817 Background: Toripalimab, a PD-1 inhibitor, is approved in China as second-line therapy for metastatic urothelial carcinoma (mUC). This subgroup analysis evaluated its efficacy and safety in previously treated patients with metastatic upper tract urothelial carcinoma (mUTUC). 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, respectively. Results: Between June 2017 and September 2019, 71 patients were enrolled. As of June 16, 2025, with a median follow-up of 70.5 months, the IRC-assessed objective response rate (ORR) was 26.8% (95% CI, 16.9–38.6), and the disease control rate 46.5%. Median duration of response was 45.0 months; median progression-free survival (PFS) 1.9 months (95% CI, 1.8–4.4) and median overall survival (OS) 11.2 months (95% CI, 7.7–31.2). PD-L1–positive tumors (n = 23) showed higher ORR (34.8% vs 20.5%), longer PFS (2.3 vs 1.8 mo; HR 0.71, 95% CI 0.40–1.28) and similar OS (11.1 vs 11.2 mo; HR 0.99, 95% CI 0.55–1.78). Among 63 patients with WES data, TMB-high tumors (≥10 mut/Mb; n = 14) achieved ORR 42.9% vs 22.4% in TMB-low, median PFS 5.3 vs 1.8 mo (HR 0.51, 95% CI 0.24–1.08; P = 0.079) and median OS 55.3 vs 11.1 mo (HR 0.49, 95% CI 0.22–1.09; P = 0.079). Frequent alterations included TP53 , KMT2D , TERT , CDKN2A/B , and FGFR3 ; responses were notable in SMARCA4 -mutated (75%) and NECTIN4 -amplified (50%) tumors. Treatment-related adverse events occurred in 95.8% of patients, grade ≥3 in 36.6%, with no treatment-related deaths. Conclusions: Toripalimab demonstrated durable efficacy and manageable safety in previously treated mUTUC. TMB-high status and limited metastatic burden were associated with better outcomes, supporting the potential of biomarker-guided immunotherapy in this rare population. Efficacy outcomes by PD-L1 and TMB subgroups in patients with mUTUC. Subgroup ORR (%) mPFS (mo) mOS (mo) Overall (n=71) 26.8 1.9 11.2 PD-L1–positive (n=23) 34.8 2.3 11.1 PD-L1–negative (n=44) 20.5 1.8 11.2 TMB-high (≥10 mut/Mb, n=14) 42.9 5.3 (HR 0.51; P = 0.079) 55.3 (HR 0.49; P = 0.079) TMB-low (<10 mut/Mb, n=49) 22.4 1.8 11.1 PD-L1, programmed death-ligand 1; ORR, objective response rate; PFS, progression-free survival; OS, overall survival; TMB, tumor mutational burden; HR, hazard ratio. Data cutoff: June 16, 2025.
Wei et al. (Sun,) studied this question.
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