Background: The phase 3, randomized, double-blind, placebo-controlled study (TAGS) evaluated the efficacy and safety of FTD/TPI (35 mg/m² given orally twice a day on days 1–5 and 8–12 of a 28-day cycle) in mGC patients who had previously received≥2 prior regimens for advanced disease and demonstrated a clinically relevant and statistically significant benefit in OS and PFS with a predictable and manageable safety profile. HRQoL data and association between QoL and time to ECOG status deterioration (2 or more) are reported here. Methods: HRQoL was evaluated using EORTC QLQ-C30 and the gastric-specific module (QLQ-STO22) questionnaires at baseline and at every 4 weeks thereafter until treatment discontinuation. Prespecified key HRQoL were changes from baseline and time to deterioration. Changes ≥10 points were deemed clinically relevant. A time-dependent Cox-regression analysis was performed to evaluate the association of 10-point Global Health Status deterioration with worsening ECOG status. Results: Of 507 patients randomized, 332/337 (98.5%) of FTD/TPI and 164/170 (96.5%) of placebo had baseline QoL data. Overall compliance was 84% for both questionnaires. Demographic and disease were generally balanced between the two groups; QoL scores were also similar between groups. HRQoL was largely maintained during treatment in both arms for most items; mean changes from baseline remained under the 10-point threshold. Clinically relevant changes from baseline were observed only for pain relief at cycle 2 (favouring FTD/TPI); and improved role functioning at cycle 3 (favouring placebo). In a sensitivity analysis including death or progression as an event, FTD/TPI was associated with a positive trend suggesting a reduced risk of QoL deterioration across all scales compared to placebo (HRs ranged from 0.57 to 0.74. A 10-point Global Health Status deterioration was associated with a worsening ECOG status (HR, 95% CI, 1.5, 1.2 to 1.86). Conclusions: During the treatment period, HRQoL remained stable for most functional and symptom scales in both arms, suggesting that HRQoL is largely maintained with FTD/TPI. Treatment with FTD/TPI was associated with a positive trend toward a lower risk of QoL deterioration than placebo across all scales. Changes in QoL were informative for patients ‘expected ECOG status. Clinical trial information: NCT02500043