A Study of Toripalimab in Adjuvant Therapy After Resection of High-risk Renal Cancer

• Study Background and Rationale Renal cell carcinoma (RCC) carries a substantial risk of recurrence post-nephrectomy, particularly in patients with intermediate-high risk, high risk, or M1 no evidence of disease (NED) status following metastasectomy. The phase III KEYNOTE-564 clinical trial demonstrated that adjuvant therapy with pembrolizumab, an anti-PD-1 antibody, significantly improved disease-free survival (DFS) compared to placebo in this patient population, establishing a new therapeutic standard. Building upon this landmark finding, the present study aims to investigate the efficacy and safety of toripalimab, another anti-PD-1 monoclonal antibody, within a similar clinical context. This single-arm, phase II trial seeks to evaluate whether toripalimab can provide comparable clinical benefits, including reduced recurrence risk and improved survival outcomes, for patients with high-risk RCC following complete surgical resection, while thoroughly assessing its safety profile.
• Study Objectives

Primary Objectives:

To evaluate the efficacy of adjuvant toripalimab as measured by investigator-assessed Disease-Free Survival (DFS) and Overall Survival (OS).

Secondary Objectives:

To assess the safety and tolerability profile of adjuvant toripalimab and patient-reported outcomes (PROs) using quality of life questionnaires..

• Trial Design and Methodology This is a single-center, prospective, single-arm, Phase II clinical trial. The design leverages the positive signal observed in the KEYNOTE-564 trial to explore the potential of a similar immunotherapeutic agent, toripalimab, in a real-world setting at a major academic center. The study will enroll patients who have undergone nephrectomy and are within the 4 to 12-week postoperative window. Treatment involves intravenous administration of toripalimab at a fixed dose of 240 mg every three weeks, for a planned treatment duration of approximately one year (17 cycles), mirroring the treatment schedule found effective in the precedent trial. Treatment will continue until disease recurrence, unacceptable toxicity, or other protocol-defined discontinuation criteria are met. The single-arm design is chosen to efficiently characterize the activity and safety of toripalimab in this specific adjuvant setting, with outcomes referenced against historical controls and the results of prior pivotal studies.
• Study Procedures and Assessments

The assessment schedule is structured to closely monitor for efficacy and safety signals, consistent with the standards set by recent practice-changing trials. Key procedures include:

Screening Period (Within 4 weeks prior to treatment initiation):

• Informed consent process.
• Confirmation of diagnosis and high-risk status via central pathology review .
• Tumor imaging via CT or MRI of the chest, abdomen, and pelvis to confirm no evidence of disease post-surgery.
• Collection of archival tumor tissue from nephrectomy/metastasectomy.
• Physical examination, vital signs, ECOG performance status assessment.
• Clinical laboratory tests: hematology, serum chemistry, thyroid function, coagulation profile, urinalysis.
• Viral serology testing (HBV, HCV, HIV).
• Pregnancy test for women of childbearing potential (WOCBP).
• Baseline quality of life assessments (EORTC QLQ-C30 and FKSI-15).

Treatment Period (Each cycle is 3 weeks):

• Pre-dose assessments (Day 1 of each cycle): Vital signs, directed physical exam, assessment of adverse events (AEs) and concomitant medications.
• Toripalimab administration: IV infusion on Day 1 of each cycle.
• Laboratory tests: Hematology and serum chemistry at every cycle; urinalysis and thyroid function tests periodically as specified in the protocol.
• Tumor imaging: CT/MRI scans of chest, abdomen, and pelvis will be performed every 12 weeks (± 7 days) from the date of treatment to assess for disease recurrence.
• Quality of Life (QoL) assessments: EORTC QLQ-C30 and FKSI-15 questionnaires will be administered at predefined cycles and at the end of treatment.

Post-Treatment Follow-up Period:

• Safety Follow-up Visit: Occurs 30 days (± 7 days) after the last dose of toripalimab for ongoing AE monitoring.
• Efficacy Follow-up: After treatment discontinuation (without disease recurrence), patients will continue tumor imaging assessments every 12 weeks (Year 1-3), then every 24 weeks (Years 4+) until disease recurrence, start of new anticancer therapy, or study end.
• Survival Follow-up: Overall survival status will be assessed via telephone or clinic visit every 12 weeks (± 7 days) until death, withdrawal of consent, or the end of the study.
• Endpoints The endpoints are selected to align with the established efficacy parameters in adjuvant RCC immunotherapy trials, facilitating a meaningful evaluation of toripalimab's benefit-risk profile.

Primary Endpoint:

• Disease-Free Survival (DFS) , defined as the time from randomization to the first documented local or distant recurrence or death from any cause.
• Overall Survival (OS): Defined as the time from randomization to death from any cause.

Secondary Endpoints: Include incidence and severity of adverse events (AEs/SAEs) graded by CTCAE v5.0, and changes from baseline in PRO scores.

• Statistical Considerations The sample size is planned to be 40-100 participants. The analysis will be primarily descriptive for this single-arm study. Efficacy analyses (DFS, OS) will be performed on the Full Analysis Set (FAS) using Kaplan-Meier methodology. Safety analyses will be conducted on the Safety Set (SS). The results will be contextualized with reference to existing data from the adjuvant RCC treatment landscape, including findings from the KEYNOTE-564 trial.

• INCLUSION CRITERIA

Participants must meet ALL of the following criteria to be eligible for study enrollment:

1.1 Informed Consent Capable of giving signed informed consent； Willing to comply with all study procedures； Signed and dated written informed consent obtained prior to any study-specific procedures.

1.2 Age and Sex Age ≥18 years at time of consent； Male and female participants eligible. 1.3 Disease Characteristics Histologically confirmed renal cell carcinoma with clear cell component; Must have undergone nephrectomy with complete resection; No evidence of residual tumor confirmed by imaging;

Must meet at least ONE of the following high-risk criteria:

pT2,with Fuhrman Grade IV or sarcomatoid,N0,M0;pT3/4,N0M0 (any grade);Any T classification with N1,M0;Post nephrectomy(total/partial) plus complete resection of metastasis, M1 NED.

1.4 Brain Metastasis No suspected or confirmed active brain metastases. 1.5 Performance Status Eastern Cooperative Oncology Group (ECOG) performance status 0-1. 1.6 Organ Function (within 14 days prior to enrollment, without transfusion or growth factor support)

Hematopoietic function:

Absolute neutrophil count ≥1,500/mm³; Platelet count ≥100,000/mm³; Hemoglobin ≥9.0 g/dL (5.6 mmol/L)

Hepatic function:

Total bilirubin ≤1.5 × ULN; AST and ALT ≤1.5 × ULN

Renal function:

Serum creatinine ≤1.5 mg/dL; OR creatinine clearance ≥60 mL/min (Cockcroft-Gault formula) 1.7 Contraception Females of childbearing potential must use medically approved contraception during treatment and for 3 months after last dose; Negative serum or urine pregnancy test within 7 days prior to randomization for women of childbearing potential; Non-lactating females; Males with female partners of childbearing potential must use effective contraception during treatment and for 3 months after last dose 1.8 Compliance Voluntarily agrees to participate by signing informed consent; Willing and able to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures

• EXCLUSION CRITERIA

Participants meeting ANY of the following criteria will be excluded from study participation:

2.1 Prior Therapy Previous radiotherapy, chemotherapy, targeted therapy, long-term or high-dose hormone therapy, or any immune checkpoint inhibitor treatment.

2.2 Concurrent Malignancy History of or current concurrent malignancy (except adequately treated basal cell carcinoma of skin, carcinoma in situ of cervix, etc.).

2.3 Allergy and Prior Immunotherapy Previous treatment with other PD-1/PD-L1 inhibitors; Known hypersensitivity to macromolecular protein preparations or any PD-1 inhibitor components.

2.4 Autoimmune Disease Active autoimmune disease or history of autoimmune disease; Exceptions:Controlled type 1 diabetes, hypothyroidism requiring only hormone replacement, skin diseases not requiring systemic treatment (vitiligo, psoriasis), or childhood asthma in complete remission without intervention in adulthood.

2.5 Immunosuppressive Therapy Current use of immunosuppressants (e.g., systemic corticosteroids >10 mg/day prednisone equivalent) for immunosuppressive purposes, continued within 2 weeks prior to enrollment.

2.6 Cardiovascular Disease

Poorly controlled cardiac clinical symptoms or diseases, including:

NYHA Class II or higher heart failure; Unstable angina pectoris; Myocardial infarction within 1 year; Clinically significant arrhythmias requiring treatment 2.7 Coagulation Function Abnormal coagulation function with bleeding tendency; Current thrombolytic or anticoagulant therapy; 2.8 Gastrointestinal Disease

Current active gastrointestinal diseases including:

Esophageal varices; Active ulcers; Inflammatory bowel disease; Risk of perforation or bleeding; 2.9 Hemorrhage and Thrombosis Events History of or current severe hemorrhage, hemoptysis, or thrombotic events within 12 months.

2.10 Infection Active infection requiring systemic therapy; Unexplained fever >38.5°C during screening or before first dose; Congenital or acquired immunodeficiency, including HIV infection or active hepatitis 2.11 Other Medical Conditions History of severe pulmonary fibrosis, interstitial pneumonia, radiation pneumonia; Live vaccination within 4 weeks prior to study treatment; History of psychotropic drug abuse, alcoholism, or drug addiction 2.12 Administrative Reasons Participation in another clinical study or within 1 month after completion of previous clinical study; Any condition that, in the investigator's judgment, may lead to early study termination affecting participant safety or data quality

• WITHDRAWAL CRITERIA

Participants will be withdrawn from study treatment if ANY of the following occurs:

3.1 Participant Request Participant or legal representative requests withdrawal 3.2 Disease Progression Confirmed disease progression 3.3 Intolerable Toxicity Occurrence of intolerable toxicities 3.4 Investigator Judgment Investigator determines continued participation may harm the participant 3.5 Protocol Violations Pregnancy Loss to follow-up Major protocol violation 3.6 Treatment Delay Any cause leading to treatment delay >2 weeks.