Vorolanib Monotherapy or in Combination With Toripalimab as Adjuvant Therapy for Patients With Intermediate-high Risk of Recurrence in Renal Cell Carcinoma

The Efficacy and Safety of Vorolanib Monotherapy or in Combination With Toripalimab for Postoperative Adjuvant Treatment of Renal Cell Carcinoma Patients With Intermediate-high Risk Recurrence Factors: A Multicenter, Randomized, Double-arm, Phase II Exploratory Study

While the 5-year survival rate for localized renal cell carcinoma (RCC) approaches 80%-95%, patients with high-risk non-metastatic disease face a substantial 30%-40% risk of recurrence/metastasis within 5 years. Emerging evidence demonstrates that combining anti-angiogenic agents with immune checkpoint inhibitors significantly extends progression-free survival (PFS) in first-line advanced/metastatic RCC settings. To address the unmet need for adjuvant strategies in intermediate/high-risk localized RCC, we propose a synergistic approach leveraging targeted therapy and immunotherapy. This dual-modality regimen may delay resistance mechanisms while enhancing disease-free survival (DFS) and overall survival (OS).

Vorolanib, a next-generation vascular endothelial growth factor receptor (VEGFR)-targeted tyrosine kinase inhibitor (TKI), exhibits unique pharmacodynamic properties that warrant investigation in adjuvant paradigms. This study evaluates two experimental arms: (1) Vorolanib combined with toripalimab, a PD-1 inhibitor. (2) Vorolanib monotherapy. This study aims to evaluate the efficacy and safety of vorolanib combined with toripalimab or vorolanib monotherapy in postoperative adjuvant therapy for intermediate/high-risk non-metastatic locally advanced renal cell carcinoma (RCC), while also investigating the correlation between postoperative minimal residual disease (MRD)-positive status and recurrence risk.

Inclusion Criteria:

• Has histologically confirmed diagnosis of localized and locally advanced stage renal cell carcinoma (RCC), with moderate to high recurrence risk

• Has intermediate-high risk, high risk, or M1 no evidence of disease (NED) RCC as defined by the following pathological tumor-node-metastasis and Fuhrman grading status:

  1. Intermediate-high risk RCC: pT1b-T2, Grade 4 or sarcomatoid, N0, M0; pT3, Any Grade, N0, M0;
  2. High risk RCC: pT4, Any Grade N0, M0; pT Any stage, Any Grade, N+, M0 M1 NED RCC participants who present not only with the primary kidney tumor but also solid, isolated, soft tissue metastases that can be completely resected at one of the following: the time of nephrectomy (synchronous) or, ≤1 year from nephrectomy (metachronous)

• Have adequate tissue for PD-L1 testing 0Has an Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 0 or 1

• Expected survival ≥ 12 months;

• Participants of childbearing potential must agree to use an adequate method of contraception, starting with the first dose of study treatment through 120 days after the last dose of study treatment

• Has adequate organ function

• Be able to understand and willing to sign the informed consent form

Exclusion Criteria:

• Patients with advanced/metastatic renal cell carcinoma (RCC) or non-clear cell renal cell carcinoma (nccRCC).
• Prior exposure to any anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibodies, or other agents specifically targeting T-cell co-stimulation checkpoints, or small molecule anti-angiogenic drugs.
• Subjects who underwent major surgery or chemotherapy within 4 weeks prior to the first dose administration, or those with postoperative duration >12 weeks who received major surgery/chemotherapy within 4 weeks before first dosing.
• Subjects with hypersensitivity to study drugs.
• Active hemorrhage, ulceration, intestinal perforation, bowel obstruction, or uncontrolled hypertension (defined as BP >140/90 mmHg or unstable during screening).
• Uncontrolled adrenal insufficiency.
• Congenital/acquired immunodeficiency (e.g., HIV infection) or active hepatitis:

HBV: HBsAg+ with HBV DNA ≥2000 IU/mL (≥10⁴ copies/mL) HCV: Anti-HCV+ with viral load >ULN

• Active autoimmune diseases (including but not limited to autoimmune hepatitis, interstitial lung disease, uveitis, colitis, hepatitis, hypophysitis, vasculitis, nephritis, hyperthyroidism, hypothyroidism) or history of autoimmune diseases. Exceptions: Vitiligo or childhood asthma fully resolved without intervention in adulthood.
• Symptomatic visceral metastases with imminent life-threatening complications (e.g., uncontrolled exudation [pleural/pericardial/abdominal], lymphangitic carcinomatosis, or >30% liver involvement).
• Severe infections requiring IV antibiotics/antifungals/antivirals within 4 weeks prior to first dose, or unexplained fever >38.5°C during screening.
• History of other malignancies within 5 years.
• Systemic corticosteroids or immunosuppressants within 14 days before first study drug administration.
• Documented active tuberculosis (Mycobacterium tuberculosis).
• Concurrent use of experimental agents or standard antineoplastic therapies.
• Active infections.
• High bleeding risk.
• Comorbidities (e.g., cardiopulmonary insufficiency) precluding radical nephrectomy/partial nephrectomy under general anesthesia.
• Pregnant/lactating women.
• Other conditions affecting trial conduct or interpretation (e.g., severe psychiatric disorders).