Toripalimab Produces Promising Clinical Activity in Metastatic Urothelial Cancer

The recombinant humanized anti–PD-1 monoclonal antibody toripalimab elicited an encouraging objective response rate (ORR) with an acceptable toxicity profile in patients with metastatic urothelial cancer who were refractory to frontline chemotherapy, according to data from a 2-year survival update of the phase 2 POLARIS-03 trial (NCT03113266).¹

Data, which were presented during the 2022 Genitourinary Cancers Symposium, showed that the agent elicited an ORR of 26.5% (95% CI, 19.7%-34.3%) in the intent-to-treat (ITT) population (n = 151). Of those who responded, 3 patients achieved complete responses, 37 experienced partial responses, and 28 had stable disease. The median duration of response (DOR) was 25.8 months (95% CI, 13.9-43.5), and the median time to response was 1.8 months (95% CI, 1.7-1.8).

The disease control rate with toripalimab was 45.0% (95% CI, 36.9%-53.3%) per independent review committee (IRC) and RECIST v1.1 criteria. Moreover, the median progression-free survival (PFS) was 2.3 months (95% CI, 1.8-3.6) and the median overall survival (OS) was 14.6 months (95% CI, 9.3-23.3).

“No new safety signal was observed in this 2-year follow-up,” lead study author Xinan Sheng, MD, of Peking University Cancer Hospital and Institute, and colleagues, wrote.

In China, those with advanced urothelial carcinoma who experienced progressive disease following standard chemotherapy have limited therapeutic options available to them. In April 2021, toripalimab was approved for use in the second-line treatment of Chinese patients with locally advanced or metastatic urothelial carcinoma.²

The multicenter, open-label, phase 2 trial enrolled patients with advanced urothelial carcinoma who experienced failure with previous systemic therapy. To be eligible for enrollment, patients needed to have an ECOG performance status of 0 or 1 and could not have previously received PD-1 or PD-L1 monoclonal antibody treatment.

Study participants received toripalimab at 3 mg/kg every 2 weeks until they experienced progressive disease, intolerable toxicity, or they voluntarily withdrew.

The primary end point of the trial was ORR by IRC, and secondary end points included safety, DOR, DCR, PFS, and OS. Exploratory end points included biomarker analyses on PD-L1 expression and tumor mutational burden (TMB).

A total of 204 patients were screened between May 2017 and September 2019; 151 patients were enrolled to a total of 15 centers.

Previously, at a data cutoff date of January 6, 2020, the agent had elicited an ORR of 25.2% (95% CI, 18.5%-32.9%) in the ITT population. At this time point, the DCR was 45.0% (95% CI, 36.9%-53.3%) per IRC and RECIST v1.1 criteria.3 The median time to response was 1.8 months, and the median DOR was not yet reached (95% CI, 14.9–not evaluable [NE]). The median PFS was 2.3 months (95% CI, 1.8-3.6), and the median OS was 20.8 months (95% CI, 10.0-NE).

The data presented at the meeting had a data cutoff date of September 8, 2021, 24 months after the last study participant had been enrolled to the trial.

When investigators utilized 10 mutations/Mb as the cutoff, those with TMB-high disease (n = 27) experienced a better ORR than those with TMB-low disease (n = 108), at 48% and 22%, respectively (P = .014). Moreover, the median PFS was better in those with TMB-high disease vs those with TMB-low disease, at 12.9 months vs 1.8 months, respectively (HR, 0.48; 95% CI, 0.31-0.74; P < .001); this was also true with regard to OS in that it was not reached in the TMB-high group vs 10.0 months in the TMB-low group (HR, 0.53; 95% CI, 0.32-0.88; P = .013).

Investigators performed whole exome sequencing on tumor biopsies and paired peripheral blood mononuclear cells. Data were available from 135 patients. The subset of patients with mutations in chromatin remodelers SMARCA4/PBRM1 or tumor suppressor RB1 were linked with more favorable responses to toripalimab vs those with wild-type genes.

In the 20 patients with FGFR2/FGFR3 mutations or FGFR2/FGFR3 gene fusions experienced an ORR of 30%. In 12 patients with NECTIN4 genomic alterations, the ORR achieved with toripalimab was 42%. Similar clinical responses with the agent were observed in those with upper tract urothelial cancer and those with lower tract disease.

Previously, treatment-related adverse effects (TRAEs) were experienced by 92.1% of patients, with 38.4% of patients reporting a grade 3 or higher effect.³ Treatment-related serious AEs were reported in 19.2% of patients.

The most common grade 3 or higher TRAEs included anemia (7.3%), urinary tract infection (3.3%), hyperglycemia (2.6%), creatinine phosphokinase increased (1.3%), red blood cells urine positive (1.3%), aspartate aminotransferase increased (1.3%), triglycerides increased (0.7%), urinary protein positive (0.7%), leukopenia (0.7%), blood cholesterol increased (0.7%), rash (0.7%), alanine aminotransferase increased (0.7%), and blood creatinine increased (0.7%).

Notably, 4.0% of patients experienced a TRAE that required discontinuation of toripalimab, and 18.5% required dose delays due to a TRAE. Immune-related AEs included hypothyroidism (8.6%), hyperthyroidism (6.6%), liver function impairment (2.6%), immune myositis (0.7%), and myocarditis (0.7%).

References

1. Sheng X, Chen H, Hu B, et al. Recombinant humanized anti-PD-1 monoclonal antibody toripalimab in patients with metastatic urothelial carcinoma (POLARIS-03 study): two-year survival update and biomarker analysis. J Clin Oncol. 2022;40(suppl 6):508. doi:10.1200/JCO.2022.40.6_suppl.508
2. NMPA approves toripalimab in patients with locally advanced or metastatic urothelial carcinoma who failed platinum-containing chemotherapy or progressed within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy. News release. Junshi Biosciences. April 12, 2021. Accessed May 13, 2022. https://bit.ly/3FJToze
3. Sheng X, Chen H, Hu B, et al. Recombinant humanized anti-PD-1 monoclonal antibody toripalimab in patients with metastatic urothelial carcinoma: results of an open-label phase II clinical study Polaris-03. J Clin Oncol. 2020;38(suppl 15):5040. doi:10.1200/JCO.2020.38.15_suppl.5040