Abstract 1673: Uveal melanoma study patients with low CD163:CD3 ratio in tumor biopsy and low serum IL-6 showed enhanced tumor shrinkage (TS) and overall survival (OS) on tebentafusp

Background: Tebentafusp, an investigational TCR–anti-CD3 bispecific fusion protein (ImmTAC) that targets gp100 and activates T cells, has shown monotherapy activity in metastatic melanoma [1-3]. In a phase I/II trial enrolling metastatic uveal melanoma patients we explored biomarkers of clinical outcomes. Methods: The effect of CD163+ macrophages on ImmTAC-mediated T cell proliferation and melanoma cell killing was assessed in vitro. Advanced uveal melanoma HLA-A*02:01+ patients (N = 127) were treated with weekly 68mcg tebentafusp after intra-patient dose escalation (NCT02570308). Serum samples (up to N=123) were profiled for 11 cytokines and chemokines. Digital image analysis of IHC enumerated immune cells per mm2 in tumor biopsies (up to N=112). Median cutoff was used for biomarker correlations with outcomes. Results: In vitro, increasing numbers of CD163+ macrophages resulted in greater inhibition of ImmTAC-mediated T cell proliferation and killing of MEL624 melanoma cells. The numbers of tumor infiltrating T cells (CD3, CD4, CD8) and CD163+ macrophages at baseline were not associated with TS. However, below median CD163:CD3 ratio was associated with greater TS (odds ratio OR=2.9, p=0.014) and OS (hazard ratio HR=0.4, p=0.001), attributable to CD163:CD8 (OR=3.6, p=0.004) but not CD163:CD4 (OR=1.9, p=0.2). Low serum IL-6 levels at baseline trended with TS (OR=2.1, p=0.09) and OS (HR=0.3, p Conclusions: Uveal melanoma patients with low levels of pre-treatment CD163:CD3 in tumor biopsy and serum IL-6 may derive the most benefit from tebentafusp. This hypothesis will be tested in samples from a randomized trial of tebentafusp (NCT03070392). [1] NCT01211262; ASCO 2019 [2] Clinical Cancer Research; 2020[3] #195; ESMO IO; 2020 Citation Format: Jessica C. Hassel, Adel Benlahrech, Sarah Stanhope, Revashnee Naidoo, Emma Leach, Laura Collins, Shaad Abdullah, Koustubh Ranade, Joseph Sacco. Uveal melanoma study patients with low CD163:CD3 ratio in tumor biopsy and low serum IL-6 showed enhanced tumor shrinkage (TS) and overall survival (OS) on tebentafusp [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1673.