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9524 Background: Cutaneous melanoma is characterized by high TMB, which is associated with increased tumor-specific neoantigen expression (Schumacher Science 2015) and an increased response rate to ICI (Yarchoan NEJM 2019). The TMB in tumors that recur/progress after ICI is not well defined. Lifileucel is a one-time, autologous TIL cell therapy under investigation for treatment of patients (pts) with advanced melanoma. We conducted a matched case-control study of prospectively enrolled pts with advanced melanoma treated with lifileucel in the ICI-naïve (IOV-COM-202 trial, Cohort 1A [C1A]) and post-ICI (C-144-01 trial, Cohort 2 [C2]) setting to investigate the potential association between prior ICI therapy, TMB, and response to lifileucel. Methods: All pts had unresectable or metastatic melanoma. Available cases from C1A (ICI-naïve pts receiving lifileucel + pembrolizumab [pembro]) were matched to controls from C2 (pts receiving lifileucel alone after progression on anti–PD-1/PD-L1 therapy); 3 controls per case were matched at least for BRAF status and disease stage at study entry, and if possible, for anatomic site of tumor harvest. Lifileucel regimen was similar in C1A and C2. In C1A, 1 dose of pembro was given after tumor harvest and before nonmyeloablative lymphodepletion and resumed after lifileucel per standard treatment, for up to 2 y. Objective response rate (ORR) was assessed by investigators per RECIST v1.1. TMB of the resected tumor was measured using the ImmunoID NeXT (C1A) or PGDx elio (C2) platform; a validated conversion factor was used to compare TMB between platforms (Vega Ann Oncol 2021). High TMB was defined as ≥10 mut/MB. Results: Seven pts in C1A and 21 in C2 were included in the case-control study and had ORR of 71.4% and 38.1%, respectively. The percentage of pts with high TMB was 57.1% in C1A and 19.0% in C2 ( P = 0.1). ORR in the low and high TMB groups was 66.7% and 75.0%, respectively, in C1A and 41.1% and 25.0% in C2; 60% of responders in C1A and 12.5% in C2 had high TMB. In logistic regression analysis adjusted for cohort, TMB was not associated with response to lifileucel (odds ratio, 1.0; 95% CI, 0.9–1.1; P = 0.8). Data on tumor mutations and neoantigens, T-cell receptor repertoire, and tumor microenvironment profile will be presented. Conclusions: Our preliminary data indicate that the efficacy (ORR) of lifileucel may be independent of TMB, regardless of treatment setting, consistent with its proposed immune checkpoint pathway-independent mechanism of action. The percentage of patients with high TMB tended to be lower in tumors with prior ICI exposure than in those that were ICI-naïve. Clinical trial information: NCT03645928; NCT02360579.