Three-year overall survival outcomes and correlative analyses in patients with non–small-cell lung cancer and high (50-89%) versus very high (≥90%) PD-L1 expression treated with first-line pembrolizumab or cemiplimab

Background: Responses to first-line PD-1 inhibition vary among patients with metastatic non-small cell lung cancer (NSCLC) and a PD-L1 TPS ≥50%.We previously reported improved clinical outcomes to first-line PD-1 inhibition in patients with metastatic NSCLC with a PD-L1 TPS of ≥90% vs 50-89% in a pilot study.Here, we report the three-year survival with first-line pembrolizumab and cemiplimab in two large independent cohorts of patients with PD-L1 TPS ≥90% vs 50-89% and characterize genomic and immunophenotypic differences between these PD-L1 expression groups, which were largely unknown. Methods:We analyzed three-year outcomes of two independent cohorts: 1) a multicenter cohort of patients from four academic centers in the US treated with pembrolizumab, and 2) EMPOWER-Lung 1, randomized, phase III trial comparing first-line cemiplimab to chemotherapy.Tumor genomic profiling and multiplexed immunofluorescence (mIF) were performed to examine genomic and immunophenotypic correlates of very high PD-L1 expression.Results: At three years of follow-up, PFS (HR, 0•69; P<0•001) and OS (HR, 0•70; P<0•01) to first-line commercial pembrolizumab were significantly improved in patients with a PD-L1 TPS ≥90% vs 50-89%.In the EMPOWER-Lung 1, patients assigned to the cemiplimab arm with a PD-L1 TPS ≥90% also had significant improvements in PFS (HR, 0•53; P<0•0001) and OS (HR, 0•63; P=0•007) compared to those with a PD-L1 of 50-89%.Tumor genomic profiling of 553 NSCLC samples revealed that mutations in STK11 and SMARCA4, were significantly more frequent in tumors with a PD-L1 TPS of 50-89% compared to those with a PD-L1 TPS ≥90% (Q<0•15), while BRCA2 were enriched in NSCLC samples with a PD-L1 TPS ≥90% J o u r n a l P r e -p r o o f 6 (Q<0•15).mIF on 93 NSCLC samples identified higher intratumoral CD8 + PD1 + T cells (P=0•02) in tumors with PD-L1 TPS ≥90% vs 50-89%. Conclusion:Pembrolizumab and cemiplimab demonstrate long-term survival benefit and favorable genomic and immunophenotypic profile in patients with advanced NSCLC with PD-L1 TPS ≥90% compared to TPS 50-89%.