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Toripalimab active in urothelial carcinoma, predictive biomarkers emerge

Bladder Cancer

Bladder Cancer

The PD-1 inhibitor toripalimab showed promising clinical activity with tumor mutational burden (TMB) emerging as a predictive biomarker in Chinese patients with urothelial carcinoma, according to 2-year data from the phase 2 POLARIS-03 trial.1

In the intent-to-treat (ITT) population, there were 3 complete responses, 37 partial responses, and 28 patients had stable disease. These results translated to an objective response rate (ORR) of 26.5% and a disease control rate of 45% as determined by an independent review committee. The median duration of response was 25.8 months. The median overall survival (OS) in the ITT population was 14.6 months.

The study defined high TMB as ≥10 mutations per million base pairs (Mb). High TMB patients had a better ORR than low TMB patients at 48% vs 22%, respectively (P = .014).

Based on previously reported data from POLARIS-03, toripalimab was approved in China in April 2021 for the treatment of patients with locally advanced or metastatic urothelial carcinoma who failed platinum-containing chemotherapy or progressed within 12 months of receiving neoadjuvant or adjuvant platinum-containing chemotherapy.2

“Toripalimab has demonstrated a manageable safety profile and encouraging clinical activity in metastatic urothelial carcinoma, patients refractory to first-line chemotherapy. Whole exome sequencing analysis identified divergent mutations in the study. We report the utility of TMB to predict not only the response rate but also the progression-free survival (PFS) and OS benefits in patients with metastatic urothelial carcinoma in response to immune checkpoint inhibitor monotherapy,” the authors wrote in their poster conclusion.

POLARIS-03 (NCT03113266) investigators enrolled 151 patients with metastatic urothelial carcinoma at 15 clinical sites from May 2017 to September 2019. Patients were treated with 3 mg/kg of toripalimab every 2 weeks until disease progression, unacceptable toxicity, or voluntary patient withdrawal. An independent review committee assessed clinical response by RECIST v1.1 criteria every 8 weeks. The investigators also evaluated TMB, tumor PD-L1 expression, and other biomarkers as potential predictors of response.

The investigators performed whole exome sequencing on tumor biopsies and paired PBMCs. Results from this process were available for 135 patients. The median TMB among these patientswas 4.1 mutations/Mb. Using 10 mutations/Mb as the cutoff, there were 27 TMB-high patients and 108 TMB-low patients.

As mentioned, ORR was higher in the TMB-high group. The TMB-high group also had better PFS vs the TMB-low group at a median of 12.9 vs 1.8 months, respectively (HR, 0.48; 95% CI, 0.31-0.74; P <.001), as well as better OS at a median of not reached vs 10 months, respectively (HR, 0.53; 95% CI, 0.32-0.88; P = .013). Also of note, the ORR in the PD-L1–positive population (n = 48) was 41.7%.

Genetic mutations also demonstrated predictive value. Response to toripalimab was observed to be better in patients with mutations in chromatin remodelers SMARCA4/PBRM1 or tumor suppressor RB1, according to the investigators. In patients with FGFR2/FGFR3 mutations or FGFR2/FGFR3 gene fusions, the ORR was 30% (6 of 20 patients), and among patients with NECTIN4 genomic alternations, the ORR was 42% (5 of 12 patients).

Regarding toxicity, there were no new safety signals compared with the prior 1-year analysis of the trial.3 At that point, it was reported that among the 151-patient ITT population, 85% of patients experienced a treatment-related adverse event (TRAE) of any grade and 20% experienced a TRAE of grade 3 or higher.

Toripalimab also has approved indications in China for melanoma and nasopharyngeal carcinoma. The PD-1 inhibitor does not have any approved indications in the United States.


1. Chen H, Sheng X, Hu B, et al. 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. J Clin Oncol 40, 2022 (suppl 16; abstr 4566). doi: 10.1200/JCO.2022.40.16_suppl.4566

2. NMPA Approves Toripalimab in Patients with Locally Advanced or Metastatic Urothelial Carcinoma. Published online April 12, 2021. Accessed June 4, 2022. https://bit.ly/3GNE84W

3. Sheng X, Chen H, Hu B, et al. Safety, Efficacy, and Biomarker Analysis of Toripalimab in Patients with Previously Treated Advanced Urothelial Carcinoma: Results from a Multicenter Phase II Trial POLARIS-03. Clin Cancer Res. 2022;28(3):489-497. doi: 10.1158/1078-0432.CCR-21-2210

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