Fruquintinib in combination with sintilimab and CAPEOX as first-line treatment for advanced gastric/gastroesophageal junction adenocarcinoma: A single-arm, open-label, multicenter phase Ib/II study (FUNCTION).

Abstract

e16033 Background: The combination of immune checkpoint inhibitors (ICIs) and chemotherapy has become the standard first-line (1L) treatment for advanced gastric/gastroesophageal junction adenocarcinoma (GC/GEJC), but the efficacy still needs to be improved. Fruquintinib, an oral and highly selective VEGFR 1/2/3 inhibitor, has shown a synergistic antitumour effect when paired with ICIs/chemotherapy. This study was aimed to evaluate the efficacy and safety of fruquintinib combined with CAPEOX and sintilimab as a 1L therapy in GC/GEJC. Methods: In this phase Ib/II trial, patients (pts) aged 18-75 years without prior exposure to anti-cancer treatment were enrolled. The Ib phase employed a 3+3 dose escalation design, pts were treated with fruquintinib 3mg/d, po, d1-14 (dose level; DL1), 4mg/d (DL2), or 5mg/d (DL3) in combination with fixed dose of sintilimab (200mg, iv, d1), oxaliplatin (130 mg/m 2 , iv, d1) and capecitabine (800 mg/m 2 , bid, po, d1-14) every 3 weeks. After up to 6–8 cycles, fruquintinib in combination with sintilimab would be administered as maintenance therapy. The primary objective of phase Ib was to determine the DLT in first treatment cycle defining the MTD and PR2D. Additional 61 pts were enrolled in the phase II dose expansion stage using RP2D. Primary endpoint of phase II was ORR per RECIST 1.1. Secondary endpoints included DCR, PFS, OS, DOR, surgical conversion rate, safety and identification of molecular biomarkers for efficacy. Results: At data cut-off (December 25, 2025), 24 pts (8 in phase Ib; 16 in phase II) had been enrolled. The pts were characterized with a median age of 59 years (range, 51-67), 45.8% GEJC, 75% lymph node metastasis, and 41.7% liver metastases. 20 pts had PD-L1 CPS available and 70% (14/20) were CPS ≥1, 30% (6/20) were CPS≥5. Two consecutive DLTs were observed at DL3, so DL2 was identified as MTD. Fruquintinib 4mg/d was defined as the RP2D. Of the 22 pts evaluable for tumor response, 18 pts achieved PR, 4 pts achieved SD. The confirmed ORR was 81.8%, the DCR was 100%. After a median follow-up of 17.74 months, the median PFS was 9.0 months (95% CI: 4.40–NA) and OS was not mature yet. Conversion surgery had been conducted in 4 pts after multidisciplinary team evaluation, with one case of pathological CR. The R0 resection rate was 100% (4/4) and R0 surgical conversion rate was 18.2% (4/22). Most TRAEs were grade 1-2 and grade 3/4 TRAEs occurred in 41.7% of pts, with platelet count decreased (12.5%) ranking the most frequent. There were no treatment related deaths in the trial. Conclusions: Fruquintinib plus sintilimab and CAPEOX showed encouraging clinical outcomes and manageable safety for untreated advanced GC/GEJC. The trial is still recruiting, more data including the subgroup analysis and potential predictive response biomarkers would be further analyzed and reported. Clinical trial information: NCT06329973 .