P2.04-32 Comparison of Clinicopathological and Genomic Characteristics Between NSCLCs with a PD-L1 Tumor Proportion Score of ≥90% vs <1%

Abstract

Determinants of PD-L1 expression in non-small cell lung cancer (NSCLC) are poorly defined. To identify characteristics associated with high vs. absent PD-L1 expression, we compared clinicopathologic and genomic features of NSCLCs at the two ends of PD-L1 expression spectrum: a PD-L1 tumor proportion score (TPS) of ≥90% or a PD-L1 TPS of <1%. We retrospectively collected clinicopathologic and genomic data (via targeted NGS) from consecutive NSCLC patients who had consented to an IRB-approved correlative research study and whose tumor PD-L1 TPS was either ≥90% or <1%. Single nucleotide variations, insertions/deletions, and copy number alterations were compared using Fisher’s exact test. Tumor mutational burden (TMB) was compared using Mann-Whitney test. 421 NSCLCs with PD-L1 TPS ≥90% (N=133) or <1% (N=288) and successfully performed NGS were identified. There was no difference in age, sex, histology, or stage at diagnosis between the two groups. Patients with a PD-L1 TPS of ≥90% were more likely to be smokers (86.5% vs 76.4%; P=0.02) compared to patients with a PD-L1 TPS of <1%, and tumors in the PD-L1 TPS ≥90% group had higher TMB (10.89 vs 8.47 mutations/megabase; P=0.004) than those in the PD-L1 TPS <1% group. Tumors in the PD-L1 TPS ≥90% group were more likely to have KRAS (47.3% vs 31.3%; P=0.002), MET exon 14 (9.6% vs 2.1%; P=0.003), and TP53 mutations (71.0% vs 49.7%; P<0.001) than those in the PD-L1 TPS <1% group. Compared to the PD-L1 TPS ≥90% group, the PD-L1 TPS <1% group was more likely to have EGFR (23.6% vs 8.2%; P<0.001) and STK11 (23.4% vs 5.0%; P<0.001) mutations, as well as the absence of known oncogenic driver mutations (35.2% vs 24.8%; P=0.04). Chromosomal gain alterations (amplification or copy number gain) of the 9p24.1 locus, where the PD-L1, PD-L2, and JAK2 genes are located, were more common in the PD-L1 TPS ≥90% group than in the PD-L1 TPS <1% group (11.4% vs 2.8%, respectively; P<0.001). Chromosomal loss alterations (copy loss or deletion) of the 9p24.1 locus were more common in the PD-L1 TPS <1% than in the PD-L1 TPS ≥90% group (27.5% vs 3.8%, respectively; P<0.001). A repeated biopsy case showed acquired loss PD-L1 expression (PD-L1 TPS changed from 90% to 0%) with concomitant acquired loss of the 9p24.1 locus. High PD-L1 expression in NSCLC is associated with tobacco use, high TMB, gain of the 9p24.1 locus and mutations in KRAS, MET exon 14, and TP53. PD-L1 negativity is associated with never smoking status, low TMB, loss of the 9p24.1 locus, mutations in EGFR and STK11, and the absence of oncogenic driver mutations.