Background: In KEYNOTE-040 (NCT02252042) (N = 495), pembro 200 mg Q3W for 24 mo yielded a clinically meaningful improvement in overall survival over SOC choice of methotrexate (Mtx), docetaxel (Dtx), or cetuximab (Ctx) in patients (pts) with R/M HNSCC, with fewer grade 3-5 drug-related adverse events. We present results of prespecified exploratory HRQoL analyses. Methods: The EORTC QLQ-C30, EORTC QLQ-H&N35, and EQ-5D were administered electronically at baseline; wks 3, 6, 9; then every 6 wk up to 1 y or end of treatment; and at 30-day safety follow-up visit. HRQoL was analyzed in pts who received ≥1 dose of study drug and had ≥1 HRQoL assessment. Mean change from baseline to wk 15 was compared using a constrained longitudinal data analysis model. Time to deterioration (TTD) (defined as ≥10-point decline from baseline) was estimated by Kaplan-Meier method and Cox regression model. Results: The HRQoL population included 469 pts (241 pembro; 228 SOC). HRQoL compliance at wk 15 was 75.3% for pembro and 74.6% for SOC. From baseline to wk 15, global health status (GHS)/QoL scores were stable for pembro (least-squares [LS] mean, 0.39; 95% CI, –3.00, 3.78) but worsened for SOC (LS mean –5.86; 95% CI, –9.6 8, –2.04); difference in LS mean between arms was 6.25 points (95% CI, 1.32, 11.18; nominal 2-sided P= 0.013). Subgroup analyses by SOC choice identified a greater difference in LS mean for GHS/QoL scores with pembro vs Dtx (10.23; 95% CI, 3.15, 17.30) compared with pembro vs Mtx (6.21; 95% CI, –4.57, 16.99) or Ctx (–1.44; 95% CI, –11.43, 8.56). Median TTD in GHS/QoL with pembro vs SOC was 4.8 and 2.8 mo (HR, 0.79; 95% CI, 0.59, 1.05; nominal 1-sided P= 0.048). Pts in the pembro arm generally had stable functioning and symptom scores at wk 15; no notable between-group differences were seen. Conclusions: Over 15 wks, pembro-treated pts had stable GHS/QoL; those receiving SOC generally showed a decline. This effect was more marked for Dtx-treated pts. Additional HRQoL analyses by SOC choice will further assess trends. Along with previously presented efficacy and safety results, these data support the clinically meaningful benefit of pembro in R/M HNSCC. Clinical trial information: NCT02252042