Toripalimab (anti-PD-1) monotherapy as a second-line treatment for patients with metastatic urothelial carcinoma (POLARIS-03): Two-year survival update and biomarker analysis.

4566 Background: Patients with advanced metastatic urothelial carcinoma (mUC) who experience disease progression after standard therapy have limited treatment options. Toripalimab was approved for the 2nd line treatment of mUC based on a phase II clinical study (POLARIS-03) in Chinese patients with mUC (NCT03113266). Here we report the two-year efficacy update and biomarker analysis of the study. Methods: Metastatic UC Patients received toripalimab 3 mg/kg Q2W until disease progression, unacceptable toxicity or voluntary withdrawal. Clinical response was assessed every 8 weeks by independent review committee (IRC) per RECIST v1.1. Tumor PD-L1 expression, tumor mutational burden (TMB), and other biomarkers were evaluated for correlation with clinical response. Results: From May 2017 to September 2019, 151 patients were enrolled from 15 participating centers. By cutoff date of September 8, 2021, no emergent of new safety signal was identified compared with the previous one-year report. By the cutoff date, 3 CR, 37 PR and 28 SD were observed among the ITT population for an ORR of 26.5% and a DCR of 45.0% as assessed by the IRC. The response was durable as the median duration of response was 25.8 months. The median OS was 14.6 months. Whole exome sequencing (WES) was performed on tumor biopsies and paired PBMCs and the results were available from 135 patients. The median TMB value was 4.1 mutations per million base pairs (Mb) in the cohort. Using 10 mutations/Mb as the cut off, TMB-high patients (n = 27) had better ORR than TMB low patients(n = 108) (48% versus 22%, p = 0.014). The TMB-high group also showed better PFS (12.9 versus 1.8 months, HR = 0.48 [95% CI:0.31-0.74], p < 0.001) and OS (not reached versus 10.0 months, HR = 0.53 [95% CI:0.32-0.88], p = 0.013) than the TMB low group. Patients with mutations in chromatin remodelers SMARCA4/PBRM1 or tumor suppressor RB1 were associated with better responses to toripalimab than patients with wild-type genes. The ORR was 30% (6/20) in patients with FGFR2/FGFR3 mutations or FGFR2/FGFR3 gene fusions, and 42% (5/12) in patients with NECTIN4 genomic alternations. The mutational signature characterized by exposure to aristolochic acid (A:T to T:A transversion) is present in both upper tract urothelial carcinoma (UTUC) and lower tract urothelial carcinoma (LTUC), but enriched in UTUC (p = 0.003). Similar clinical responses were observed in UTUC and LTUC. Conclusions: Toripalimab has demonstrated a manageable safety profile and encouraging clinical activity in metastatic UC patients refractory to 1st line chemotherapy. WES analysis identified divergent mutations in the study. We report the utility of TMB to predict not only the response rate but also the PFS and OS benefits in patients with mUC in response to an ICI monotherapy. Clinical trial information: NCT03113266.