Immunotherapy has established the new standard for first-line treatment of advanced or metastatic gastric cancer. However, current second-line options-predominantly consisting of targeted therapy plus chemotherapy or chemotherapy alone-confer only modest clinical benefit. Notably, pivotal phase III second-line trials (REGARD, RAINBOW, RAINBOW-Asia, FRUTIGA) exclusively enrolled patients who progressed on chemotherapy regimens; thus, high-quality evidence guiding second-line treatment specifically for immunotherapy-refractory patients remains scarce, representing a significant unmet medical need.
Anti-angiogenic agents have demonstrated capacity to ameliorate the hypoxic, immunosuppressive tumor microenvironment while exerting synergistic anti-tumor effects when combined with immune checkpoint inhibitors. Exploratory studies evaluating immunotherapy combined with anti-angiogenic therapy plus chemotherapy in advanced gastric cancer patients after first-line failure have yielded encouraging efficacy signals (NCT03966118, NCT04982276), with objective response rates of 30-40% and median progression-free survival approaching 6 months.
Based on this, the investigators aim to evaluate the efficacy and safety profile of fruquintinib combined with nab-paclitaxel and Iparomlimab and Tuvonralimab Injection (a novel bispecific antibody) as second-line treatment for patients with advanced gastric cancer who have experienced disease progression during or after first-line immunotherapy-containing regimens.
≥ 18 years
Pathologically or cytologically confirmed diagnosis of gastric cancer (GC) or gastroesophageal junction (GEJ) cancer.
Failure of first-line treatment with PD-1/PD-L1 inhibitors
With measurable lesions according to RECIST 1.1 criteria.
History of gastrointestinal perforation and/or fistula within 6 months prior to the first dose of study medication.
Uncontrolled pleural, pericardial, or peritoneal effusions requiring repeated drainage.
Hypersensitivity to any component of monoclonal antibodies, fruquintinib, or albumin-bound paclitaxel.
Severe adverse reactions to prior immunotherapy.
Single group
Fruquintinib
Drug3 mg qd, po, q3W; After 6 cycles of combination therapy, maintenance treatment consisting of Iparomlimab and Tuvonralimab Injection plus Fruquintinib will continue until disease progression, intolerable toxicity, initiation of new antitumor therapy, withdrawal of informed consent, or investigator's determination that the subject should discontinue from study treatment.
Iparomlimab and Tuvonralimab
Drug5.0 mg/kg, Day 1, q3W, iv. After 6 cycles of combination therapy, maintenance treatment consisting of Iparomlimab and Tuvonralimab Injection plus Fruquintinib will continue until disease progression, intolerable toxicity, initiation of new antitumor therapy, withdrawal of informed consent, or investigator's determination that the subject should discontinue from study treatment.
Paclitaxel (albumin-bound)
Drug250 mg/m², Day 1, q3W
Progress-free Survival(PFS)
The time from enrollment until tumor progression or death from any cause, whichever occurred first
Objective response rate (ORR)
The proportion of patients with a confirmed complete response or partial response
Disease control rate (DCR)
The proportion of patients with a best overall response of confirmed complete or partial response, or stable disease
Overall Survival (OS)
The time from randomization to death from any reason
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Dai, Guanghai
Lead sponsor
Chinese PLA General Hospital
Sponsor institution
