Co-primary endpoint of overall survival for tebentafusp (tebe)-induced rash in a phase 3 randomized trial comparing tebe versus investigator’s choice (IC) in first-line metastatic uveal melanoma.
Authors: Jessica Cecile Hassel, Piotr Rutkowski, Jean-Francois Baurain, Marcus O. Butler, Max Schlaak, Ryan Sullivan, Sebastian Ochsenreither, Reinhard Dummer, John M. Kirkwood, Anthony M. Joshua, Joseph J. Sacco, Alexander Noor Shoushtari, Marlana Orloff, Richard D. Carvajal, Omid Hamid, Shaad Essa Abdullah, Chris Holland, Howard Goodall, Paul Nathan, Sophie Piperno-Neumann
Journal: Journal of Clinical Oncology (2021)

9527 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 &lt; 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.