A Trial‐Level Benefit–Toxicity Mapping Framework for Adjuvant Therapy in Renal Cell Carcinoma: A Focused Review

ABSTRACT Background Adjuvant systemic therapy for renal cell carcinoma (RCC) has evolved from vascular endothelial growth factor tyrosine kinase inhibitors (VEGF‐TKIs) to immune checkpoint inhibitors (ICIs) and emerging combination strategies. However, the interpretation of adjuvant trial results requires consideration not only of disease‐free survival (DFS) benefit but also of severe toxicity, treatment discontinuation, comparator structure, and trial risk composition. Methods We conducted a focused review of randomized Phase III adjuvant RCC trials identified through PubMed and prespecified publicly available trial reports. Peer‐reviewed trials were included in the primary evidence set, and contemporary conference reports were incorporated as an exploratory update. Trial‐level data were extracted for efficacy, grade ≥ 3 adverse events (AEs), AE‐driven and patient‐initiated treatment discontinuation, and protocol‐defined risk composition. A descriptive benefit–toxicity mapping framework was used to visualize DFS benefit, treatment‐limiting toxicity, severe AE burden, and high‐risk patient proportion without implying indirect treatment ranking. Results Nine peer‐reviewed trial programs and one conference‐only report were included. TKI‐based trials showed limited and inconsistent DFS benefit, with only S‐TRAC meeting its primary endpoint, while grade ≥ 3 AE burden was consistently high (60%–72%) and patient‐initiated discontinuation was frequent. Among ICI‐based trials, KEYNOTE‐564 showed DFS benefit, whereas IMmotion010 and CheckMate 914 Part A were negative. RAMPART (conference report) and LITESPARK‐022 showed additional DFS signals with ICI‐based combinations, accompanied by AE‐driven discontinuation in approximately one‐third of patients, with important differences in risk composition and comparator design. Conclusions Trial‐level benefit–toxicity mapping contextualizes adjuvant RCC trials by integrating DFS benefit, toxicity burden, treatment‐limiting events, and risk composition, without implying direct cross‐trial ranking.