Background: In the phase 3 KEYNOTE-811 study (NCT03615326), first-line (1L) pembro with tras + chemo (pembro arm) yielded superior PFS and improved ORR with durable responses versus placebo (pbo) with tras + chemo (pbo arm) in pts with HER2+ metastatic gastric or gastroesophageal junction (G/GEJ) adenocarcinoma, notably in pts with PD-L1 combined positive score (CPS) ≥1. Key prespecified exploratory HRQOL outcomes supporting these data are presented. Methods: Pts with untreated histologically or cytologically confirmed advanced HER2+ G/GEJ adenocarcinoma, measurable disease per RECIST v1.1 by investigator, and ECOG PS of 0 or 1 were randomly assigned 1:1 to receive pembro 200 mg or pbo IV every 3 weeks (Q3W) with tras + chemo (cisplatin + 5-fluorouracil or capecitabine + oxaliplatin). HRQOL was evaluated in pts who received ≥1 dose of study treatment and completed ≥1 pt-reported outcome (PRO) assessment. End points were least squares mean (LSM) change from baseline, time to deterioration (TTD), and overall improvement/stability rate in prespecified subscales of EORTC QLQ-C30, QLQ-STO22, EuroQol EQ-5D-5L. LSM changes from baseline were analyzed at wk 24 when prespecified completion and compliance rates of ~60% and 80%, respectively, were met, based on review of blinded data. Results: In the PRO analyses, 685 pts were evaluable (345 pembro with tras + chemo; 340 pbo with tras + chemo). Median time from randomization to data cutoff (May 25, 2022) was 28.4 mo (range, 9.3-42.6). Completion rates were >92% at baseline and >55% at wk 24 for all assessments in both arms. Similar changes in PRO scores from baseline to wk 24 were observed for the pembro versus pbo arms (Table). Similar percentages of pts in each arm had improved or stable scores for the EORTC QLQ-C30 GHS/QOL and physical functioning scales and EORTC QLQ-STO22 subscales. TTD was similar between arms for all prespecified subscales. Conclusions: The addition of pembro to tras + chemo did not negatively affect HRQOL during treatment. Combined with safety and efficacy data, these results support the use of pembro with tras + chemo for first-line treatment of pts with HER2+ advanced gastric cancer. Clinical trial information: NCT03615326.