Background: Fruquintinib (F), a highly selective and potent oral inhibitor of VEGFRs 1, 2, and 3, significantly improved the OS in metastatic colorectal cancer (Li J, et al, JAMA 2018; Dasari A, et al, LANCET 2023). FRUTIGA was a randomized, double-blind, placebo (PBO)-controlled, phase 3 study evaluating the efficacy and safety of F plus paclitaxel (PTX) vs PTX alone in patients (pts) with advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma who experienced disease progression (PD) on fluoropyrimidine- or platinum-containing first-line chemotherapy. Methods: Eligible pts were randomized 1:1 to receive F (4 mg, once daily, 3 weeks on/1 week off) or matching PBO orally, plus PTX (80 mg/m², intravenously, days 1/8/15 per cycle) in 4-week cycles until PD or intolerable toxicity; treatment of PTX was allowed for up to 6 cycles. PFS and OS were dual-primary endpoints with α split and recycle. The study was considered positive when at least one endpoint met statistical significance. Results: 703 pts were randomized (F+PTX 351 vs PBO+PTX 352), and 699 pts received at least 1 dose of study drug (350 vs 349). PFS was significantly improved with F+PTX vs PBO+PTX (median PFS [mPFS] 5.55m vs 2.73m; HR = 0.569; p< 0.0001). The overall response rate was significantly higher in F+PTX group (42.5% vs 22.4%, p < 0.0001). Median OS (mOS) was 9.63m with F+PTX and 8.41m with PBO+PTX (HR = 0.956; p = 0.6064). Given an imbalance of pts receiving subsequent antitumor therapies (F+PTX 52.7% vs PBO+PTX 72.2%), post-hoc analyses were performed using cox-proportional hazards model adjusting for subsequent antitumor therapies and baseline factors. Results showed a nominal statistically significant improvement in OS with F+PTX (HR range 0.793-0.828; p range 0.0105-0.0350 with different subsequent antitumor therapy factors). Furthermore, among pts with lymph node metastases and non-diffuse G/GEJ adenocarcinoma (190 vs 208), mPFS was even more prolonged (6.08m vs 2.69m; HR = 0.454; p< 0.0001) and OS also showed a nominal statistically significant improvement (mOS 9.56m vs 7.85m; HR = 0.767; p = 0.0233). The most common TEAEs of Grade ≥ 3 were neutropenia (60.0% vs 36.4%), leukopenia (42.9% vs 23.5%), and anemia (11.7% vs 10.6%). The safety profile was consistent with F and PTX. No new safety signals were identified. Conclusions: FRUTIGA (NCT03223376) was a positive study by reaching statistical significance for one primary endpoint, PFS, and demonstrated improvement in the other primary endpoint, OS, that was not statistically significant, possibly due to the imbalance of subsequent antitumor therapies. These data support F+PTX as a potential new second-line treatment option for pts with advanced G/GEJ adenocarcinoma. Clinical trial information: NCT03223376.