Is there still a role for sorafenib in metastatic renal cell carcinoma? A systematic review and meta-analysis of the effectiveness of sorafenib over other targeted agents

Background: The treatment of metastatic renal cell carcinoma (mRCC) has largely improved over the last decade, due to the availability of several targeted agents (TAs). Sorafenib was the first TA to report a benefit in terms of PFS in this disease, and it has largely been used as a comparator in randomized trials. We tested its activity compared to other TAs by performing a systematic review and meta-analysis. Methods: MEDLINE/PubMed, the Cochrane library, and the ASCO university websites were searched for randomized phase II or III trials that compared other TAs to sorafenib in mRCC. Data extraction was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. The measured outcomes were progression free survival (PFS), overall survival (OS), and the overall response rate (ORR). Sub-analyses were performed for MSKCC prognostic groups and lines of therapy. Results: A total of 3094 patients were evaluable for PFS. Other TAs significantly reduce the risk of progression compared to sorafenib (HR = 0.78; 95% CI, 0.72-0.85; p < 0.001). This difference remains significant in patients in a good prognostic group with respect to both first- (HR = 0.61; 95%CI, 0.44-0.85; p = 0.003) and second-line therapy (HR = 0.58; 95% CI, 0.42-0.79; p < 0.001). No significant differences were, however, found in patients with an intermediate prognosis in terms of both first- (HR = 0.80; 95% CI, 0.60-1.00; p = 0.05) and second-line treatment (HR = 0.89; 95% CI, 0.73-1.07; p = 0.21).In 2922 patients evaluable for OS, no significant difference was found between other TAs and sorafenib (HR = 1.07; 95% CI, 0.97-1.18; p = 0.18). A benefit was also not identified when the analysis was limited to patients treated with first or subsequent lines of therapy or in patients previously treated with sunitinib. Significant differences were found in terms of the ORR in the 2963 evaluable patients favoring other TAs (RR = 1.48; 95% CI, 1.24-1.76; p < 0.001). This difference remain significant when a sub-analysis was performed per line of therapy. Conclusions: Other TAs improve PFS but not OS when compared to sorafenib. The use of sorafenib in patients with an intermediate prognosis, especially in second-line therapy, does not have a detrimental effect on PFS and might be an option for certain patients.