Case report: durable complete response to pembrolizumab plus lenvatinib in a metastatic upper tract urothelial carcinoma patient with high tumor mutational burden and an immune-active tumor microenvironment.

Immune checkpoint inhibitors (ICIs) have been approved as an emerging first-line treatment option for advanced and metastatic urothelial carcinoma whose tumors express programmed death-ligand 1 (PD-L1). However, the efficacy of immunotherapy in PD-L1-negative urothelial carcinoma patients remains unclear, and biomarkers beyond PD-L1 expression to predict response to immunotherapy need investigation. Here, we report a metastatic renal pelvis urothelial carcinoma patient with PD-L1 negative expression that responded dramatically to first-line pembrolizumab plus lenvatinib. By the recent follow-up in March 2022, the patient had a complete radiological response for 3.4 years, with no recurrence even during the 23-month drug-withdrawal period. The results of the next-generation sequencing using the tumor sample revealed a high tumor mutational burden (TMB), which may be independently driven by the pathogenic mutation in TP53 , TERT , NCOR1 , and TSC2 genes. Besides, the tumor microenvironment exhibited an immune-active signature with relatively abundant CD8+ cells and M1 tumor-associated macrophages but scarce regulatory T cells may also explain the great benefit of the combination therapy. Our case provides a direction for identifying biomarkers beyond PD-L1 expression to screen urothelial carcinoma patients who benefit from ICI as well as ICI-based therapy.