Clinical relevance of molecular biomarkers in urothelial carcinomas treated with chemotherapy, immunotherapy or targeted-therapies

Background: Advanced urothelial carcinoma (UC) is a neoplastic disease with a very poor prognosis. In the last few years novel treatments beyond platinum-based chemotherapy such as immunotherapy with checkpoint inhibitors (CPIs) and targeted therapy with Fibroblast-Growth-Factor-Receptor (FGFR) inhibitors have reached clinical practice. Nevertheless, the role of Programmed Death receptor Ligand 1 (PD-L1) evaluation on tumor tissue in predicting response to CPIs is still debated. On the other hand, while predictive for specific inhibitors, it is not clear if FGFR alterations are able to discern a different response to chemotherapy or CPIs. Materials and Methods: To evaluate the clinical role of PD-L1 and FGFR aberrations two different approaches were applied. For PD-L1 a systematic review and meta-analysis was performed, selecting three measures of effect: the objective response ratio (ORR) and the Hazard Ratio (HR) for overall survival (OS) of patients treated with CPIs with elevated PD-L1 expression vs patients with low PD-L1 expression; the HR for OS of patients with elevated PD-L1 expression treated with CPIs vs chemotherapy. To evaluate the role of FGFR alterations all consecutive patients with advanced UC from 2018 to 2022 tested for FGFR and treated with at least one line of systemic therapy were enrolled in a retrospective, mono institutional study. Clinical data was collected from clinical charts, anonymized and organized in an electronic database. Survivals were estimated with Kaplan-Meir method, and the association between the presence of FGFR alterations and OS, PFS was analyzed with the log-rank test. Results: After literature research, 13 studies were deemed eligible, of which 8 for ORR and OS comparison between patients with high and low PD-L1 expression treated with CPIs, and 5 with OS comparison between patients with high PD-L1 treated with CPIs vs chemotherapy. The pooled ORR for tumor response was 2.9 with a 95% CI of 2.32 to 3.63 and a p<0.0001 in favor of the patients with an elevated expression of PD-L1. For the same subgroups, the pooled HR was 0.65 with a 95% CI 0.57 to 0.73 in favor of high PD-L1 expression. For patients with high PD-L1 expression treated with immunotherapy the pooled HR was 0.79 with a 95% CI 0.61 to 1.02; displaying only a trend for reduction in the risk of death when compared with patients treated with chemotherapy. In our institution from 2018 to 2022, 160 patients with UC were tested for FGFR alterations, of them 148 were eligible for this study. Of the 126 patients of the chemotherapy group 23 harbored FGFR mutations or translocations (18.3%). Median PFS was 7 months in the FGFR negative subgroup and 9 months in the positive one, HR = 1.32, p= 0.23. Median OS was 20 months in the former subgroup vs 15 months, HR= 0.98. Of 72 patients treated with CPIs, 13 were positive for FGFR (18.1%). Median PFS in this group was 2 vs 4 months in the FGFR negative one, HR= 1.22, p= 0.5. Patients with a FGFR alteration had a median OS of 5 versus 17 months , with an HR of 1.58, p= 0.2. Excluding the patients who received FGFR inhibitors after immunotherapy, median OS was 3.5 months with an HR of 3.5, p= 0.001. Conclusions: PD-L1 has a prognostic role for metastatic UC, and an elevated expression is associated with a higher chance of response to CPIs. However, it does not seem to have enough predictive power to lead to the choice of a treatment with CPIs over chemotherapy, especially in the first line setting. On the other hand, FGFR alterations, seem to be associated with a lower OS in patients treated with immunotherapy, if they do not receive an FGFR inhibitor after the failure of CPIs. Conversely, no correlation with response to platinum-based chemotherapy was found.