outcome. In exploratory analyses, longer OS associated with lower baseline serum IL-6 (n = 43) or TNFα (n = 44). Conclusions: IMCgp100 is a first-in-class, TCR-based bispecific with monotherapy efficacy in advanced melanoma. AEs were manageable and consistent with MoA. Association between IMCgp100 efficacy and on-target TRAEs, previously reported for bispecifics to heme lineage antigens, is now recognized for solid tumor lineage antigens. Pivotal studies in UM are ongoing. Clinical trial information: NCT01211262