Benmelstobart Plus Anlotinib Versus Sunitinib as First-Line Treatment for Advanced Non-Clear Cell Renal Cell Carcinoma

This is a prospective, randomized, open-label, parallel-group, multicenter Phase III study evaluating the efficacy and safety of benmelstobart plus anlotinib versus sunitinib as first-line treatment for advanced non-clear cell renal cell carcinoma.

A total of 126 participants are planned, with 84 assigned to benmelstobart plus anlotinib and 42 assigned to sunitinib. Eligible participants are adults with histologically confirmed advanced non-clear cell renal cell carcinoma, an Eastern Cooperative Oncology Group performance status of 0 or 1, and at least one measurable lesion according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1). Chromophobe renal cell carcinoma, collecting duct carcinoma, and renal medullary carcinoma are excluded.

Participants in the experimental group will receive benmelstobart 1200 mg intravenously every 3 weeks plus anlotinib 12 mg orally once daily on days 1 through 14 of each 21-day cycle. Participants in the control group will receive sunitinib 50 mg orally once daily on days 1 through 28 of each 42-day cycle. Treatment interruptions, dose modifications, and discontinuation will follow the protocol.

The primary endpoint is progression-free survival. Secondary assessments include overall survival, objective response rate, disease control rate, duration of response, quality of life, and safety. Tumor response will be assessed using RECIST 1.1, with additional immune-related response assessments using iRECIST in the experimental group. Adverse events will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0.

Exploratory biomarker analyses are planned to examine associations between treatment outcomes and tumor or blood-based markers, including PD-L1 expression, tumor mutational burden, genomic alterations, and gene expression profiles.

• Benmelstobart (Drug): 1200 mg administered by intravenous infusion on day 1 of each 21-day cycle.
• Anlotinib (Drug): 12 mg administered orally once daily on days 1 through 14 of each 21-day cycle, followed by 7 days without anlotinib. Dose modifications will follow the protocol.
• Sunitinib (Drug): 50 mg administered orally once daily on days 1 through 28 of each 42-day cycle, followed by 14 days without sunitinib. Dose modifications will follow the protocol.

Primary outcomes

• Progression-Free Survival (PFS) [From randomization to disease progression or death, whichever occurs first, assessed up to 48 months.]: Time from randomization to the first documented disease progression according to RECIST 1.1 or death from any cause, whichever occurs first.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* 1\. Voluntary participation with signed informed consent and willingness to comply with study procedures.

  2\. Age 18 years or older. 3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and estimated life expectancy of at least 3 months.

  4\. Histologically confirmed advanced non-clear cell renal cell carcinoma, including papillary or unclassified renal cell carcinoma, but excluding chromophobe renal cell carcinoma, collecting duct carcinoma, and renal medullary carcinoma. Advanced disease includes stage IV, unresectable, locally recurrent, or metastatic disease. Tumors with a predominantly non-clear cell component are eligible.

  5\. At least one measurable lesion according to RECIST 1.1. 6. Adequate organ function, defined as:
* Hemoglobin >=80 g/L.
* Absolute neutrophil count >=1.5 x 10\^9/L.
* White blood cell count >=3.5 x 10\^9/L.
* Platelet count >=80 x 10\^9/L.
* Alanine aminotransferase and aspartate aminotransferase <=2.5 times the upper limit of normal (ULN), or <=5 times ULN in participants with liver or bone metastases.
* Total bilirubin <=1.5 times ULN.
* Serum creatinine <=1.5 times ULN or creatinine clearance >=60 mL/min.
* Activated partial thromboplastin time, international normalized ratio, and prothrombin time <=1.5 times ULN.

  7\. Women of childbearing potential must be confirmed not pregnant before enrollment. All participants must use adequate contraception throughout treatment and for 4 weeks after treatment ends.

Exclusion Criteria:

* 1\. Chromophobe renal cell carcinoma, collecting duct carcinoma, or renal medullary carcinoma.

  2\. Known hypersensitivity to benmelstobart, anlotinib, sunitinib, or any excipient of the study drugs.

  3\. Antitumor monoclonal antibody therapy or other investigational drug treatment within 4 weeks before enrollment; prior systemic anti-PD-1 or anti-PD-L1 treatment for metastatic disease.

  4\. Prior anlotinib, sunitinib, or other systemic antiangiogenic therapy for metastatic disease.

  5\. Use of immunosuppressive agents or systemic corticosteroids for immunosuppression at doses greater than 10 mg/day of prednisone or equivalent within 2 weeks before enrollment.

  6\. Active autoimmune disease or a history of autoimmune disease. 7. Congenital or acquired immunodeficiency. 8. Local radiotherapy within 4 weeks before enrollment. 9. Gastrointestinal perforation or major surgery within 4 weeks before enrollment. Diagnostic biopsy and placement of a peripherally inserted central catheter or infusion port are permitted.

  10\. Arterial or venous thromboembolic events within 6 months before enrollment or randomization, including cerebrovascular accident, transient ischemic attack, deep vein thrombosis, or pulmonary embolism. Prior catheter-related thrombosis associated with chemotherapy may be permitted if considered resolved by the investigator.

  11\. Active bleeding or a bleeding tendency, including clinically significant hemoptysis greater than 50 mL/day within 3 months before enrollment, gastrointestinal bleeding, bleeding gastric ulcer, positive baseline fecal occult blood, or vasculitis.

  12\. Urine protein >=2+ requires assessment of 24-hour urinary protein. Participants must meet the protocol requirements for urinary protein excretion.

  13\. Corrected QT interval >470 milliseconds. Participants whose QT prolongation is attributed to a pacemaker, without other cardiac abnormalities, require discussion with the sponsor's study physician before eligibility is determined.

  14\. Suspected additional primary cancer or an uncured malignancy within the previous 5 years, except clearly cured or curable malignancies such as basal cell or squamous cell skin cancer, cervical carcinoma in situ, breast carcinoma in situ, or localized low-risk prostate cancer. Participants with prostate cancer meeting the protocol criteria of stage <=T2b, Gleason score <=7, and prostate-specific antigen <=20 ng/mL, if measured, may participate after definitive treatment without biochemical recurrence.

  15\. Hypertension not adequately controlled with medication, defined as systolic blood pressure >=160 mmHg or diastolic blood pressure >=100 mmHg.

  16\. Myocardial infarction, severe or unstable angina, cardiac dysfunction above New York Heart Association class II, clinically significant supraventricular or ventricular arrhythmia, or symptomatic congestive heart failure within 6 months before randomization.

  17\. Interstitial lung disease, noninfectious pneumonitis, or uncontrolled systemic disease, including uncontrolled diabetes, pulmonary fibrosis, or acute pneumonia.

  18\. Live attenuated vaccination within 28 days before the first study dose or planned live attenuated vaccination during the study.

  19\. Human immunodeficiency virus infection or known acquired immunodeficiency syndrome; active hepatitis B, defined as HBV DNA >=500 IU/mL; active hepatitis C, defined as HCV RNA above the assay detection limit; or concurrent hepatitis B and hepatitis C infection.

  20\. Severe infection within 4 weeks before the first study dose, including bacteremia or severe pneumonia requiring hospitalization; an active infection of CTCAE grade >=2 requiring systemic antibiotics within 2 weeks before the first dose; or unexplained fever >38.5 degrees Celsius during screening or before the first dose, unless considered tumor-related by the investigator. Evidence of active tuberculosis within 1 year before the first dose.

  21\. Previous or planned allogeneic bone marrow transplantation or solid organ transplantation.

  22\. Peripheral neuropathy of grade >=2. 23. Active brain metastases, carcinomatous meningitis, spinal cord compression, or brain or leptomeningeal disease identified on screening imaging. Treated brain metastases may be eligible if treatment was completed at least 14 days before enrollment, symptoms are stable, and imaging confirms no intracranial hemorrhage.

  24\. Conditions significantly affecting oral drug absorption, including inability to swallow, chronic diarrhea, or clinically significant intestinal obstruction.

  25\. Pregnancy, breastfeeding, or planned pregnancy during the study. 26. Other serious physical or psychiatric illness, laboratory abnormalities, or circumstances that may increase study-related risk, interfere with study results, or make participation inappropriate in the investigator's judgment.