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

[BACKGROUND] 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).

[PATIENTS AND METHODS] 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.

[RESULTS] 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.

[CONCLUSION] 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.