Background: The KEYNOTE-061 trial showed that anti-PD-1 monotherapy did not improve overall survival compared to chemotherapy in the second-line treatment of advanced GC/GEJC. Preclinical and clinical data have demonstrated the synergistic anti-tumor effect of fruquintinib, a highly selective oral VEGFR 1/2/3 inhibitor, in combination with immune checkpoint inhibitors (ICIs). Additionally, the phase III study (NCT03223376) of fruquintinib combined with paclitaxel in second-line GC/GEJC has yielded positive topline results. This study aims to assess the safety and efficacy of fruquintinib combined with sintilimab (an anti-PD-1 antibody) as a second-line therapy for GC/GEJC. Methods: In this phase II, open-label trial (NCT05625737), patients (pts) aged 18-75 years who were HER2-negative and had failed first-line standard therapy were enrolled. Eligible pts received fruquintinib at 4mg/day orally on days 1-14 and sintilimab at 200 mg intravenously on day 1, with treatment repeated every 3 weeks. The primary endpoint was objective response rate (ORR) per RECIST v1.1. Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. An optimal Simon two-stage design was employed: if more than 1 pt achieved objective responses in the first stage (n = 7), the study would proceed to the second stage and enroll an additional 19 pts; otherwise, the study would be terminated. Results: At data cut-off (August 31, 2023), 7 pts were enrolled in the first stage and additional 7 pts in the second stage. Pts characteristics included: median age 50 (range 33–71); 29% male; 57% with ECOG PS 1; 57% with peritoneal metastasis, and 71% having previously received immunotherapy. Of the 12 pts evaluable for tumor response, 4 achieved partial responses, and 4 had stable disease, resulting in a confirmed ORR of 33.3% (95% CI: 9.9-65.1%) and a DCR of 66.7% (95% CI: 34.9-90.0%). The median PFS was 5.09 months (95% CI: 2.69–NA), while OS results were pending maturity. Grade 1-2 treatment-emergent adverse events (TEAEs) occurred in ≥20% of pts, including decreased white blood cell count (36%), hypertriglyceridemia (29%), abdominal pain (29%), decreased lymphocyte count (21%), and elevated aspartate transaminase and alanine transaminase (21%). Grade 3/4 TEAEs occurred in only one patient, consisting of increased blood bilirubin levels, aspartate transaminase elevation, and alanine transaminase elevation. No treatment-related deaths were reported. Conclusions: The combination of fruquintinib and sintilimab as a second-line therapy has demonstrated promising anti-tumor activity and an acceptable safety profile in pts with advanced GC/GEJC. The trial is ongoing, and further data analysis and reporting are anticipated. Clinical trial information: NCT05625737.