Toripalimab in patients with previously treated advanced upper tract urothelial carcinoma: a subgroup analysis of the phase II POLARIS-03 trial.

Toripalimab, a PD-1 inhibitor, is approved in China as second-line therapy for metastatic urothelial carcinoma. This subgroup analysis evaluated its efficacy and safety in previously treated patients with metastatic upper tract urothelial carcinoma (mUTUC). In the phase II POLARIS-03 trial, patients with mUTUC received toripalimab (3 mg/kg Q2W) until progression or unacceptable toxicity. Tumor response was assessed by an independent review committee (IRC) per RECIST v1.1. PD-L1 expression and tumor mutational burden (TMB) were assessed by immunohistochemistry and whole-exome sequencing (WES), respectively. Between June 2017 and September 2019, 71 patients with mUTUC were enrolled. As of June 16, 2025, median follow-up of 70.5 months, the IRC-assessed objective response rate (ORR) was 26.8% (95% CI, 16.9-38.6), and disease control rate (DCR) was 46.5%. Median duration of response was 45.0 months; median progression-free survival (PFS) and overall survival (OS) were 1.9 months and 11.2 months, respectively. PD-L1-positive patients showed higher ORR (34.8% vs 20.5%) and longer PFS (2.3 vs 1.8 months; HR = 0.71). Among 63 patients with WES data, TMB-high patients (≥10 muts/Mb; n = 14) had higher ORR (42.9% vs 22.4%) and numerically longer PFS and OS. Frequent mutations included TP53, KMT2D, TERT, CDKN2A/B, and FGFR3. ORR reached 75.0% in SMARCA4-mutated tumors and 50.0% in NECTIN4-amplified cases. Toripalimab demonstrated promising activity and manageable safety in pretreated mUTUC. High TMB was associated with numerically improved outcomes, suggesting its potential role as an exploratory biomarker for response to PD-1 blockade in this population.