Efficacy of Immune Checkpoint Inhibitors in Upper Tract Urothelial Carcinomas: Current Knowledge and Future Directions

Simple Summary Upper tract urothelial carcinoma (UTUC) represents 5 to 10% of urothelial carcinoma. Their mutational profile is different as compared to bladder urothelial carcinoma (UC). While immune checkpoint inhibitors are now part of the therapeutic landscape of urothelial carcinoma, data concerning their use in UTUC patient’s treatment remain scarce. The aim of this review is to summarize the available evidence and the biological rationale of using immune checkpoint inhibitors in high-grade UTUC. We reviewed the latest molecular characterization data and proposed an insight for future therapeutic strategies based on molecular alteration profiles. Abstract Upper tract urothelial carcinoma (UTUC) represents a rare and aggressive malignancy arising from the renal pelvis or ureter. It can develop sporadically or have a hereditary origin, such as Lynch syndrome, caused by DNA mismatch repair deficiency, leading to microsatellite instability phenotype. According to molecular characterization studies, UTUC presents different mutational profiles as compared to urinary bladder urothelial carcinomas. In particular, it has been reported that UTUC harbored a higher level of FGFR3 alterations associated with a T-cell depleted immune microenvironment. The therapeutic landscape in urothelial carcinoma is rapidly evolving, with immune checkpoint inhibitors forming part of the standard of care. A greater understanding of the molecular alterations and immune microenvironment leads to the development of new treatment combinations and targeted therapy. This review summarizes the available evidence concerning the use of immune checkpoint inhibitors and the biological rationale underlying their use in high-grade UTUC.