This is a multicenter, single-arm, phase 2 clinical trial designed to evaluate the clinical efficacy of combination therapy with zanzalintinib and pembrolizumab in patients with locally advanced intermediate- to high-risk, high-risk, or resectable metastatic clear cell renal cell carcinoma.
The neoadjuvant treatment period consists of a total of 6 cycles; pembrolizumab is administered every 3 weeks, and zanzalintinib is administered orally once daily. A drug washout period of at least 21 days is required prior to the last dose before surgery.
Surgery will be performed after completion of the neoadjuvant treatment and following a drug washout period of at least 21 days.
The adjuvant treatment period begins at least 28 days after surgery, and pembrolizumab is administered every 3 weeks for a total of 11 cycles.
Radiologic response assessments are conducted at predefined time points during the neoadjuvant period, and pathologic response is evaluated using resected tissue obtained at the time of surgery.
* Study duration: Approximately 30 months (18 months for enrollment + 12 months for treatment and follow-up) * Planned sample size: 48 patients (including an estimated 10% dropout rate) Tumor size and disease stage will be assessed using baseline imaging performed prior to treatment, and tumor response will be evaluated through predefined scheduled imaging assessments conducted during treatment. Tumor response will be evaluated during treatment via imaging at regular intervals per cycle. Surgery will be scheduled after the completion of 6 cycles, following a minimum 21-day washout period (±7 days at the investigator's discretion). If postoperative recovery is adequate (at least 28 days, ±14 days at the investigator's discretion), adjuvant Pembrolizumab treatment will commence.
Subjects with clear cell renal cell carcinoma (clear cell RCC) confirmed by pathological or cytological diagnosis.
Locally advanced disease or resectable metastatic disease.
Resectable intermediate- to high-risk or high-risk patients are eligible for enrollment.
Resectability is determined by multidisciplinary Resectability will be determined based on multidisciplinary evaluation. Resectable metastatic disease is defined as cases in which, in the presence of a primary tumor, complete resection of both the primary tumor and all identifiable metastatic lesions is deemed feasible by multidisciplinary assessment. All metastatic lesions must be amenable to complete resection within the planned surgical schedule. Subjects will be excluded from enrollment if metastatic lesions have already been completely resected prior to study entry, are deemed unresectable, or are expected to have residual disease after attempted resection.
Concurrent anticancer treatments other than the investigational therapy, including chemotherapy, curative radiotherapy, surgery, immunotherapy, biological therapy, or tumor embolization.
Radiation therapy for bone metastasis within 2 weeks, any other radiation therapy within 4 weeks before first dose of study treatment. Systemic treatment with radionuclides within 6 weeks before first dose of study treatment. Subjects with clinically relevant ongoing complications from prior radiation therapy are not eligible.
Known brain metastases or cranial epidural disease unless adequately treated with radiotherapy and/or surgery (including radiosurgery) and stable for at least 4 weeks before first dose of study treatment.
History of prior treatment with anti-PD-1, anti-PD-L1, anti-PD-L2 therapies, or vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors.
Single group
Zanzalintinib and Pembrolizumab
DrugTreatment consists of a neoadjuvant and an adjuvant phase, during which Zanzalintinib and Pembrolizumab are administered. Patients will receive a total of 6 cycles (21 days per cycle) of combination therapy as neoadjuvant treatment, followed by surgery. After srugery, patients will receive 11 additional cycles of adjuvant Pembrolizumab.
Overall Response Rate
Tumor response will be evaluated radiologically in accordance with RECIST version 1.1 and defined as the proportion of complete response (CR) or partial response (PR). As a primary endpoint, the objective response rate will be assessed every 9 weeks (±7 days) during the neoadjuvant treatment period.
safety and tolerability
Incidence of adverse events (AEs) and serious adverse events (SAEs) based on CTCAE version 5.0 criteria.
major pathologic response
Defined as 10% or less residual viable tumor in the resected specimen.
event-free survival, EFS
Time from treatment initiation to the occurrence of the first event, including relapse, progression, or death.
overall survival, OS
Time from treatment initiation to death from any cause.
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