Background: IMCgp100 is a bispecific biologic comprised of a soluble T cell receptor recognizing the gp100 antigen fused to a scFV anti-CD3 and redirects T cell lysis of melanoma cells expressing gp100. Safety and preliminary efficacy of IMCgp100 were assessed in a Ph 1/2 study in metastatic UM (mUM). Methods: HLA-A*0201+ pts with mUM were treated with QW dosing of IMCgp100 iv at Cycle 1, Day 1 (C1D1, 20 mcg) and C1D8 (30 mcg), followed by the escalated dose administered at C1D15 and beyond. Results: Pts with mUM (n = 19), elevated LDH (87%), liver metastases (100%), and median of 4 prior therapies (0 – 8) were treated across 4 doses (54 to 73 mcg) in Ph 1; 23 pts were treated in the Ph 2 RP2D (68 mcg) expansion cohort. Related AE included pruritus (90%), pyrexia and fatigue (84%), and hypotension (74%). Gr 3/4 related AE include AST elevation, erythema and hypotension (all, 16%). Ten of the 19 pts in Ph 1 were treated at or above the RP2D. Objective PR by RECIST in Ph 1 were observed in 2 pts and minor responses in 4 pts (6/19 responses); median duration of response was 30.6 wk. One year PFS rate by irRC was 66% (95% CI [39, 83]). One year OS rate in Ph 1 was 74% (95% CI [48, 88]). Median OS in this cohort has not been reached (median follow up of 15.9 mo). The PKPD relationship of exposure was modeled with extent and duration of lymphocyte trafficking. The EC50 for lymphocyte extravasation to the periphery was estimated at 1.4 ng/mL. At high doses, maximal trafficking of 50% was observed compared to baseline. The extent of lymphocyte trafficking is saturable, however the duration was dose dependent. The EC90 represents the dose of 70 mcg, supporting the RP2D. In the full cohort (n = 42), rash of Gr ≥2 within the first 3 weeks of dosing is associated with prolonged OS when compared to pts with mild (G1) or no occurrence of rash (HR 0.122, 95% CI [0.03, 0.45], p = 0.0015). Conclusions: IMCgp100 is tolerable with the intra-patient escalation dosing regimen and leads to prolonged OS. A potential association of prolonged OS with rash severity was observed. PKPD modeling demonstrates a relationship between lymphocyte trafficking and exposure to IMCgp100. Pivotal trials in the setting of metastatic UM continue to enroll (NCT03070392, NCT02570308). Clinical trial information: NCT02570308