First-line Immunotherapy-based Combinations for Metastatic Renal Cell Carcinoma: A Systematic Review and Network Meta-analysis

CONTEXT: There have been substantial changes in the management of patients with metastatic renal cell carcinoma (mRCC) over the past decade, with upfront immunotherapy-based combinations replacing targeted therapies. A broad range of combinations have been approved, and comparisons of their efficacy and safety are needed to guide the optimal choice of first-line therapy.

OBJECTIVE: To perform indirect comparisons of efficacy and safety of first-line immune checkpoint inhibitor (ICI)-based combination therapies for mRCC.

EVIDENCE ACQUISITION: We searched multiple databases and abstracts of major scientific meetings up to February 2021 to identify phase III randomized controlled trials of patients receiving first-line ICI-based combination therapies for mRCC. Progression-free survival (PFS) and overall survival (OS) were the primary endpoints. The secondary endpoints included complete response rates (CRRs), objective response rates (ORRs), grade ≥3 treatment-related adverse events (TRAEs), and rates of treatment discontinuation due to adverse events (AEs). Subgroup network meta-analyses were performed based on patients' risk group categories and programmed death ligand 1 (PD-L1) expression status.

EVIDENCE SYNTHESIS: Six trials were included in our network meta-analyses comprising 5121 patients. Nivolumab plus cabozantinib had the highest likelihood of providing the maximal OS (P score: 0.7573). Lenvatinib plus pembrolizumab demonstrated the highest likelihood of PFS (P score: 0.9906) and ORR (P score: 0.9564). CRRs were more likely to be associated with nivolumab plus ipilimumab (P score: 0.8682). In patients with ≥1% PD-L1 expression, the highest likelihood of better PFS was associated with lenvatinib plus pembrolizumab and nivolumab plus ipilimumab. Nivolumab plus ipilimumab was also associated with the lowest rates of grade ≥3 TRAEs; while the highest likelihood of AE-related treatment discontinuation was associated with lenvatinib plus pembrolizumab and nivolumab plus ipilimumab.

CONCLUSIONS: Our network meta-analysis suggests that combinations of ICIs and tyrosine kinase inhibitors (TKIs) provide superior PFS, ORR, and OS to ICI-ICI combinations, regardless of the on International mRCC Database Consortium risk group. However, an ICI-ICI combination could be the optimal treatment for tumors with increased PD-L1 expression. The newly introduced ICI-TKI combinations, nivolumab plus cabozantinib and lenvatinib plus pembrolizumab, showed promising activity and are likely to have an important role in the mRCC treatment strategy.

PATIENT SUMMARY: The use of immune checkpoint inhibitor (ICI)-based combinations (ICI plus tyrosine kinase inhibitor and ICI-ICI) improved oncological outcomes of metastatic renal cell carcinoma. Programmed death ligand 1 (PD-L1) expression status could help guide physicians and patients to select the appropriate treatment strategy.