Toripalimab and Lenvatinib With or Without SBRT Before Surgery for Non-Clear Cell Kidney Cancer (TL-SBRT-nccRCC)

Inclusion Criteria:

• Voluntary written informed consent.
• Age 18 years or older.
• ECOG performance status of 0 or 1 and life expectancy of at least 6 months.
• Histologically confirmed, resectable, nonmetastatic locally advanced non-clear cell renal cell carcinoma, excluding chromophobe and collecting duct carcinoma. Eligible disease includes T3aNxM0, T3bNxM0 without level III or IV venous tumor thrombus, T4NxM0, or TxN1M0.
• At least one measurable lesion according to RECIST version 1.1.
• Adequate organ function: hemoglobin ≥80 g/L; absolute neutrophil count ≥1.5 × 10^9/L; white blood cell count ≥3.5 × 10^9/L; platelets ≥80 × 10^9/L; ALT and AST ≤2.5 × upper limit of normal (ULN); total bilirubin ≤1.5 × ULN; serum creatinine ≤1.5 × ULN or creatinine clearance ≥60 mL/min; APTT, INR, and PT ≤1.5 × ULN.
• Women of childbearing potential must be confirmed not pregnant before enrollment. All participants must use adequate contraception during treatment and for 4 weeks after treatment completion.
• Willingness and ability to comply with study procedures.

Exclusion Criteria:

• Known hypersensitivity to toripalimab, lenvatinib, or their excipients.
• Chromophobe or collecting duct renal cell carcinoma.
• Anticancer monoclonal antibody or another investigational drug within 4 weeks before enrollment; prior PD-1/PD-L1-directed treatment for metastatic disease; or prior lenvatinib or another antiangiogenic drug.
• Distant organ metastasis or inability to undergo surgery.
• Systemic immunosuppressive treatment, including prednisone >10 mg/day or equivalent, within 2 weeks before enrollment.
• Active autoimmune disease, a history of autoimmune disease, or congenital or acquired immunodeficiency.
• Poorly controlled cardiac disease, uncontrolled hypertension, or clinically significant cardiovascular events within 6 months before enrollment.
• Chemotherapy, targeted therapy, or radiotherapy within 2 weeks before enrollment.
• Gastrointestinal perforation or major surgery within 4 weeks before enrollment.
• Arterial or venous thromboembolic event within 6 months before enrollment, except resolved catheter-associated thrombosis as judged by the investigator.
• Active bleeding or a significant bleeding tendency, including clinically significant hemoptysis of more than 50 mL/day within 3 months before enrollment.
• Urine dipstick protein ≥2+ or 24-hour urine protein ≥1.0 g.
• Corrected QT interval >470 ms, subject to the protocol-specified review for pacemaker-related QT prolongation.
• Suspected additional primary malignancy.
• Interstitial lung disease, noninfectious pneumonitis, or another uncontrolled systemic disease.
• Live attenuated vaccine within 28 days before first treatment or planned live attenuated vaccination during the study.
• Active hepatitis B (HBV DNA ≥500 IU/mL), active hepatitis C (HCV RNA above the assay detection limit), or hepatitis B and C coinfection.
• Severe infection within 4 weeks before first treatment; CTCAE grade ≥2 active infection requiring systemic antibiotics within 2 weeks before first treatment; unexplained fever >38.5°C during screening or before first treatment unless attributed to the tumor by the investigator; or evidence of active tuberculosis within the preceding year.
• Prior or planned allogeneic bone marrow or solid-organ transplantation.
• Peripheral neuropathy of grade ≥2, active brain metastases, leptomeningeal disease, or spinal cord compression.
• Inability to swallow oral medication, chronic diarrhea, clinically significant intestinal obstruction, or another condition substantially affecting oral-drug absorption.
• 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 results, or make participation inappropriate in the investigator's judgment.