Biomarker-driven assessment of immunochemotherapy with or without fruquintinib as first-line treatment for advanced gastric/GEJ adenocarcinoma: Initial clinical results and subgroup analysis from the MGC-FLORA study.

Abstract

4063 Background: The MGC-FLORA study is a prospective biomarker-exploratory trial primarily designed to identify predictive biomarkers (including gut microbiota and blood-based biomarkers) for first-line immunochemotherapy in advanced gastric/gastroesophageal junction (G/GEJ) adenocarcinoma. A key exploratory question is whether adding anti-angiogenic therapy (fruquintinib) modifies the efficacy landscape and its associated biomarkers. This interim analysis compares clinical outcomes between chemotherapy plus immunotherapy (CHEM cohorts) and chemotherapy plus immunotherapy plus fruquintinib (FRUQ cohorts). The FRUQ cohort is concurrently registered as an independent phase II clinical study (NCT06158919). Methods: This analysis included patients enrolled before September 30, 2025, with follow-up until January 15, 2026. Patients with previously untreated, unresectable locally advanced or metastatic G/GEJ adenocarcinoma were enrolled into two cohorts in this non-randomized study: CHEM (PD-1 inhibitor plus XELOX/SOX) and FRUQ (PD-1 inhibitor plus XELOX/SOX plus fruquintinib 4mg QD, days 1-14). After 6 induction cycles, oxaliplatin was discontinued in both cohorts, and maintenance therapy consisted of S-1/capecitabine plus PD-1 inhibitor, with or without continued fruquintinib. Blood and stool samples were collected at baseline (C1D1), after two treatment cycles, and at progression for future biomarker analysis (gut microbiota, cfDNA/cfRNA); the present report focuses on clinical outcomes. Results: A total of 126 patients were included (CHEM: n = 83; FRUQ: n = 43), with a median follow-up of 10.97 months. In the overall population, median PFS was 8.38 months and median OS was 18.53 months. Among evaluable patients, ORR was 47.1% (16/34) in the CHEM cohort versus 76.7% (33/43) in the FRUQ cohort, indicating a higher response rate with the addition of fruquintinib. Median PFS was 8.38 months for CHEM and 10.35 months for FRUQ (HR = 0.63, 95% CI 0.37-1.08; p = 0.09). After propensity score matching for sex, age, liver metastasis status, number of target lesions, and Claudin18.2 expression (n = 29 per cohort), the PFS benefit associated with fruquintinib became more pronounced (HR = 0.45, 95% CI 0.20-1.02; p = 0.05). Conclusions: This initial analysis from the biomarker-oriented MGC-FLORA study suggests that the addition of fruquintinib to first-line immunochemotherapy may improve clinical efficacy in advanced G/GEJ adenocarcinoma. Consistent trends toward prolonged PFS were observed in both the overall and propensity score–matched populations, supporting a potential therapeutic benefit of fruquintinib. These findings warrant further validation in randomized trials and integrated biomarker analyses.