Efficacy and safety of first- versus second-generation fibroblast growth factor receptor (FGFR) inhibitors in advanced or metastatic urothelial carcinoma with FGFR alterations: a systematic review and meta-analysis

Introduction We reviewed the clinical studies on fibroblast growth factor receptor (FGFR) inhibitors for the treatment of urothelial carcinoma to conduct the meta-analysis of clinical efficacy and safety, aiming to provide more precise treatment options for patients with FGFR alterations. Method We performed the literature search and screening, then calculated and analyzed using the STATA 14.0 software and Review Manager 5.3 software. Results A total of 1528 patients from seventeen studies focusing on seven different FGFR inhibitors were collected. The efficacy analysis indicated the pooled objective response rate (ORR) was 32% (95% CI 26% to 39%) and the pooled disease control rate (DCR) was 64% (95% CI 53% to 75%) for patients with FGFR alterations treated with FGFR inhibitors. The pooled ORR and DCR of second-generation FGFR inhibitors were both significantly higher than those of first-generation FGFR inhibitors (ORR: 0.35, 95% CI 0.29 to 0.41 versus 0.07, 95% CI 0.02 to 0.16, p < 0.001; DCR: 0.68, 95% CI 0.61 to 0.75 versus 0.27, 95% CI 0.16 to 0.40, p < 0.001). The safety analysis indicated any-grade TRAEs were comparable between first- and second-generation FGFR inhibitors, but grade ≥3 TRAEs were significantly less frequent with second-generation FGFR inhibitors versus first-generation FGFR inhibitors (0.49, 95% CI 0.40 to 0.57 versus 0.67, 95% CI 0.57 to 0.76; p = 0.006). The common target toxicities associated with FGFR inhibitors, such as hyperphosphatemia, stomatitis and PPES, were more frequently occurred in second-generation FGFR inhibitors compared to first-generation FGFR inhibitors. Conclusion The second-generation FGFR inhibitors have advantages in both efficacy and safety, but special adverse reactions still require additional attention.