Background: Tebentafusp is a bispecific (gp100 x CD3) ImmTAC that can redirect T cells to target gp100+ melanoma cells. In a Phase (Ph) 3 trial, tebentafusp demonstrated an overall survival (OS) benefit (HR 0.51) compared to investigator's choice (IC) in first line HLA-A*02:01+ patients with metastatic uveal melanoma (mUM). Gp100, which has limited expression in normal cells, is overexpressed in melanoma, including skin melanoma, supporting the investigation of tebentafusp in non-uveal melanoma. In a first-in-human trial, tebentafusp monotherapy demonstrated a promising 1-year OS (~74%) in anti-PD(L)1 naïve HLA-A*02:01+ patients with metastatic cutaneous melanoma (mCM). In a subsequent Ph1 trial, tebentafusp combined with anti-PDL1, with or without anti-CTLA4, demonstrated a 1-year OS of 75% in patients with mCM who progressed on prior anti-PD(L)1 therapy, which compares favorably with recent benchmarks (1-year OS 38%-57%) in similar patient populations.^1-3 The promising activity of tebentafusp as monotherapy and in combination with anti-PD(L)1 agents in advanced melanoma (AM) provides the rationale to conduct a Ph2/3 trial of tebentafusp (TEBE-AM; NCT05549297) in patients who have progressed on standard of care therapies. In mUM trials, RECIST response underestimated the OS benefit of tebentafusp, whereas a strong association was shown between OS and early reduction in ctDNA levels relative to baseline.⁴ As an early measure of changes in tumor burden, ctDNA reduction is included as an innovative dual primary endpoint with OS for the Ph2 part of this study. Methods: TEBE-AM is a multicenter, open-label, seamless Ph2/3 study in HLA-A*02:01+ patients with non-uveal AM who have progressed on prior anti-PD(L)1, received prior ipilimumab, and a prior BRAF/MEK inhibitor regimen if actionable BRAF mutation is present. Patients are randomly assigned (1:1:1) to receive tebentafusp monotherapy, tebentafusp combined with pembrolizumab, or IC. In the IC arm, patients may enroll in clinical trials of investigational agents, receive local standard of care, or receive best supportive care, while being followed for key endpoints. Randomization into the Ph3 portion will commence immediately following completion of accrual into the Ph2 portion. Efficacy from the Ph2 portion may inform changes to the Ph3 design. Primary endpoints are ctDNA reduction relative to baseline and OS in Ph2 and OS in Ph3. Ph2 enrollment opened in Jan 2023 in the US and is expected to open in other countries mid-2023. Clinical trial registration: NCT05549297. 1. Zimmer L, et al. Eur J Cancer 75:47–55, 2017. 2. Silva IPD, et al. J Clin Oncol 38:10005–10005, 2020. 3. Arance AM, et al. J Clin Oncol 39:S9504, 2021. 4. Carvajal RD, et al. Nat Med 28:2364-2373, 2022. Clinical trial information: NCT05549297.