Second-Line Systemic Therapies in Metastatic Renal Cell Carcinoma: Current Insights and Future Directions

Over the past few decades, the incidence of renal cell carcinoma (RCC) has rapidly increased with a considerable portion of patients presenting with metastatic disease (mRCC) and subsequent poor prognosis. Survival drops even further for those whose diseases progress on first-line therapy including immune-checkpoint inhibitors (ICIs) and vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs). In this review, we highlight the main second-line systemic therapies including TKIs, mTOR inhibitors, ICIs, and HIF-2α inhibitors along with their mechanisms of action and supporting clinical trials. We also highlight ongoing trials investigating novel second-line therapies such as the LITESPARK-011 trial contrasting belzutifan/lenvatinib with cabozantinib and the ENTRATA study examining glutaminase inhibitors including telaglenastat. The recent wave of key clinical trials has substantially increased the therapeutic options available to patients whose diseases have progressed on ICIs or VEGFR-TKIs. However, survival outcomes and the quality of life of mRCC patients on second-line treatments are still relatively limited, indicating a need for continued innovation and drug development in the field and continued trial recruitment at high-volume cancer centers.