Adjuvant immune checkpoint inhibitor-based systemic therapies for high-risk renal cell carcinoma after nephrectomy: systematic review and network meta-analysis

Purpose Immune checkpoint inhibitor (ICI)-based systemic therapies were recently introduced to adjuvant management of renal cell carcinoma (RCC) in patients at high risk of recurrence. We aimed to compare the efficacy and safety of different drug combinations. Material and methods We systematically searched MEDLINE, Embase, and Web of Science in July 2026 to identify randomized controlled trials evaluating adjuvant ICI-based systemic therapies for high-risk RCC after nephrectomy. The outcomes of interest were disease-free survival (DFS), overall survival (OS), and rates of adverse events (AEs). We conducted a frequentist random-effects NMA. Risk of bias was assessed via RoB 2 tool, and certainty of evidence (CoE) was assessed via CINeMA framework (PROSPERO: CRD420261362360). Results Six trials ( n = 5838) were included. For DFS, pembrolizumab + belzutifan (HR 0.51, 95% CI 0.39–0.67, CoE Moderate, indirect evidence), durvalumab + tremelimumab (HR 0.65, 95% CI 0.45–0.93, CoE Moderate), and pembrolizumab monotherapy (HR 0.71, 95% CI 0.59–0.86, CoE High) significantly improved DFS compared to placebo/observation. Furthermore, pembrolizumab + belzutifan demonstrated a clinically and statistically significant improvement compared with pembrolizumab monotherapy (HR 0.72, 95% CI 0.59–0.87, CoE High). For OS, pembrolizumab + belzutifan (HR 0.51, 95% CI 0.30–0.87, CoE Moderate, indirect evidence) and pembrolizumab monotherapy (HR 0.66, 95% CI 0.48–0.90, CoE High) showed significant survival benefits over placebo/observation. However, pembrolizumab + belzutifan and durvalumab + tremelimumab were associated with a three- to five-fold increase in the risk of grade ≥3 AEs compared to placebo/observation. CoE was downgraded due to risk of bias from open-label designs, indirectness, and imprecision. Conclusion Pembrolizumab + belzutifan and durvalumab + tremelimumab significantly improve DFS in patients with high-risk RCC compared to placebo/observation. However, their substantial toxicity requires careful patient selection, balancing potential DFS benefits against distinct tolerability profiles.