Abstract 1035: Early ctDNA reduction is associated with better overall survival in the Ph 3 trial of tebentafusp in previously untreated metastatic uveal melanoma
Authors: Sullivan Ryan , Collins Laura , Rodrigues Manuel , Nathan Paul , Hassel Jessica C. , Dummer Reinhard , Kirkwood John , Rutkowski Piotr , Baurain Jean-Francois , Butler Marcus O. , Schlaak Max , Ochsenreither Sebastian , Abdullah Shaad E. , Holland Chris , Ranade Koustubh , Shoushtari Alexander N. 
Published: June 2023

Abstract
Background: Tebentafusp (tebe), a bispecific ImmTAC (gp100 × CD3) showed significant overall survival (OS) benefit (HR 0.51) versus investigator’s choice in a Phase (Ph) 3 trial in first line (1L) HLA-A*02:01 pts with metastatic uveal melanoma (mUM) [Nathan NEJM 2021]. In a Ph2 trial of tebe in previously treated mUM, OS was improved regardless of RECIST best response and the degree of early reduction in ctDNA was a better predictor of OS [Carvajal Nat Med 2022]. Here we sought to replicate these results in the Ph3 trial of tebe in 1L mUM pts.
Methods: 1L HLA-A*02:01 pts with mUM received 68mcg tebe weekly iv after intra-patient dose escalation (NCT03070392). RECISTv1.1 assessed by investigators. Sera (N=202) collected at baseline (BL) and week 9 on tebe were analyzed for ctDNA using targeted mPCR-NGS assay for mutations in 15 genes including GNAQ, GNA11, SF3B1, CYSLTR2, PLCB4 and EIF1AX. OS was analyzed in subsets with &gt;0-3 log reductions in mean tumor molecules (MTM) per ml of serum on treatment. Data cutoff 4-Apr-2022.
Results: 123/202 (61%) evaluable pts had detectable ctDNA mutations in one or more UM genes at baseline. MTM at BL was correlated with tumor burden as assessed by sum of longest diameters (Spearman’s ρ=0.62, P=1.6e-14). By week 9, ctDNA reduction was observed in 108 (88%) pts, including 61/73 with RECIST response of progressive disease (PD), 34/36 with stable disease (SD) and 13/14 with partial response (PR). Deeper reductions in ctDNA were associated with progressively longer OS (Table 1). Best overall responses in pts with ctDNA clearance on tebe were PD in 20 (44%), SD in 16 (36%) and PR in 9 (20%).
Conclusions: In this Ph3 trial, ctDNA reduction by week 9 on tebentafusp was strongly associated with improved OS, even in pts with best RECIST response of PD or SD, confirming the Ph2 data. Early ctDNA reduction, which occurs at a much higher frequency than RECIST response, may be a better surrogate of tebentafusp efficacy in mUM.
Table 1. *HRs estimated from Kaplan-Meier analysis for subsets above v below ctDNA reduction threshold ctDNA subset N (%) OS hazard ratio (95% CI)* 1-year OS % ctDNA absent at baseline 79/202 (39%) NA 90% ctDNA detected at baseline 123/202 (61%) NA 62% No decrease by week 9 15/123 (12%) NA 43% Any (&gt;0 log) decrease by week 9 108/123 (88%) 0.51 (0.28-0.96) 64% ≥0.1 log 105/123 (85%) 0.48 (0.27-0.84) 65% ≥0.5 log 88/123 (72%) 0.47 (0.3-0.74) 70% ≥1 log 65/123 (53%) 0.33 (0.21-0.51) 80% ≥2 log 50/123 (41%) 0.32 (0.2-0.51) 82% ≥3 log (clearance) 45/123 (37%) 0.28 (0.17-0.46) 86%
Citation Format: Ryan Sullivan, Laura Collins, Manuel Rodrigues, Paul Nathan, Jessica C. Hassel, Reinhard Dummer, John Kirkwood, Piotr Rutkowski, Jean-Francois Baurain, Marcus O. Butler, Max Schlaak, Sebastian Ochsenreither, Shaad E. Abdullah, Chris Holland, Koustubh Ranade, Alexander N. Shoushtari. Early ctDNA reduction is associated with better overall survival in the Ph 3 trial of tebentafusp in previously untreated metastatic uveal melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1035.