Approaches to First-Line Therapy for Metastatic Clear Cell Renal Cell Carcinoma

Four immuno-oncology (IO)-based combinations have demonstrated overall survival benefit as frontline treatment of metastatic clear cell renal cell carcinoma (mccRCC). Choosing among the available combinations depends on treating physician's interpretation of existing data without level I evidence to inform choice of therapy. Landmark trials of mccRCC are reviewed and perspective on treatment options is provided.The four IO-based combinations reviewed are ipilimumab/nivolumab (IO/IO), pembrolizumab/axitinib (IO/TKI), nivolumab/cabozantinib (IO/TKI), and pembrolizumab/lenvatinib (IO/TKI). The ipilimumab/nivolumab combination is notable for durable efficacy after extended 4-year follow-up. IO/TKI combinations have clinical efficacy across all IMDC risk groups with higher response rates and longer progression-free survival (PFS) but also had higher ≥ grade 3 adverse events rate. Patient tumor burden, performance status, and IMDC risk group are factors in choosing an IO-based treatment. IO/IO and IO/TKI combinations for mccRCC have distinct efficacy and toxicity profiles. Future studies are needed to identify biomarkers to optimize patient outcomes.