Abstract Background: CT (fluorouracil/platinum) + H is standard of care (SoC) for 1L HER2-positive mGC/GEJC based on the ToGA Phase 3 study. ToGA post hoc analyses showed that lowest H trough concentration (Cycle 1 Ctrough) quartile pts had shorter overall survival (OS) than pts in higher quartiles, and that they were enriched for poorer prognostic factors at baseline, e.g. ECOG 2, no prior gastrectomy, ?2 metastatic sites. HELOISE (NCT01450696) investigated whether higher dose H (HD H) + CT, when compared to SoC H + CT, improves OS in 1L HER2-positive mGC/GEJC. Methods: Pts with the high risk features above were randomized 1:1 to loading dose H 8 mg/kg then SoC H maintenance 6 mg/kg every 3 weeks (q3w) or loading dose H 8 mg/kg then HD H maintenance 10 mg/kg q3w until progression; each arm combined with cisplatin 80 mg/m2 + capecitabine 800 mg/m2 in cycles 1-6. The primary objective was HD H OS superiority (target HR 0.75, all randomized pts); other objectives included pharmacokinetics (PK) and safety. Final results are from an interim analysis for futility at 125 OS events. Results: 248 pts had been randomized at clinical cutoff, Feb 13, 2015. Baseline characteristics/demographics were balanced overall, with median ages 58.5 and 62.6 years in the SoC H and HD H arms, respectively; 23% of pts per arm were female. Safety was comparable between arms, with no difference in congestive heart failure (0% each). The OS futility boundary was crossed (HR 1.24 > 0.95); safety, efficacy, and PK data are shown in the table. A marked increase in mean Ctrough was observed following the first HD H cycle vs SoC H. SoC H (8 mg/kg + 6 mg/kg) + CTHD H (8 mg/kg + 10 mg/kg) + CTPrimary tumorn=124n=124Gastric/GEJ, n (%)95 (76.6)/29 (23.4)101 (81.5)/23 (18.5)Treatmentn=124n=123Median H cycles/median capecitabine cycles/median cisplatin cycles, n6.5/6.0/6.06.0/6.0/5.0Safety, pts with ≥1:n=124n=123Any grade adverse event (AE), n (%)113 (91.1)112 (91.1)Serious AE (SAE)/SAE cardiac disorder, n (%)30 (24.2)/3 (2.4)35 (28.5)/4 (3.3)Efficacyn=124n=124OS events, n (%)58 (46.8%)67 (54.0%)Median OS, months12.510.6Stratified OS HR (95% CI)1.24 (0.86-1.78) Log-rank P=0.24Median PFS, months5.755.59Stratified PFS HR (95% CI)1.04 (0.76-1.40) Log-rank P=0.82PK: Mean Ctrough, μg/mL (% coefficient of variation)Cycle 1, 8 mg/kg loading H (n=101 and 99)17.1 (82.9)18.1 (100.1)Cycle 2, first dosing HD H (n=94 and 77)19.3 (45.7)35.6 (54.6)Cycle 7, steady-state H (n=51 and 44)31.4 (45.1)58.1 (47.5) Conclusions: Although HD H maintenance dosing is associated with higher H concentrations in HELOISE, we observed no increased efficacy (OS, PFS) and no new safety signals. HELOISE confirms SoC H (8 mg/kg loading dose followed by H 6 mg/kg q3w maintenance doses) as SoC with CT for 1L treatment of HER2-positive mGC/GEJC. Citation Format: Manish A. Shah, Ruihua Xu, Yung-Jue Bang, Paulo M. Hoff, Tianshu Liu, Luis A. Herraez-Baranda, Fan Xia, Amit Garg, Mona Shing, Josep Tabernero. HELOISE: phase IIIB randomized multicenter study comparing two trastuzumab (H) dose regimens combined with chemotherapy (CT) as first-line (1L) therapy in patients (pts) with HER2-positive metastatic gastric/gastroesophageal junction adenocarcinoma (mGC/GEJC). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT108.