Efficacy and safety of adjuvant immune checkpoint inhibitors in resected renal cell carcinoma: Systematic review and meta-analysis of phase III trials.

Abstract

e16514 Background: Phase III trials of adjuvant immune checkpoint inhibitors (ICIs) in resected renal cell carcinoma (RCC) have yielded conflicting results. Pembrolizumab improved disease-free survival (DFS) in KEYNOTE-564, whereas atezolizumab, nivolumab-based, and perioperative regimens were negative. Whether benefit represents a class effect is unclear. Methods: A systematic review identified phase III randomized controlled trials of adjuvant or perioperative ICIs versus placebo/observation in resected RCC at increased risk of recurrence. The primary endpoint was DFS/recurrence-free survival (RFS); secondary endpoints included overall survival (OS) and safety. Random-effects meta-analyses with Hartung–Knapp adjustment were performed, with heterogeneity quantified by I². Results: Five trials met inclusion criteria (KEYNOTE-564, IMmotion010, CheckMate 914 Parts A and B, PROSPER; N = 3,947). Pooled DFS/RFS favored ICIs but did not reach statistical significance: hazard ratio (HR) 0.86 (95% CI 0.73–1.01, p = 0.058; I² = 13%). Only KEYNOTE-564 (pembrolizumab) met its primary endpoint (HR 0.72, 95% CI 0.59–0.87), whereas atezolizumab, adjuvant nivolumab (with or without ipilimumab), and perioperative nivolumab each showed nonsignificant effects (HRs 0.87–0.95). OS data were available from three trials (KEYNOTE-564, PROSPER, IMmotion010); the pooled OS HR was 0.90 (95% CI 0.36–2.25, p = 0.68) with substantial heterogeneity (I² = 73%), reflecting a significant OS benefit only in KEYNOTE-564 (HR 0.62, 95% CI 0.44–0.87) and a numerical increase in risk of death with perioperative nivolumab in PROSPER (HR 1.28, 95% CI 0.84–1.95). Grade ≥3 treatment-related adverse events occurred in 14–28% of ICI-treated patients versus 1.2–5% with placebo/observation, and discontinuations due to toxicity in 10–29% versus approximately 2%, respectively; 13 treatment-related deaths were reported across ICI arms. Conclusions: Across contemporary phase III trials, adjuvant ICIs for resected RCC do not demonstrate a consistent class-wide benefit. The DFS/RFS and emerging OS advantages appear specific to pembrolizumab, whereas atezolizumab, nivolumab-based regimens, 6-month treatment courses, and perioperative strategies have not improved outcomes. Current evidence supports pembrolizumab as the only evidence-based adjuvant ICI for high-risk RCC, and highlights the need for further biomarker-driven and regimen-optimized studies.