Combination therapies in patients with favorable risk metastatic renal cell Carcinoma: A Systematic Review and Meta-Analysis

Introduction Immunotherapy (IO)-based combination therapies have emerged as the standard of care for first-line treatment of metastatic renal cell carcinoma (mRCC) among patients classified as intermediate and poor risk. However, in the favorable risk group, the available data remains less compelling. This study aims to assess and compare the effectiveness of IO-based combination therapies versus tyrosine kinase inhibitor (TKI) monotherapy in patients with favorable risk group according to the International mRCC Database Consortium (IMDC). Methods Recent update data from phase-III RCTs of IO-based combinations approved by the Food and Drug Administration were used. Studies that provided data on progression free survival (PFS) and overall survival (OS) of IMDC favorable risk were included in the analysis. Results A cohort of 1,088 patients categorized within the IMDC favorable risk group was enrolled for analysis. In comparison to sunitinib, the combination of immunotherapy (IO) and tyrosine kinase inhibitor (TKI) exhibited a reduction in the risk of disease progression (HR=0.67, 95% CI: 0.55-0.82; p<0.001). Conversely, the combination of IO and IO displayed an elevated risk of disease progression (HR=1.60, 95% CI: 1.13-2.26; p=0.008). However, neither the IO plus TKI (HR=0.99, 95% CI: 0.79-1.24; p=0.92) nor IO plus IO (HR=0.94, 95% CI: 0.64-1.37; p=0.75) combinations demonstrated a noteworthy improvement in overall survival (OS). Notably, within the IO plus TKI subgroup, combination therapy yielded a higher objective response rate (ORR) (OR=0.40, 95% CI: 0.28-0.57; p<0.001). On the other hand, the IO plus IO combination displayed a lower ORR than sunitinib (OR=2.54, 95% CI: 1.51-4.27; p<0.001). Conclusions In the first-line treatment of IMDC favorable-risk mRCC, IO and TKI combinations show enhanced progression-free survival and response rate without improving overall survival. This emphasizes the demand for further exploration of combination therapies in this patient group.