Clinical significance of inter-assay discrepancy in PD-L1 evaluation for the efficacy of pembrolizumab in advanced NSCLC with high PD-L1 expression.

INTRODUCTION: Programmed cell death ligand-1 (PD-L1) expression is a predictive biomarker for the efficacy of anti-programmed cell death receptor-1/PD-L1 antibodies in advanced non-small cell lung cancer (NSCLC). Although several assays have been approved for evaluating PD-L1 expression status, inter-assay discordance has been observed between some assays. The clinical significance of these discrepancies is still unclear. METHODS: We retrospectively reviewed treatment-naïve NSCLC patients whose PD-L1 expression was evaluated using both 22C3 and SP142 assays. Among those, efficacy analysis was performed for patients with PD-L1 tumor proportion score (TPS) ≥ 50 % (22C3), who had received first-line pembrolizumab monotherapy. Additionally, transcriptome analysis was conducted in the available tumors with TPS ≥ 50 % to investigate the distinct immune profiles that accompany inter-assay discordance. RESULTS: In total, 611 patients were eligible. Among 198 patients with TPS ≥ 50 %, 91 (46 %) had tumor cell score ≤ 1 (SP142, i.e., inter-assay discrepancy). In the 52 patients who received first-line pembrolizumab monotherapy, treatment efficacy was significantly lower in patients with the discrepancy than that in those without (objective response rate: 18 % vs. 83 %, p < 0.001; median progression-free survival [months]: 3.2 vs. 8.3, p < 0.001). Transcriptome analysis revealed significantly more CD274 splice variants with aberrant 3'-terminal sequences in tumors with the inter-assay discrepancy than in those without. CONCLUSION: The inter-assay discrepancy in the PD-L1 status of tumor cells between the 22C3 and SP142 assays, reflecting an imbalance in the CD274 splice variants, could be a biomarker for primary resistance against pembrolizumab monotherapy in high PD-L1-expressing NSCLCs.

Whole-genome sequencing reveals the molecular implications of the stepwise progression of lung adenocarcinoma.

The mechanism underlying the development of tumors, particularly at early stages, still remains mostly elusive. Here, we report whole-genome long and short read sequencing analysis of 76 lung cancers, focusing on very early-stage lung adenocarcinomas such as adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma. The obtained data is further integrated with bulk and spatial transcriptomic data and epigenomic data. These analyses reveal key events in lung carcinogenesis. Minimal somatic mutations in pivotal driver mutations and essential proliferative factors are the only detectable somatic mutations in the very early-stage of AIS. These initial events are followed by copy number changes and global DNA hypomethylation. Particularly, drastic changes are initiated at the later AIS stage, i.e., in Noguchi type B tumors, wherein cancer cells are exposed to the surrounding microenvironment. This study sheds light on the pathogenesis of lung adenocarcinoma from integrated pathological and molecular viewpoints.