The standard of care for patients (pts) with intermediate- to high-risk localized clear cell renal cell carcinoma (ccRCC) is surgical resection. Recently, adjuvant pembrolizumab was shown to reduce risk of relapse and improve overall survival. In melanoma, neoadjuvant ICI has superior efficacy compared to adjuvant ICI. Therefore, neoadjuvant ICIs warrant further investigation in ccRCC.
NESCIO is a randomized, non-comparative, open-label, three-arm, two-stage phase 2 trial in pts with resectable intermediate- to high-risk ccRCC. Pts were randomized to receive two cycles of nivolumab 360 mg (arm A), ipilimumab 1 mg/kg + nivolumab 3 mg/kg (arm B), or nivolumab 360 mg + relatlimab 360 mg (arm C), all q3wks, followed by a CT-scan and nephrectomy. The primary endpoint was pathologic response rate. Secondary endpoints included safety, objective response rate (ORR) per RECIST 1.1, surgical morbidity (Clavien-Dindo), EFS and RFS.
Between Apr 2022 and Feb 2025, 43 pts were included, of which 42 (14 per arm) evaluable for the primary endpoint. Baseline characteristics were balanced between arms. In total, 97.7% of tumors were ≥T3, 25.6% N+, and 51.2% ≥ grade 2. Pathologic response rates were 7.1% in arm A (1 partial pathologic response (pPR)), 14.3% in arm B (2 near-complete pathologic responses), and 14.3% in arm C (1 pPR and 1 complete pathologic response). ORR were 0% in arm A, 7.1% in arm B (1 partial response), and 0% in arm C. Most pts (95.2%) had stable disease. One pt (arm A) had progressive disease prior to surgery. Grade ≥3 immune-related (IR) adverse events were seen in 6.7% in arm A, 42.8% in arm B and 14.2% in arm C. Surgery was delayed >2 wks due to IR toxicity in one pt (arm A). Grade III-IV surgical complications occurred in 0% in arm A, 7.1% in arm B and 14.2% in arm C. RNA sequencing was performed on 40 baseline and 41 post-treatment samples for translational analyses.
Six wks of neoadjuvant ICI resulted in acceptable toxicity and remarkable pathologic responses in a limited number of pts with intermediate- to high-risk ccRCC. Future analyses of survival outcomes and translational data will be pivotal to evaluate efficacy and predictive biomarkers of neoadjuvant ICI in ccRCC.
NCT05148546, Registered December 8, 2021.