Background: Although 1^st-line PD-1 monotherapy has improved survival in advanced NSCLC with a PD-L1 TPS ≥50%, responses occur in ̃45% of patients (pts). We previously showed that among pts treated with 1^st-line pembrolizumab, clinical outcomes were significantly improved in those with a PD-L1 TPS of ≥90% compared to a TPS of 50-89%. Here, we report the 3-year survival analysis to 1^st-line pembrolizumab in pts with a PD-L1 TPS ≥90% vs 50-89%, and characterize genomic and immunophenotypic differences between these PD-L1 expression groups. Methods: Pts with stage IV EGFR/ALK wild-type NSCLC and PD-L1 TPS ≥50% who received 1^st-line pembrolizumab at the Dana-Farber Cancer Institute (DFCI) and Memorial Sloan Kettering Cancer Center (MSKCC), with a minimum follow-up of 3 years were included. Comprehensive tumor genomic profiling and multiplexed immunofluorescence (mIF) were performed to examine genomic and immunophenotypic correlates of very high PD-L1 expression on separate cohorts of NSCLC at the DFCI. Results: Among 396 pts, median age was 69, 53.3% were women, 90.1% had a history of tobacco use, 83.6% had a ECOG performance status of 0-1, and 28.8% had a KRAS mutation. At a median follow-up of 42.6 months, median progression-free (mPFS) and overall survival (mOS) in the entire cohort were 5.1 months, and 19.0 months, respectively. When compared to pts with a PD-L1 TPS of 50-89% (N = 252), those with PD-L1 TPS ≥90% (N = 144) had a significantly longer mPFS (6.0 vs 4.5 months, HR 0.67, p < 0.001), and longer mOS (30.2 vs 16.9 months, HR 0.66, p < 0.01). Kaplan-Meier estimates of the 3-year PFS and OS were 24.9% and 47.0% in the PD-L1 TPS ≥90% groups, and 9.4% and 27.7% in the PD-L1 TPS 50-89% group, respectively. A PD-L1 TPS ≥90% was confirmed to be an independent predictor of improved PFS (HR 0.68, p < 0.01) and OS (HR 0.67, p < 0.01) in multivariable analysis. Tumor genomic profiling from a separate cohort of 500 NSCLC samples revealed that mutations in STK11, KEAP1, FBXW7, and CTNNB1 were significantly more frequent in tumors with a PD-L1 TPS of 50-89% compared to those with a PD-L1 TPS ≥90% (q < 0.05). mIF on 91 NSCLCs identified significantly higher CD8+PD1+ T cells and PD-L1+ immune cells in tumors with PD-L1 TPS ≥90% vs 50-89% (p < 0.05). Conclusions: Pembrolizumab monotherapy continues to demonstrate a meaningful long-term survival benefit in pts with advanced NSCLC and a PD-L1 TPS ≥90%. NSCLCs with very high PD-L1 TPS may have a more favorable genomic and immunophenotypic profile. These findings have implications for treatment selection and clinical trial interpretation and design.