Background: RATIONALE-305 (NCT03777657), demonstrated statistically significant and clinically meaningful improvements in overall survival (OS) with TIS + chemo (n=501) over PBO + chemo (n=496) as 1L treatment in patients (pts) with advanced G/GEJC. This analysis examined HRQoL outcomes of the RATIONALE-305 study at final analysis. Methods: Adults with previously untreated, unresectable, or metastatic GC/GEJC, were randomized (1:1) to TIS 200 mg or PBO IV once every 3 weeks plus investigator-choice of chemo. HRQoL was assessed using EORTC QLQ-C30 and the QLQ-STO22. A mixed model for repeated measures using PRO endpoints at clinical Cycles 4 and 6 was performed. Time to deterioration was examined. Results: TIS + chemo had improved outcomes than PBO + chemo (Table) as indicated by least-squares mean change from baseline to Cycle 6 for QLQ-C30 GHS/QoL (2.52 [95% CI:0.29 to 4.74]), physical functioning (2.46 [95% CI: 0.49 to 4.43]), fatigue (-3.01 [95% CI: -5.78 to -0.24]), and the STO22 index score (-1.62 [95% CI: -3.12 to -0.12]), as well as maintaining upper gastrointestinal (GI) symptoms (-1.74 [95% CI: -3.55 to 0.06)] and pain (-1.88 [95% CI: -4.03 to 0.27]). Pts receiving TIS + chemo had a lower risk for deterioration of GHS/QoL (0.77 [95% CI: 0.60 to 0.98]), physical functioning (0.72 [0.57 to 0.92]), STO22 index score (0.64 [0.45 to 0.92]), pain/discomfort (HR: 0.74 [0.58-0.96]), and upper GI symptoms (0.73 [0.56 to 0.95]). Conclusions: Pts treated with TIS + chemo had better HRQoL outcomes vs pts treated with PBO + chemo, particularly for GHS/QoL, physical functioning, fatigue, GC/GEJC symptoms, pain/discomfort, and upper GI symptoms These results, along with prolonging of OS and other secondary efficacy endpoints, as well as a tolerable safety profile, support the benefit of TIS + chemo as a potential 1L treatment option for GC/GEJC. Clinical trial information: NCT03777657.