Adjuvant therapy for renal cell carcinoma: lessons from past failures and new opportunities in the era of immune checkpoint inhibition

Abstract

Renal cell carcinoma (RCC) has historically posed a significant therapeutic challenge in the adjuvant setting. Although surgical resection remains the cornerstone of curative-intent treatment for localized disease, a substantial proportion of patients with high-risk pathological features will experience recurrence following nephrectomy. Over several decades, multiple adjuvant strategies, including cytokine-based immunotherapy and vascular endothelial growth factor (VEGF)-targeted agents, failed to deliver consistent disease-free or overall survival benefits, often limited by toxicity and poor tolerability. These repeated disappointments reinforced the perception that effective adjuvant therapy in RCC was elusive. The emergence of immune checkpoint inhibition has fundamentally reshaped this landscape, with adjuvant pembrolizumab demonstrating disease-free and overall survival benefit in selected patients with resected clear-cell RCC at increased risk of recurrence, including those with M1 no evidence of disease, thereby establishing a new standard of care for certain high-risk populations. In contrast, several contemporaneous trials evaluating alternative immune checkpoint strategies failed to meet primary endpoints, underscoring that benefit is not class-wide and is highly dependent on patient selection and disease biology. Against this background, rather than simply tracing the historical evolution of adjuvant therapy, this review examines the broader challenges of adjuvant management after RCC resection, including why most postoperative approaches failed, how current evidence has redefined care for selected patients, and what barriers remain to optimizing outcomes. Particular emphasis is placed on recurrence risk assessment, patient selection, treatment-related toxicity, and the need for biomarker-driven, precision-based strategies to guide the next generation of adjuvant treatment.

Keywords: adjuvant therapy; biomarker-driven stratification; immune checkpoint inhibitors; pembrolizumab; precision oncology; renal cell carcinoma.