Clinicopathological and genomic correlates of programmed cell death ligand 1 (PD-L1) expression in nonsquamous non-small-cell lung cancer.

Programmed cell death ligand 1 (PD-L1) tumor proportion score (TPS) is the primary clinically-available biomarker of response to immunotherapy in non-small-cell lung cancer (NSCLC), but factors associated with PD-L1 expression are not well understood. Consecutive nonsquamous NSCLCs with successful PD-L1 assessment and targeted next-generation sequencing were included in this retrospective study. Clinicopathological characteristics, gene mutations, and copy number changes in gene and chromosomal arms were compared among three PD-L1 expression groups: negative (TPS < 1%), low (TPS 1%–49%), and high (TPS ≥ 50%). A Q -value <0.25 was considered significant after multiple comparisons correction. A total of 909 nonsquamous NSCLCs were included. High PD-L1 expression compared with low and negative PD-L1 expression was associated with increased tobacco exposure (median pack-years: 25 versus 20 versus 20, respectively; P = 0.01), advanced stage at diagnosis (76% versus 67% versus 61% with advanced stage of disease, respectively; P < 0.001), and higher tumor mutational burden (TMB) (median 12.2 versus 10.6 versus 10.6 mutations/megabase, respectively; P < 0.001). Negative PD-L1 expression when compared with high PD-L1 expression was associated with: mutations in STK11 (19% versus 5%; Q < 0.001), EGFR (22% versus 11%; Q < 0.001), CTNNB1 (4.3% versus 0.4%; Q = 0.04), APC (5% versus 1%; Q = 0.17), and SMARCA4 (9% versus 4%; Q = 0.20); copy number loss of CD274 (PD-L1, 28% versus 6%; Q < 0.001), PDCD1LG2 (PD-L2, 28% versus 6%; Q < 0.001), and JAK2 genes (27% versus 7%; Q < 0.001), loss of chromosomal arm 9p (23% versus 10%; Q = 0.04), and gain of 1q (46% versus 21%; Q < 0.001). High PD-L1 expression compared with negative PD-L1 expression was associated with copy number gain of CD274 (11% versus 3%; Q = 0.01) and PDCD1LG2 (11% versus 3%; Q = 0.01). NSCLCs with CD274 loss, compared with those without loss, had a lower response rate (23% versus 9%; P = 0.006) and shorter progression-free survival (3.3 versus 2.0 months; P = 0.002) on immunotherapy. PD-L1 expression is associated with specific genomic alterations and clinicopathologic characteristics in nonsquamous NSCLC. • PD-L1 expression is highly variable in nonsquamous NSCLC and is associated with distinct clinicopathological and genomic features. • Tobacco exposure, stage at diagnosis, and tumor mutational burden are associated with PD-L1 expression. • PD-L1 expression ≥50% is associated with copy gain of CD274 (PD-L1) , PDCD1LG2 (PD-L2), JAK2 , and the 9p24.1 locus. • PD-L1 negativity is associated with STK11 , EGFR , CTNNB1 , APC , and SMARCA4 mutations, as well as loss of CD274 , PDCD1LG2 , JAK2 , and the 9p24.1 locus. • CD274 copy loss is associated with lower response rate and shorter progression-free survival to immune checkpoint inhibitors in NSCLC. [ABSTRACT FROM AUTHOR]