Editor's Note: In recent years, the emergence and breakthrough progress of multiple targeted and immunotherapy drugs, along with their combination regimens, have brought significant transformation to the systemic treatment of esophageal and gastric cancer. The field has evolved from monotherapy with targeted or immune agents to an era of dual or multi-immunotherapy combinations.

At the 2025 American Society of Clinical Oncology Gastrointestinal Cancers Symposium (ASCO GI 2025) held on January 23, the results of a Phase Ib/II study evaluating fruquintinib in combination with the SOX regimen and toripalimab in patients with advanced metastatic gastric or gastroesophageal junction adenocarcinoma (GC/GEJC) drew widespread attention (Abstract #423). Oncology Frontier has compiled an in-depth analysis of this study and is honored to have Dr. Xiangrui Meng from The First Affiliated Hospital of Zhengzhou University provide expert insights and commentary. The following is a summary of the discussion.

Study title

Updated Results from the Phase Ib/II Study of Fruquintinib in Combination with SOX and Toripalimab for the Treatment of Advanced Metastatic Gastric or Gastroesophageal Junction Adenocarcinoma (GC/GEJC)

Dr. Xiangrui Meng：PD-L1 expression is widely recognized as a predictive biomarker for the efficacy of immunotherapy in advanced gastric cancer, as recommended by treatment guidelines. However, multiple subgroup analyses and meta-analyses have shown that PD-L1 low-expression populations, including those with CPS <1, <5, or <10, do not significantly benefit from immunotherapy.

In September 2024, the U.S. Food and Drug Administration (FDA) Oncology Drug Advisory Committee (ODAC) voted 10 to 2 against the use of PD-1 inhibitors as first-line therapy for PD-L1-negative (CPS <1), HER2-negative, microsatellite-stable gastric and gastroesophageal junction adenocarcinoma. This decision may have significant implications for clinical practice guidelines.

For patients with CPS <5, which accounts for approximately 39 to 50 percent of cases, and especially CPS <1, which accounts for 17 to 22 percent, overcoming immune resistance remains a major challenge. Tumor immunotherapy resistance is closely linked to the immunosuppressive tumor microenvironment. Preclinical and clinical studies have demonstrated that VEGF-targeted tyrosine kinase inhibitors, such as apatinib, anlotinib, and lenvatinib, can effectively inhibit tumor angiogenesis, normalize tumor vasculature, and reprogram the tumor immune microenvironment from a cold tumor to a hot tumor, thereby enhancing the effectiveness of immunotherapy.

This study incorporated fruquintinib, a VEGF-TKI, into a standard regimen of a PD-1 inhibitor and chemotherapy, leading to superior ORR and prolonged PFS in patients with CPS <5 and CPS <1. These findings suggest that fruquintinib may help overcome immune resistance, making the VEGF-TKI plus PD-1 inhibitor plus chemotherapy regimen a promising treatment option for PD-L1-negative or low-expression gastric cancer patients.

Dr. Xiangrui Meng

  • Department of Oncology, The First Affiliated Hospital of Zhengzhou University
  • MD, Associate Chief Physician
  • Vice Chair, Youth Committee, Henan Anti-Cancer Association’s Clinical Research on Anti-Tumor Drugs Committee
  • Standing Member, Esophageal Cancer Committee, Henan Anti-Cancer Association
  • Standing Member, Soft Tissue Sarcoma Committee, Henan Anti-Cancer Association
  • Member, Esophageal Cancer Committee, Beijing Cancer Prevention and Treatment Association
  • Member, Henan Anti-Cancer Association’s Clinical Research on Anti-Tumor Drugs Committee
  • Member, Henan Geriatric Oncology Society
  • Member, Henan Chemotherapy Committee
  • Member, Henan Neuroendocrine Tumor Committee
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