Background – The immune checkpoint, TIGIT, is a potential anti-tumor target. We assessed relationships between TIGIT expression, effector T-cell (Teff) gene expression, PD-L1 status, and real-world progression-free survival (rwPFS) in 1L mNSCLC.

Methods – Biopsy samples from pts with mNSCLC were sequenced by Tempus xR (whole-transcriptome RNA-sequencing assay) and PD-L1 (immunohistochemistry [IHC]) and physician-documented clinical response data were extracted from the Tempus real-world deidentified database. rwPFS after 1L anti–PD-(L)1 treatment (ICI) or 1L anti–PD-(L)1 treatment + chemotherapy (ICI + chemo) was compared between groups by gene expression level (high [≥ median] vs low [< median]) overall and by PD-L1 IHC status (tumor cell score: negative [< 1%], low [1%–50%], or high [≥ 51%]).

Results – TIGIT expression was highly correlated with Teff, FOXP3, CD274, CD8A, and IKZF1 (P < 0.01) in adenocarcinoma (n = 974) and squamous (n = 314) mNSCLC. TIGIT expression and PD-L1 status by IHC were positively correlated (P < 0.001); however, 36% of pts in the PD-L1-high subgroup had low tumor TIGIT expression, and 39% in the PD-L1-negative subgroup had high tumor TIGIT expression. High vs low TIGIT expression was associated with numerically longer rwPFS for ICI (n = 94 vs 95; hazard ratio [HR] 0.65, P = 0.05) or ICI + chemo (n = 496 vs 497; HR 0.84, P = 0.06). rwPFS was also numerically longer for high vs low Teff gene set expression: HRs of 0.57 (P = 0.01) for ICI and 0.79 (P = 0.02) for ICI + chemo. When TIGIT expression was normalized to Teff, HRs for high vs low expression were 1.02 (P = 0.95) for ICI and 1.20 (P = 0.06) for ICI + chemo. rwPFS results for TIGIT normalized to Teff in PD-L1 subgroups were similar, including in the PD-L1 high subgroup (ICI, P = 0.58; ICI + chemo, P = 0.23). Results were validated with the OAK/POPLAR data set (n = 891; advanced NSCLC; anti–PD-L1 or chemo).

Conclusions – Our findings suggest TIGIT expression correlates with Teff better than PD-L1 expression. Thus using high PD-L1 expression as a biomarker may limit identification of pts who may respond to anti-TIGIT therapies. Importantly, combining anti-TIGIT and anti–PD-(L)1 may lead to enhanced T-cell activation in pts whose tumors express high levels of TIGIT with low Teff levels.

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