Background: In the phase 3 KEYNOTE-598 study (NCT03302234), OS (HR, 1.08; 95% CI, 0.85–1.37; P = 0.74) and PFS (1.06; 95% CI, 0.86–1.30; P = 0.72) were not improved for pembro + ipi vs pembro + placebo in patients (pts) with previously untreated metastatic NSCLC with PD-L1 tumor proportion score (TPS) ≥50% and without EGFR/ALK genomic alterations. Incidence of treatment-related grade 3–5 AEs, fatal AEs, and AEs leading to discontinuation was higher with pembro + ipi vs pembro + placebo. We present prespecified patient-reported outcome (PRO) analyses from KEYNOTE-598. Methods: Pts (n = 568) with previously untreated stage IV NSCLC with PD-L1 TPS ≥50% were randomized 1:1 to pembro 200 mg Q3W for up to 35 cycles + ipi 1 mg/kg or placebo Q6W for up to 18 cycles. The EORTC QLQ-C30, QLQ-LC13, EQ-5D-5L, and NSCLC-SAQ were administered at cycles 1‒7, then every 3 cycles through cycle 19, and every 4 cycles until PD or a maximum of 35 cycles. Change from baseline in global health status (GHS)/quality of life (QoL) score from the QLQ-C30 and the time to true deterioration (TTD) in the composite endpoint of cough (LC13), chest pain (LC13), or dyspnea (C30) were secondary objectives in KEYNOTE-598. Change from baseline in GHS/QoL was analyzed using a constrained longitudinal data analysis model with missing at random assumption. Difference in TTD was evaluated using a Cox proportional hazards model and stratified log-rank test. PROs were analyzed in all pts who completed ≥1 PRO assessment and received ≥1 dose of study treatment. P values are two-sided and nominal. Results: As of data cutoff (Sept 1, 2020), PRO analyses included 280 pts in the pembro + ipi group and 280 pts in the pembro + placebo group. QLQ-C30 completion rates were 95.7% in the pembro + ipi group vs 96.1% in the pembro + placebo group at baseline and 63.6% vs 70.0% at week 18. QLQ-LC13 completion rates were 95.4% vs 96.4% at baseline and 63.6% vs 69.6% at week 18. Mean QLQ-C30 GHS/QoL scores at baseline were 62.8 in the pembro + ipi group and 64.2 in the pembro + placebo group and were similar between the groups across the follow-up period. Least squares (LS) mean (95% CI) change from baseline to week 18 in GHS/QoL scores was improved in both groups (pembro + ipi: 3.7 [0.9‒6.5]; pembro + placebo: 4.1 [1.4‒6.9]), with no significant difference between groups (LS mean difference −0.4 [−4.0 to 3.1], P = 0.82). Median TTD in composite of cough, chest pain, or dyspnea was not reached (NR; 95% CI, 13.0 mo–NR) in the pembro + ipi group vs 20.0 (95% CI, 12.7–NR) mo in the pembro + placebo group (hazard ratio, 0.98 [95% CI, 0.74‒1.30]; P = 0.91). Conclusions: There was no difference in health-related QoL or TTD in lung cancer symptoms between pembro + ipi and pembro + placebo in pts with previously untreated metastatic NSCLC with PD-L1 TPS ≥50%. Clinical trial information: NCT03302234