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.

461 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. Early clinical studies investigating the combination of immunotherapy with anti-angiogenic drugs have demonstrated favorable efficacy. Therefore, it is worth exploring whether the addition of fruquintinib, a potent VEGFR-1,2,3 inhibitor, to the combination of PD-1 inhibitor and chemotherapy can further enhance the survival benefits for patients with unresectable locally advanced or metastatic HER2-negative GC. Methods: This is an open-label, single-center clinical study. The enrolled patients were all no less than 18 years old with HER2 negative locally advanced unresectable or metastatic gastric or gastrooesophageal junction adenocarcinoma, without any systemic anticancer treatment for advanced disease. Eligible patients received 6 cycles of combined first line treatment with fuquinitinib (4mg daily, d1-14, q3w, oral) combined with PD-1 inhibitor (sintilimab 200mg or nivolumab 360mg intravenously q3w) and chemotherapy (XELOX or SOX) regimen. The following maintenance treatment was fuquinitinib combined with PD-1 inhibitor and S-1/capecitabine until disease progression or intolerable toxicity. The primary endpoint was progress free survival (PFS). Secondary endpoints included objective response rate (ORR), overall survival (OS), duration of response (DoR), disease control rate (DCR) and safety. Results: At the cutoff date on Sep 18, 2024, a total of 27 patients were enrolled and received at least one dose of treatment. 23 patients had received the response evaluation, with an ORR of 60.9% (14/23; 95%CI 38.5-80.3) and DCR of 100% (23/23 95%CI 85.2-100.0). In the intention to treatment (ITT) population, the median PFS was 9.79 months (95% CI 5.29-NA). Safety profile indicated that 22.2% (6/27) experienced grade≥3 adverse events. The most common grade ≥ 3 adverse reactions mainly include neutropenia (7.4%, 2/27) and thrombocytopenia (7.4%%, 2/27). 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. Enrollment in the trials is still ongoing. Clinical trial information: NCT06158919 .