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

This single-center, nonrandomized, two-cohort Phase II study will evaluate neoadjuvant toripalimab and lenvatinib with or without stereotactic body radiotherapy (SBRT) in patients with resectable, nonmetastatic locally advanced non-clear cell renal cell carcinoma. Approximately 36 participants will be enrolled. Both cohorts will receive six 21-day cycles of toripalimab and lenvatinib; one cohort will also receive SBRT to the primary renal tumor. Surgery is planned after neoadjuvant treatment. The primary outcome is the percentage of necrotic tumor cells in the resected tumor specimen.

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.