A Phase III Randomized Controlled Trial of Serplulimab Plus Fruquintinib as Adjuvant Therapy for High-Risk Non-Clear Cell Renal Cell Carcinoma

People with non-clear cell renal cell carcinoma may remain at high risk of cancer recurrence even after surgery has removed all visible disease. This study will test whether treatment after surgery with serplulimab plus fruquintinib improves outcomes compared with observation alone. This is a multicenter, randomized, open-label Phase III study. Approximately 108 adults will be assigned in a 1:1 ratio to receive the drug combination or observation. Participants in both groups will undergo scheduled follow-up. The main measure is the proportion of participants who remain free of recurrence two years after randomization. The study will also assess recurrence-free survival over time, overall survival, safety, and exploratory biomarkers.

Inclusion Criteria: * Voluntarily provides written informed consent and is willing and able to comply with study procedures. * Is 18 to 80 years of age, inclusive. * Has an Eastern Cooperative Oncology Group performance status of 0 or 1 and a life expectancy of at least 3 months. * Has histologically confirmed high-risk non-clear cell renal cell carcinoma, including papillary, unclassified, or genetically defined non-clear cell subtypes. High-risk disease is defined according to the AJCC 8th edition as newly diagnosed T2 disease with sarcomatoid differentiation; T2 grade 4 disease; T3NxM0, T4NxM0, or TxN1M0 disease; or recurrent or metastatic renal cell carcinoma (TxNxM1) that has undergone R0 resection. * Signs informed consent no more than 12 weeks after surgery. * Has no definite evidence of tumor on physical examination and baseline imaging of the brain, chest, abdomen, and pelvis (CT or MRI), or whole-body PET-CT. * Has no definite evidence of bone metastasis on bone scan. * Has adequate organ function, defined as: * Hemoglobin ≥70 g/L; absolute neutrophil count ≥1.5 × 10\^9/L; white blood cell count ≥3.0 × 10\^9/L; and platelet count ≥80 × 10\^9/L. * ALT and AST ≤2.5 × the upper limit of normal (ULN), or ≤5 × ULN in the circumstances specified in the protocol for liver or bone metastases; total bilirubin ≤1.5 × ULN. * Serum creatinine ≤2 × ULN or creatinine clearance ≥30 mL/min. * Activated partial thromboplastin time, international normalized ratio, and prothrombin time ≤1.5 × ULN. * If of childbearing potential, has a confirmed nonpregnant status before enrollment. All participants agree to use adequate contraception during treatment and for 6 months after treatment ends. Exclusion Criteria: * Chromophobe renal cell carcinoma, collecting duct carcinoma, or renal medullary carcinoma. * Known hypersensitivity to either study drug, its active ingredient, or any excipient. * Prior treatment with an antitumor monoclonal antibody or another investigational drug, including prior anti-PD-1 or anti-PD-L1 therapy. * Inability to start study treatment within 12 weeks after surgery. * Prior treatment with fruquintinib or another antiangiogenic drug. * Use of immunosuppressive medication or systemic corticosteroids at a dose greater than 10 mg/day prednisone equivalent within 2 weeks before enrollment. * Current or previous active autoimmune disease, except for the conditions expressly permitted by the protocol, including certain conditions requiring no systemic treatment during the preceding 2 years and stable endocrine conditions controlled with replacement therapy. * Uncontrolled cardiac symptoms or disease, congenital or acquired immunodeficiency, or uncontrolled hypertension despite medication. * Prior use of traditional Chinese medicine with an established anticancer indication before enrollment. * Gastrointestinal perforation within 4 weeks before enrollment; a serious arterial or venous thrombotic event within 6 months before enrollment; or active bleeding or a bleeding tendency. * Urine protein of 3+ or greater on dipstick testing, or 24-hour urine protein ≥2 g. * Suspected additional primary malignancy. * Interstitial lung disease, noninfectious pneumonitis, or an uncontrolled systemic illness. * Receipt of a live attenuated vaccine within 28 days before the first study-drug dose, or anticipated need for one during the study. * HIV infection or known AIDS; active hepatitis B (HBV DNA ≥500 IU/mL); active hepatitis C (detectable HCV RNA); or concurrent hepatitis B and C infection. * Severe infection within 4 weeks before the first study-drug dose; grade ≥2 active infection requiring systemic antibiotics within 2 weeks before the first dose; unexplained fever \>38.5°C during screening or before the first dose, unless judged by the investigator to be tumor-related; or evidence of active tuberculosis within the preceding year. * Major surgery within 28 days before randomization, except for the procedures expressly permitted by the protocol. * Prior or planned allogeneic bone marrow or solid-organ transplantation. * Grade ≥2 peripheral neuropathy; active brain or meningeal metastases, carcinomatous meningitis, or spinal cord compression. The protocol permits previously treated brain metastases under specified stability and imaging conditions. * A condition that substantially impairs absorption of oral medication, such as inability to swallow, chronic diarrhea, or clinically significant bowel obstruction. * Pregnancy, breastfeeding, or plans to become pregnant during the study. * Any other serious physical or psychiatric illness or laboratory abnormality that may increase study risk, interfere with interpretation of results, or make participation unsuitable in the investigator's judgment.