Abstract A008: TIGIT, CD155 (PVR), and Trop-2 expression characterization across histology and PD-L1 subgroups in non−small cell lung cancer (NSCLC)

Abstract Background: Response to first-line therapy remains <50% with median overall survival <2 years despite new anti-PD-(L)1 antibodies. New immuno-oncology combinations aim to improve outcomes and counter anti-PD-(L)1 resistance. Novel combinations of domvanalimab (dom, anti-TIGIT) ± sacituzumab govitecan (SG, Trop-2−directed ADC) ± zimberelimab (zim, anti-PD-1) ± standard of care are being studied in NSCLC in the VELOCITY-Lung (NCT05633667), EDGE-Lung (NCT05676931), STAR-121 (NCT05502237), EVOKE-02 (NCT05186974), and EVOKE-03 (NCT05609968) clinical trials. We aimed to determine the prevalence of biomarkers relevant to dom (TIGIT and its ligand CD155), zim (PD-1’s ligand PD-L1), and SG (Trop-2) across NSCLC histologies and PD-L1 subgroups to inform ongoing clinical trial biomarker evaluations. Methods: IHC assays on commercially procured NSCLC samples from US, Europe, and Vietnam were analyzed for PD-L1 (VENTANA PD-L1 [SP263] at Roche Tissue Diagnostics [RTD]; 22C3 pharmDx at CellCarta [CC]), Trop-2 (EPR20043 FLA at RTD), TIGIT (SP410 FLA at RTD), and CD155 (MOS757-APD at CC). Either percent tumor cell (TC; SP263) or percent tumor proportion score (TPS; 22C3) was used to quantify PD-L1 expression on TCs; both scores were used for later analyses. TIGIT, scored on immune cells (IC), was normalized to percent tumor area. H-scores (scale 0-300) were used for Trop-2 and CD155. Biomarker prevalence was evaluated in histology and PD-L1 subgroups (TC or TPS; negative, <1%; low, 1-49%; high, ≥50%). Statistical comparisons were derived from t tests. Results: Tissue from 307 NSCLC samples (nonsquamous [nsq], n=207; squamous [sq], n=100) was analyzed. PD-L1 expression was comparable between histological subgroups, while greater percent total IC was seen in the PD-L1-high vs -negative subgroups (P=4.6×10-4). In the sq samples, TIGIT expression was significantly higher in PD-L1-high vs -negative subgroups (median 10% vs 4%, P=2.9×10-4). In the PD-L1 negative subgroup, 88% and 11% of samples had >1% and >10% TIGIT expression, respectively. TIGIT strongly correlated with percent IC (Spearman correlation; nsq r=0.8, sq r=0.77) regardless of histology and did not correlate with CD155 or Trop-2 expressed on TCs. Significantly higher Trop-2 (P=4.6×10-5), TIGIT (P=3.8×10-4) and CD155 (P=8.5×10-4) expression were seen in sq vs nsq samples, and a moderate correlation (r=0.37) between CD155 and Trop-2 was observed in nsq samples. Neither biomarker was associated with percent IC; yet, there was significantly higher CD155 expression in PD-L1-high vs -low (P=0.02) or -negative (P=7.2×10-4) subgroups. Conclusions: TIGIT was expressed across histology and PD-L1 subgroups, including PD-L1 negative, suggesting dom/zim as a potential treatment combination across NSCLC subtypes and PD-L1 subgroups. Consistent with published data, CD155 and TIGIT expression were significantly higher in PD-L1-high and sq samples. These biomarkers’ predictive/prognostic values will be evaluated in the context of efficacy in clinical studies testing combinations of dom/zim and SG in NSCLC. Citation Format: Marianna Zavodovskaya, Biao Li, Kai-Wen Lin, Michael Sharpnack, Stacie Lambert. TIGIT, CD155 (PVR), and Trop-2 expression characterization across histology and PD-L1 subgroups in non−small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr A008.