9533 Background: Pembrolizumab (P) is now widely used as standard of care (SOC) in advanced NSCLC. We sought to identify prognostic factors influencing survival with it in a real-world setting. Methods: We conducted a retrospective cohort study of with advanced NSCLC patients who initiated treatment with SOC P monotherapy at our center from 2/11/16 to 10/15/19 (data cutoff 1/15/20). Patient demographic, clinicopathologic, therapeutic and outcomes data were extracted. Survival time was defined from start of P. Cox proportional hazards and logistic regression were utilized. Results: Of 74 patients with median follow up of 83.9 weeks, 30 (40.5%) were alive at cutoff. Patient characteristics at start of therapy were: 36 (48.6%) female, median age 68.5 yr (range 33-87), 10 (13.5%) with symptomatic brain metastases; 54 (72.9%) treatment-naïve, 29 (39.2%) with ECOG performance status (PS) ≥2. Tumor characteristics were: 53 (71.6%) with PD-L1 tumor proportion score (TPS) ≥50%, median PD-L1 TPS 75% (range 1-100), tumor mutational burden (TMB) tested in only 37 (50%) patients, median TMB 8 mut/mB (range 1-62). Any grade immune-related adverse events (irAE) occurred in 33 (44.6%) patients, while 16 (21.6%) received systemic steroids. Median survival was 43.3 wks (95% CI 29-104.1). Multivariable regression showed ECOG PS of ≥2 as the strongest risk factor for death (Table). We next evaluated differences in characteristics of patients who were alive vs dead within 12 wks of starting P, by which initial response assessments are completed in routine practice. ECOG PS was the only significantly different baseline variable, even after multivariable adjustment (p = 0.002). Conclusions: ECOG PS of ≥2 is a poor prognostic risk factor associated with P monotherapy in advanced NSCLC. Though comprising a clinically significant subset of patients in real-world, they were not included in landmark trials (KEYNOTE-024 & 042). Prospective evaluation is warranted. [Table: see text]