Background: Tebe is a bispecific consisting of an affinity-enhanced T cell receptor fused to an anti-CD3 effector that can redirect T cells to target gp100+ cells. In this Phase (Ph) 3, randomized trial of first line (1L) metastatic uveal melanoma (mUM) [NCT03070392], tebe significantly improved overall survival (OS) vs. investigator’s choice (IC) in the intention-to-treat population (ITT). In previous trials, tebe-related skin adverse events (AEs), hypothesized to be on-target, off-tumor activity against gp100-expressing melanocytes, were associated with improved OS. This association was tested prospectively as a co-primary endpoint in the Ph3 study. Methods: 378 1L HLA-A*02:01+ mUM pts were randomized 2:1 to tebe (n = 252) or IC (n = 126). Co-primary endpoints were 1) OS in all randomized pts (ITT) and 2) OS in tebe-randomized pts who develop any grade rash in week (wk) 1 vs. all receiving IC. Rash was defined as composite of preferred AE terms. Melanocyte-related AEs (MRAEs) were defined as pigment change AEs in the skin or hair. Overall study-wide alpha was controlled at 0.05, with 90% assigned to ITT and 10% to rash. This analysis was conducted on the first interim analysis (data extracted Nov-2020). Results: In the 245 tebe treated pts, the characteristic skin related AEs included most frequently rash (at any time) in 201 pts (82%), pruritis in 167 pts (68%), MRAEs in 109 pts (45%) and erythema in 69 pts (28%). While rash, erythema and pruritis mostly occurred in the first 4 weeks, MRAEs occurred after a median of 2.7 mo. Rash captures most pts, 201/227 (89%), who have any of these skin related AEs. Rash occurred in 146 pts (60%) by wk 1; 179 pts (73%) by wk 2; and 195 pts (80%) by wk 3. Tebe pts with wk 1 rash had significantly longer OS vs. the IC arm, HR 0.35 (95% CI 0.23, 0.53), p < 0.0001. The estimated 1-yr OS rates were 83% vs 58%, respectively. When expanded to include tebe pts with rash through wk 3, the 1-yr OS rate of 75% was still numerically higher than IC. The 50 (20%) tebe pts who did not experience rash by week 3 had 1-yr OS rate of 55%. Conclusions: In 1L mUM pts, tebe significantly improved OS compared to IC in the ITT analysis. Week 1 rash, presumed due to tebe redirection of T cells to gp100+ skin melanocytes, was associated with a very strong OS benefit. Therefore, rash may be a marker that the immune system can be mobilized by tebe to target gp100+ cells. The vast majority of tebe pts will develop a rash at some point, and tebe pts without rash may still derive benefit. Clinical trial information: NCT03070392