Sequential Therapy For Advanced Renal Cell Carcinoma: Systematic Review Of Comparative Efficacy, Safety, And Emerging Molecular Predictors

Advanced renal cell carcinoma has undergone a profound therapeutic evolution with the sequential integration of vascular endothelial growth factor targeted therapies mammalian target of rapamycin inhibition and immune checkpoint blockade. Although contemporary first line regimens are increasingly standardized treatment selection beyond progression remains heterogeneous and largely empiric. Cabozantinib and the combination of lenvatinib plus everolimus are both guideline endorsed subsequent line options supported by randomized evidence against everolimus yet no definitive head to head comparison or validated predictive biomarkers currently exist to guide optimal choice. This review synthesizes data from pivotal randomized trials real world observational cohorts translational studies and international clinical practice guidelines evaluating these two regimens in advanced renal cell carcinoma. The phase three METEOR trial established cabozantinib as a standard of care with durable improvements in progression free and overall survival and preserved quality of life across prognostic subgroups. The randomized phase two lenvatinib plus everolimus study demonstrated substantial progression free survival benefit and objective response but with higher toxicity requiring individualized dose management. The widespread adoption of immune checkpoint inhibitor based frontline combinations has further complicated sequencing decisions and increased reliance on both regimens in the post immune setting despite limited prospective validation. Emerging translational evidence suggests biologically plausible distinctions including mesenchymal epithelial transition factor driven invasive phenotypes favoring cabozantinib and mammalian target of rapamycin pathway dependence potentially relevant to lenvatinib plus everolimus although such associations remain retrospective and exploratory. Ongoing comparative trials including NCT05012371 are expected to inform relative efficacy but lack mandatory tissue based molecular or spatial profiling. Collectively available evidence confirms the indispensable role of both regimens while underscoring a critical unmet need for prospective biopsy anchored trials integrating genomic and spatial analyses to enable precision guided treatment sequencing.