Precision adjuvant therapy after nephrectomy for high-risk clear-cell renal cell carcinoma: a narrative review
Abstract
Adjuvant therapy for renal cell carcinoma has moved from repeated negative trials to an evolving postopera-tive treatment landscape. Pembrolizumab is the first systemic therapy after nephrectomy to demonstrate both disease-free survival (DFS) and overall survival (OS) benefit in patients with clear-cell renal cell carcinoma (ccRCC) at increased risk of recurrence. However, clinicopathological eligibility exposes some patients already cured by surgery to immune-related toxicity and cannot identify microscopic residual disease. This narrative review integrates mature KEYNOTE-564 outcomes, the active-control LITESPARK-022 trial of pembrolizumab plus belzutifan, RAMPART findings, prior negative immune-checkpoint inhibitor and tyrosine-kinase inhibi-tor trials, and emerging biomarkers. We explicitly distinguish established standard care, promising but not yet mature strategies, and interventions that remain investigational. One year of pembrolizumab is the estab-lished evidence-based option for medically suitable KEYNOTE-564-eligible patients. Pembrolizumab plus bel-zutifan improves DFS versus pembrolizumab alone and is approved in the United States, but OS is immature, toxicity is greater, and its place in other regions remains unsettled. Dual-checkpoint blockade, postoperative treatment allocation based on kidney injury molecule-1 (KIM-1) or circulating tumor DNA (ctDNA), molecular subtypes, programmed death-ligand 1 expression, and radiomics remain investigational. No biomarker is vali-dated to select routine adjuvant therapy, and efficacy in non-clear-cell histologies has not been established. We propose a conceptual three-axis framework integrating clinicopathological recurrence risk, candidate residu-al-disease signals, and treatment fitness or patient preference. It is a decision aid, not a validated algorithm. At present, precision resides mainly in risk stratification, fitness assessment, and shared decision-making; mo-lecular treatment selection awaits prospective validation.
Keywords: Renal cell carcinoma, precision oncology, targeted therapy, immunotherapy, biomarkers