Updated results of fruquintinib combined with PD-1 inhibitors and chemotherapy in the first-line treatment of HER2-negative advanced gastric or gastroesophageal junction adenocarcinoma (FDZL-FIX): A single-arm, open-label phase 2 study.

4046 Background: For unresectable locally advanced or metastatic HER2-negative gastric cancer (GC), the combination of chemotherapy with immunotherapy, specifically PD-1 inhibitors, has emerged as a new standard of care in first-line treatment of advanced GC, but the patients’ outcomes remain poor. Fruquintinib (Fru) is a highly selective inhibitor of VEGFR1/2/3. We sought to explore the efficacy and safety of fruquintinib combined with PD-1 inhibitors and chemotherapy in the first-line treatment of HER2-negative advanced gastric or gastroesophageal junction adenocarcinoma. Here, we report the updated results. Methods: Eligible pts with HER2 negative locally advanced unresectable or metastatic gastric or gastrooesophageal junction adenocarcinoma, without any systemic anticancer treatment for advanced disease were included in the study. pts received 6 cycles of combined first line treatment with Fru (4mg p.o. qd, d1-14, q3w, ) combined with PD-1 inhibitor (investigator's choice of sintilimab 200mg or nivolumab 360mg intravenously q3w) and chemotherapy (investigator's choice of XELOX or SOX) regimen. The following maintenance treatment was Fru combined with PD-1 inhibitor and S-1/capecitabine until disease progression or intolerable toxicity. The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), overall survival (OS), disease control rate (DCR) and safety. Results: As of Jan 24, 2025, a total of 33 pts (22 male, 11 female) median age 62 (range: 35-77) were enrolled and received at least one dose of treatment. 30 patients had at least one tumor assessment post treatment, with an ORR of 80.0% (24/30; 95%CI 61.4-92.3) and DCR of 100%(30/30; 95%CI 88.4-100.0). In the intention to treatment (ITT) population, the median PFS was 9.43 months (95% CI 5.29-13.24) and the 9-month PFS rates was 57% (95%CI 40.0-83.0). The most common AEs of all grades were neutrophil count decreased (33.3%), palmar-plantar erythrodysesthesia syndrome (33.3%), and fatigue (30.3%). Conclusions: The combination of fruquintinib and chemotherapy with PD-1 blockade in the first-line treatment for unresectable locally advanced or metastatic HER2-negative GC had shown promising efficacy and acceptable safety profile. The results warrant further investigations in a large cohort. Clinical trial information: NCT06158919 .