Abstract 3321: Real-world clinical outcome analyses in head and neck squamous cell carcinoma (HNSCC) to uncover TIGIT biology in patients treated with first-line immune checkpoint inhibitors

Introduction: ICIs are approved for HNSCC. T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibition motif domain (TIGIT) is a potential ICI anti-tumor target. Understanding how effector T cell (Teff) and TIGIT expression levels in tumors correlate with real-world outcomes of 1L treatment can highlight the role of TIGIT as a potential target. Methods: Deidentified real-world pt data, including whole-transcriptome RNA sequencing (RNA-seq) and progression-free survival (PFS), were acquired from Tempus AI, Inc. Data from pts with metastatic HNSCC (mHNSCC) who received 1L therapy with ICI, ICI + chemotherapy (chemo), or chemo were analyzed. Gene expression correlations, including between TIGIT and a Teff gene set (geometric mean of: CD8A, GZMA, GZMB, IFNG, EOMES, and PRF1) were assessed by Pearson correlation coefficients. Human papilloma virus (HPV) status was extrapolated by an HPV gene signature (GGA2, SPIB, CD200, ADAM28, BCL2, VCAM1, ICOSLG, STAG3). Real-word PFS (rwPFS) was assessed using the Kaplan-Meier method and compared by expression level (high vs low) of TIGIT, Teff gene set, and TIGIT normalized by Teff gene set. Results: The cohort included pts with 1L ICI (n = 27), ICI + chemo (n = 62), and chemo (n = 159). At baseline, TIGIT expression (N = 276 biopsies with RNA-seq) was highly correlated with Teff gene set (R = 0.852, P < 0.001) and FOXP3 expression (R = 0.853, P < 0.001). Correlations were consistent when stratified by HPV status (HPV+ or HPV−) or programmed death-ligand 1 (PD-L1) status (combined positive score: < 1, 1-19, and ≥ 20). Higher immune marker expression and numerically improved rwPFS for ICI + chemo were observed for HPV+ vs HPV− status. High vs low TIGIT expression was associated with numerically improved rwPFS for ICI (n = 13 vs 14; HR [95% CI], 0.86 [0.23-3.22]) or ICI + chemo (n =31 each; HR [95% CI], 0.4 [0.18-0.9]; P = 0.023). Similar results were observed for high vs low Teff gene set expression (ICI: HR [95% CI], 0.54 [0.13-2.16]; ICI + chemo: HR [95% CI], 0.66 [0.3-1.42]). When TIGIT expression was normalized to Teff gene set expression, rwPFS was numerically shorter for high vs low expression in ICI (HR [95% CI], 1.25 [0.33-4.8]) or ICI + chemo (HR [95% CI], 1.37 [0.64-2.95]). Conclusions: TIGIT expression was highly correlated with Teff gene set expression and FOXP3 in HNSCC tumors. Improved rwPFS with HPV+ status was likely due to a more immunogenic tumor microenvironment. High Teff or TIGIT expression in tumors was associated with improved rwPFS with 1L ICI-containing regimens. However, after normalization of TIGIT expression by Teff infiltration, the presence of TIGIT-high tumors was associated with worse rwPFS with ICI-based treatment. Thus, combining anti-TIGIT and anti-PD-1 treatments could bring more benefit in a 1L mHNSCC setting to pts with TIGIT-high tumors. Citation Format: Meghna Das Thakur, Xiaoyong Fu, Shahed Iqbal, Joon Rhee. Real-world clinical outcome analyses in head and neck squamous cell carcinoma (HNSCC) to uncover TIGIT biology in patients treated with first-line immune checkpoint inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3321.