Perioperative Trial With IO/TKI for Multi-stage Clear Cell Renal Cell Carcinoma

The IO/TKI regimens which combines Immune checkpoint inhibitors (IO) with Tyrosine Kinase Inhibitors (TKI) have become the standard first-line option for advanced ccRCC. Currently, IO/TKI regimens are serving as neoadjuvant treatment in arising clinical trials for ccRCC. Although anatomical change reflected by radiological response is reported in most neoadjuvant trials, only few studies focus on evaluation for pathological response in ccRCC. The TRIPLE-PATH trial is an investigator initiated prospective, open-label phase II trial with the main objective to evaluate the clinical activity of preoperative/neoadjuvant therapy of toripalimab plus lenvatinib as mesured by pathological response of resected primary lesion in multi-stage ccRCC. Patients with ccRCC will be enrolled into 3 different cohorts based on their clinical TNM at the time of screening: localized ccRCC (cT1-2N0M0), locally advanced ccRCC (cT3-4N0M0 or cTanyN1M0), and metastatic ccRCC (cTanyNanyM1). Toripalimab (240mg Q3W) will be administered intravenously on the 1st day, and lenvatinib (20mg QD) will be administered orally once daily of each 3 weeks cycle. Patients in all cohorts will receive 4 cycles of preopertive/neoadjuvant toripalimab (240mg Q3W IV) plus lenvatinib (20mg QD PO), and a subsequent partial/radical nephrectomy 7-10 days after the last cycle. For adjuvant/postoperative treatment, patients who undergo R0 resection presented with cT1-2aN0M0G4/cT2bN0M0G3-4/cT3-4N0M0Gany/cTanyN1M0Gany will receive adjuvant doses of toripalimab (240mg Q3W IV) for 17 cycles; patients who undergo simultaneous resection of all oligometastases considered as "no evidence of disease" (M1 NED) will also receive adjuvant doses of toripalimab (240mg Q3W IV) for 17 cycles; patients who undergo R1 resection or presented with M1 disease cannot be definitely resected will receive postoperative doses of toripalimab (240mg Q3W IV) plus lenvatinib (20mg QD PO) for 17 cycles. Specific follow-up for the enrolled patients is required in the TRIPLE-PATH trial. Longitudinal CT/MRI is utilized to assess the radiological response. Tissues and body fluid samples collected from the patients will be utilized for biomarker and multi-omic analysis. The primary endpoint of the TRIPLE-PATH trial is major pathological response (MPR) in the primary lesion according to the pathological response reporting guidelines by the International Neoadjuvant Kidney Cancer Consortium (INKCC). Simon's two-stage minimax design is adopted by TRIPLE-PATH. An initial of 12 patients per cohort (36 in total) will be recruited, following an interim analysis. Recruitment to any cohort will be suspended if MPR is not observed in any patient at the interim analysis. If MPR is observed in at least 1 patient, additional 9 patients will be recruited in each cohort to at most 21 patients. Considering potential 15% dropout rate in each cohort, an anticipation of 25 patients will be recruited for each cohort (75 in total) in this study.