(UroToday.com) At the 2022 American Society of Clinical Oncology Annual Meeting held in Chicago and virtually, the poster session focused on Kidney and Bladder cancers on Saturday afternoon included a presentation from Dr. Haige Chen discussing the role of toripalimab, an anti-PD-1 antibody, as monotherapy for second-line treatment of metastatic urothelial carcinoma (UC).
Advanced UC has been long recognized to have a poor long-term prognosis. While cisplatin-based chemotherapy remains the guideline recommended treatment approach for those who are eligible, recently, there has been clinical trial data supporting immune checkpoint inhibitors targeting PD-1/L1 both as maintenance therapy for those who are cisplatin-eligible and as an alternative first-line therapy for those who are ineligible. Based on data from the phase II POLARIS-03 trial (NCT03113266), toripalimab was approved as a second line treatment in metastatic UC. In this abstract, the authors provide an updated two-year efficacy analysis and further granular data with biomarker stratification.
In this phase II trial, patients with metastatic UC received toripalimab 3 mg/kg every two weeks until disease progression, unacceptable toxicity, or voluntary withdrawal. Routine assessment of clinical response was performed every 8 weeks by independent review committee (IRC) per RECIST v1.1. The authors further assessed tumor PD-L1 expression, tumor mutational burden (TMB), and other biomarkers for correlation with clinical response.
The authors enrolled 151 patients from 15 participating centers between May 2017 and September 2019. With a data cutoff of September 8, 2021, this updated follow-up demonstrated no emergent of new safety signal, compared with the previous one-year report.
Among the 151 enrolled patients, 3 patients were observed to have complete response (CR), 37 to have a partial response (PR), and 28 to have stable disease (SD) among the ITT population. Thus, the objective response rate (ORR) was 26.5% and disease control rate (DCR) was 45.0% as assessed by the IRC. Responses seen were durable as the median duration of response was 25.8 months. The median OS was 14.6 months.
The authors performed whole exome sequencing (WES) on tumor biopsies and paired PBMCs among 135 patients with available tissue. The median TMB value was 4.1 mutations per million base pairs (Mb). Using 10 mutations/Mb as a dichotomizing threshold, 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 longer 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.
Mutations in chromatin remodelers SMARCA4/PBRM1 or tumor suppressor RB1 genes were associated with better responses to toripalimab than those 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.
Notably, 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), responses to toripalimab were observed in patients with both upper tract and lower tract disease.
The authors, therefore, conclude that this extended follow-up shows that toripalimab has a manageable safety profile and encouraging clinical activity in patients with metastatic UC who progress following first-line chemotherapy.Presented by: Haige Chen, Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China