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

Prior treatment

• 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.
• 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.
• 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.

Other illness

• Known hypersensitivity to either study drug, its active ingredient, or any excipient.
• Uncontrolled cardiac symptoms or disease, congenital or acquired immunodeficiency, or uncontrolled hypertension despite medication.
• Suspected additional primary malignancy.
• Interstitial lung disease, noninfectious pneumonitis, or an uncontrolled systemic illness.
• A condition that substantially impairs absorption of oral medication, such as inability to swallow, chronic diarrhea, or clinically significant bowel obstruction.

Lab values

• 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.

Other

• Chromophobe renal cell carcinoma, collecting duct carcinoma, or renal medullary carcinoma.
• Urine protein of 3+ or greater on dipstick testing, or 24-hour urine protein ≥2 g.
• Pregnancy, breastfeeding, or plans to become pregnant during the study.

• 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.