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

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.

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.

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.

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.