A Prospective, Single-Arm, Multicenter Clinical Study of High-Risk Localized and Locally Advanced Renal Clear Cell Carcinoma

This is a prospective, single-arm, multicenter clinical study designed to evaluate the efficacy and safety of **QL1706** (an anti-PD-1/CTLA-4 combination antibody, also known as *Aipaluo Tuoworilimab*) combined with **lenvatinib** as neoadjuvant therapy for high-risk localized and locally advanced clear cell renal cell carcinoma (ccRCC), followed by QL1706 monotherapy as postoperative adjuvant therapy.

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**Study Population**

Patients with histologically or cytologically confirmed locally advanced or high-risk localized clear cell renal cell carcinoma who are candidates for neoadjuvant therapy and surgical resection, defined by the following staging criteria (AJCC):

• **Locally advanced (Stage III ccRCC):**
• cT3a G3-4 cN0 M0;
• cT3b-T4 G_any cN0 M0;
• cT_any cN1 G_any M0;
• **High-risk localized ccRCC:**
• cT1b G4 or with sarcomatoid features, cN0 cM0;
• cT2 G3-4, cN0 M0.

**Study Phases** The study consists of four phases: **Screening**, **Neoadjuvant Treatment**, **Postoperative Adjuvant Treatment**, and **Follow-up**.

• **Screening Period (28 days):** After signing informed consent, eligible subjects undergo screening evaluations and assessments. Those who meet all inclusion/exclusion criteria proceed to treatment.

**Neoadjuvant Treatment Period (21-day cycles)**

• From Cycle 1, on Day 1 of each cycle, subjects receive QL1706 **5 mg/kg** intravenously, Q3W, for **4 cycles**. If the infusion is interrupted, the total interruption time is permitted to be ≤8 hours (at room temperature).
• Concurrently, from Cycle 1, subjects receive oral lenvatinib **12 mg** once daily (QD) for **4 cycles** (21 days/cycle).
• Tumor response is evaluated every **2 cycles** using RECIST 1.1.
• Subjects proceed to surgical resection after completion of 4 cycles, unless a termination event occurs (clinical progression, radiographic progression confirmed by the investigator per RECIST 1.1, unacceptable toxicity, withdrawal of informed consent, or meeting criteria for treatment discontinuation).

**Adjuvant Treatment Period (21-day cycles)**

• Based on postoperative pathology results, subjects who are eligible for adjuvant immunotherapy (as assessed by the investigator and with patient consent) will receive adjuvant therapy.
• QL1706 **5 mg/kg** is administered intravenously on Day 1 of each 21-day cycle for **13-17 cycles**. Infusion interruption is allowed for a total of ≤8 hours (at room temperature).
• Imaging assessments are performed every **3 months (±7 days)** after treatment initiation until recurrence/metastasis, initiation of new anti-cancer therapy, withdrawal of consent, or death, or until a maximum of **21 cycles** of treatment (whichever occurs first). Additional imaging may be performed at any time if clinically indicated.

At the end of treatment, subjects undergo safety assessments and imaging evaluations, followed by a safety follow-up visit up to **90 days after the last dose of QL1706** or **30 days after the last dose of other study drugs** (whichever is longer). After the safety follow-up, survival follow-up is performed every **90 days (±7 days)** to collect and record survival status and subsequent anti-cancer treatments.

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**Study Endpoints**

• **Primary endpoint:** Objective response rate (ORR) assessed by the investigator per RECIST 1.1.
• **Secondary endpoints:** Pathological complete response rate (pCR rate), median disease-free survival (mDFS), 12-month and 24-month DFS rates, median overall survival (mOS), and safety profile.

**Sample Size** The study plans to enroll **54 subjects**.

Inclusion criteria

• Ability to understand and agree to comply with the study requirements and assessment schedule, and voluntarily provide written informed consent (ICF) prior to any trial-related procedures.
• Age ≥ 18 years and ≤ 75 years, male or female.
• Histologically or cytologically confirmed localized and locally advanced clear cell renal cell carcinoma.
• Locally advanced renal cell carcinoma (stage III per AJCC): cT3a G3-4 cN0 M0; cT3b-T4 Gany cN0 M0; cTany cN1 Gany cM0; or high-risk localized renal cell carcinoma: cT1b G4 or with sarcomatoid features cN0 cM0; cT2 G3-4 cN0 cM0.
• No prior treatment with any immune checkpoint inhibitor.
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1.
• Life expectancy ≥ 3 months.
• At least one measurable lesion according to RECIST v1.1.
• Planned to receive neoadjuvant therapy and surgical resection.
• Adequate major organ function within 7 days prior to treatment, meeting the following criteria: A. Hematology: absolute neutrophil count ≥ 1.5 × 10⁹/L; hemoglobin ≥ 80 g/L; platelet count ≥ 90 × 10⁹/L. B. Blood biochemistry: total bilirubin ≤ 1.5 × upper limit of normal (ULN); ALT and AST ≤ 2.5 × ULN (for subjects with liver metastases, ALT or AST ≤ 5 × ULN is permitted); serum creatinine ≤ 1.5 × ULN or creatinine clearance ≥ 50 mL/min. C. Left ventricular ejection fraction ≥ 50%. D. Activated partial thromboplastin time (APTT), international normalized ratio (INR), and prothrombin time (PT) ≤ 1.5 × ULN. E. Normal thyroid function, defined as thyroid-stimulating hormone (TSH) within the normal range. If baseline TSH is outside the normal range, subjects with total T3 (or free T3) and free T4 within the normal range are also eligible. F. Cardiac enzymes and troponin within normal limits (isolated laboratory abnormalities deemed clinically insignificant by the investigator are also allowed).
• Female subjects of childbearing potential must agree to use effective contraception (e.g., intrauterine device, contraceptive pill, or condom) during the study and for 6 months after study completion; serum pregnancy test must be negative within 72 hours prior to the first dose, and they must not be breastfeeding. Male subjects must agree to use effective contraception during the study and for 6 months after study completion.

Exclusion criteria

• Presence of symptomatic or untreated known brain metastases or other central nervous system (CNS) metastases. CNS metastases that have been completely resected and/or irradiated with documented stability or improvement are not exclusionary, provided that computed tomography (CT) shows stability for at least 4 weeks prior to screening, with no evidence of cerebral edema and no requirement for glucocorticoids or anticonvulsants
• Patients with advanced or metastatic renal cell carcinoma, or non-clear cell renal cell carcinoma
• Known hypersensitivity to the investigational product or any of its excipients; or previous allergy to Chinese hamster ovary cell products or other recombinant human or humanized antibodies.
• Prior discontinuation of immunotherapy due to severe and/or life-threatening immune-related adverse events
• Adverse events from prior anti-tumor therapy have not recovered to ≤ Grade 1 per NCI-CTCAE v5.0 at enrollment (except for alopecia or other toxicities deemed by the investigator to be tolerable and not clinically significant)
• Presence of any active autoimmune disease or history of autoimmune disease, including but not limited to: interstitial pneumonia, enteritis, hepatitis, hypophysitis, vasculitis, nephritis, hyperthyroidism, hypothyroidism (patients on hormone replacement therapy may be considered for inclusion); patients with psoriasis or childhood asthma/allergy that has completely resolved and requires no intervention in adulthood may be considered, but those requiring bronchodilators for medical intervention are excluded
• History of immunodeficiency, including positive HIV test, or other acquired or congenital immunodeficiency diseases, or history of organ transplantation or allogeneic bone marrow transplantation.
• Presence of poorly controlled cardiac symptoms or diseases, including but not limited to: heart failure ≥ NYHA class II, unstable angina, myocardial infarction within 1 year, and clinically significant supraventricular or ventricular arrhythmias that have not been clinically intervened or remain poorly controlled after intervention
• Severe infection (CTCAE > Grade 2) within 4 weeks prior to the first dose of study drug, such as severe pneumonia requiring hospitalization, bacteremia, infectious complications, etc.; active pulmonary inflammation on baseline chest imaging; signs or symptoms of infection or need for oral or intravenous antibiotic therapy within 14 days prior to the first dose of study drug (prophylactic antibiotics are allowed).
• Active pulmonary tuberculosis infection identified by history or CT, or history of active pulmonary tuberculosis infection within 1 year prior to enrollment, or history of active tuberculosis infection more than 1 year ago without adequate treatment.
• Positive HBV DNA test; hepatitis C (positive anti-HCV antibody with HCV RNA above the lower limit of quantification of the assay).
• Diagnosis of another malignancy within 5 years prior to the first dose of study drug, except for malignancies with low risk of metastasis or death, such as adequately treated basal cell carcinoma or squamous cell carcinoma of the skin, or cervical carcinoma in situ, which may be considered for enrollment.
• Known hereditary or acquired bleeding or thrombotic tendency (e.g., hemophilia, coagulation disorders, thrombocytopenia, etc.), or currently receiving thrombolytic or anticoagulant therapy.
• Clinically significant bleeding symptoms or clear bleeding tendency within 3 months prior to enrollment, such as daily hemoptysis ≥ 2.5 mL, lower gastrointestinal bleeding, esophageal-gastric varices with bleeding risk, bleeding gastric ulcer, or vasculitis, etc.
• Arterial/venous thrombotic events occurring within 6 months prior to enrollment, such as cerebrovascular accident (including transient ischemic attack, cerebral hemorrhage, cerebral infarction), deep vein thrombosis, and pulmonary embolism.
• Pregnant or breastfeeding female patients.
• According to the investigator's judgment, any other factors that may compel premature termination of the study, such as other serious concomitant diseases (including psychiatric disorders) requiring concomitant treatment, alcoholism, drug abuse, family or social factors that may affect subject safety or compliance.
• Currently participating in another clinical study, unless it is an observational (non-interventional) clinical study or follow-up of an interventional study.