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

A Single-Center, Two-Cohort Phase II Study of Neoadjuvant Toripalimab and Lenvatinib With or Without Stereotactic Body Radiotherapy in Nonmetastatic Locally Advanced Non-Clear Cell Renal Cell Carcinoma

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Nonmetastatic Locally Advanced Non-Clear Cell Renal Cell Carcinoma
• Intervention / Treatment: Drug: Toripalimab; Drug: Lenvatinib; Radiation: Stereotactic Body Radiotherapy

Detailed Description

Eligible participants with histologically confirmed, resectable, nonmetastatic locally advanced non-clear cell renal cell carcinoma will be enrolled into two nonrandomized cohorts. Cohort A will receive toripalimab 240 mg intravenously on day 1 of each 21-day cycle plus lenvatinib 12 mg orally once daily for six cycles. Cohort B will receive the same systemic treatment plus SBRT to the primary renal tumor at a total dose of 40 Gy in five fractions, delivered after completion of cycle 2 and before cycle 4. Tumor response will be assessed by imaging during and at the end of neoadjuvant treatment. Surgery will follow neoadjuvant treatment; the operating physician will determine the surgical approach based on imaging. Resected tumor specimens will be assessed for tumor cell necrosis and pathological response. Participants will be followed for recurrence, survival, and adverse events.

• Study Type: Interventional
• Enrollment (Estimated): 36
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Yulu Peng; Phone Number: 02087342318; Email: pengyl1@sysucc.org.cn

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Toripalimab Plus Lenvatinib; Toripalimab 240 mg intravenously every 3 weeks plus lenvatinib 12 mg orally once daily for six 21-day cycles, followed by surgery.	Drug: Toripalimab; Toripalimab 240 mg by intravenous infusion on day 1 of each 21-day cycle for six cycles.; Drug: Lenvatinib; Lenvatinib 12 mg orally once daily during six 21-day cycles of neoadjuvant treatment.
Experimental: Toripalimab Plus Lenvatinib and SBRT; Toripalimab 240 mg intravenously every 3 weeks plus lenvatinib 12 mg orally once daily for six 21-day cycles. SBRT at 40 Gy in five fractions is delivered to the primary renal tumor after cycle 2 and before cycle 4, followed by surgery.	Drug: Toripalimab; Toripalimab 240 mg by intravenous infusion on day 1 of each 21-day cycle for six cycles.; Drug: Lenvatinib; Lenvatinib 12 mg orally once daily during six 21-day cycles of neoadjuvant treatment.; Radiation: Stereotactic Body Radiotherapy; SBRT to the primary renal tumor, 40 Gy in five fractions, after cycle 2 and before cycle 4.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Tumor Cell Necrosis Rate (TCNR)	Percentage of necrotic tumor cells in the resected tumor specimen, calculated from prespecified multisite pathological sampling.	At surgery following neoadjuvant treatment, approximately 5 to 6 months after the first dose.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
R0 Resection Rate	Percentage of enrolled participants who undergo complete tumor resection with microscopically negative margins.	At surgery following neoadjuvant treatment, approximately 5 to 6 months after the first dose.
Objective Response Rate (ORR)	Percentage of participants with investigator-assessed complete or partial response according to RECIST version 1.1.	From baseline through the final preoperative tumor assessment, approximately 18 weeks.
Disease Control Rate (DCR)	Percentage of evaluable participants with complete response, partial response, or stable disease according to RECIST version 1.1.	From baseline through the final preoperative tumor assessment, approximately 18 weeks.
Major Pathological Response (MPR) Rate	Percentage of resected participants with no more than 10% residual viable tumor in the tumor bed.	At surgery following neoadjuvant treatment, approximately 5 to 6 months after the first dose.

Collaborators and Investigators

• Sponsor: Sun Yat-sen University

Study record dates

Study Major Dates

• Study Start (Estimated): November 10, 2026
• Primary Completion (Estimated): December 31, 2029
• Study Completion (Estimated): December 31, 2030

Study Registration Dates

• First Submitted: November 2, 2026
• First Submitted That Met QC Criteria: November 2, 2026
• First Posted (Actual): November 6, 2026

Study Record Updates

• Last Update Posted (Actual): November 6, 2026
• Last Update Submitted That Met QC Criteria: November 2, 2026
• Last Verified: November 1, 2026

More Information

Terms related to this study

• Keywords: Non-clear cell renal cell carcinoma; Neoadjuvant therapy; Toripalimab; Lenvatinib; Stereotactic body radiotherapy; Nephrectomy
• Additional Relevant MeSH Terms: Investigative Techniques; Therapeutics; Surgical Procedures, Operative; Radiotherapy; Stereotaxic Techniques; Neurosurgical Procedures; toripalimab; Radiosurgery; lenvatinib
• Other Study ID Numbers: 2024-FXY-233-Urology; 2024-FXY-233-Urology (Other Identifier: Sun Yat-sen University cancer center)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

IPD Plan Description

Individual participant data will not be shared because this small study collects sensitive clinical, imaging, and molecular data that could increase the risk of participant re-identification. Study results will be reported in aggregate form.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No