Contemporary management of locally advanced and metastatic renal cell carcinoma: An update of current evidence

Abstract

Management of renal cell carcinoma (RCC), particularly locally advanced (laRCC) and metastatic disease (mRCC), has evolved rapidly with the integration of immune checkpoint inhibitors, targeted therapies, and multimodal strategies. The aim of this review is to provide an updated, evidence-based overview of current treatment paradigms and emerging concepts.

A comprehensive literature review was conducted focusing on pivotal phase III trials, contemporary guidelines (EAU, NCCN), and recent advances in systemic therapy, surgery, and metastasis-directed approaches. Key domains included: (i) management of locally advanced RCC; (ii) first-line systemic therapy in clear cell mRCC; (iii) second- and later-line treatment; (iv) non-clear cell and sarcomatoid variants; and (v) oligometastatic and oligoprogressive disease.

Adjuvant immunotherapy, particularly in regard to pembrolizumab, has become standard in selected high-risk laRCC following nephrectomy. In mRCC immune checkpoint inhibitor–based combination therapies (IO–IO or IO–TKI) have demonstrated superior survival outcomes in comparison to monotherapy. Novel agents such as HIF-2α inhibitors (e.g., belzutifan) are expanding treatment options in later lines. Increasing emphasis is placed on individualized strategies, including active surveillance in favorable-risk patients and metastasis-directed therapy in oligometastatic disease.

The management of la/mRCC is increasingly personalized and multidisciplinary. While immunotherapy-based combinations dominate current practice, ongoing trials and biomarker development will further refine treatment sequencing and patient selection.