Treatment Selection in First-line Metastatic Renal Cell Carcinoma—The Contemporary Treatment Paradigm in the Age of Combination Therapy

The treatment landscape of metastatic renal cell carcinoma has evolved rapidly over the last decade. Recent combination approaches heralded by targeting immune checkpoints cytotoxic T-lymphocyte antigen 4 and programmed death-1 (PD-1) have been followed in consecutive years by protocols targeting vascular endothelial growth factor receptor, PD-1, and programmed death ligand-1. The differences in baseline patient characteristics, statistical plans, follow-up length, biomarker-derived approaches, and trial design make cross-trial comparisons difficult. Given the regulatory approval of a number of these regimens, the current available evidence is reviewed herein for combination first-line regimens with published randomized phase 3 trial data.Combination approaches have transformed outcomes for patients. Durable disease control and prolonged overall survival have been achieved by both doublet immune checkpoint blockade and vascular endothelial growth factor receptor plus PD-1 blockade. Rationale for variations in trial outcome are offered, alongside approaches to navigating patient-empowered treatment selection, focusing on predictive tools, biomarkers, and the role of real-world data.Advances in the genomic, molecular, and immunologic understanding of metastatic clear cell renal cell carcinoma have lifted the survival curves for this disease markedly in recent years. Combination approaches will remain standard of care in the first-line setting. However, thoughtful study design is needed to accurately estimate outcomes and integrate novel approaches into the treatment armamentarium.