Background: In the double-blind, phase 3 KEYNOTE-189 study (NCT02578680), pembro + pem + plt significantly improved OS and PFS over pbo + pem + plt as first-line therapy for nonsquamous NSCLC. Grade 3-5 drug-related AE rates were higher with pembro. We report the prespecified patient-reported outcome (PRO) analyses from KEYNOTE-189. Methods: 616 patients (pts) were randomized to pembro 200 mg Q3W or pbo for 2 y; all pts received pem + 4 cycles of carboplatin or cisplatin. The EORTC QLQ-C30 and QLQ-LC13 were administered at cycles 1-5, then every 3 cycles during yr 1 and every 4 cycles during yrs 2 and 3. Key PRO outcomes were change from baseline to wks 12 and 21 in the QLQ-C30 global health status/QoL score and time to deterioration in the composite of cough, chest pain, or dyspnea. PROs were analyzed in all treated pts who completed ≥1 PRO instrument (n = 602). P values are nominal and 2-sided. Results: QLQ-C30 and QLQ-LC13 compliance was ~90% at baseline and wk 12 in both arms and was ~75% with pembro and ~63% with pbo at wk 21. Mean baseline scores were 61.98 and 60.56 in the pembro and pbo arms. At wks 12 and 21, global health status/QoL scores were stable with pembro and decreased with pbo, with significantly greater decrement with pbo at wk 21 (Table). The proportion of improved global health status/QoL was similar at wk 12 (28.9% with pembro vs 26.5% with pbo; P = .5450) but was greater with pembro at wk 21 (30.1% vs 22.5%; P = .0496). Median time to deterioration in the composite of cough, chest pain, or dyspnea was NR with pembro (95% CI 10.2 mo-NR) vs 7.0 mo (95% CI, 4.8-NR) with pbo (HR 0.81; 95% CI 0.60-1.09; nominal 2-sided P = .081). Conclusions: In this double-blind trial, pembro + pem + plt maintained or improved HRQoL over pem + plt alone despite a higher grade 3-5 treatment-related AE rate. Along with superior efficacy, these data support the use of pembro + pem + plt as first-line therapy for metastatic nonsquamous NSCLC. Clinical trial information: NCT02578680