Oncologic Outcomes and Features of Non-Clear Cell RCC Histology After Surgical or Systemic Therapy: A Systematic Review

Abstract

Background: Non-clear cell renal cell carcinoma (nccRCC) represents a heterogeneous group of malignancies comprising approximately 20-25% of all RCC cases, with limited prospective data to guide treatment selection. This systematic review synthesizes evidence on oncologic outcomes across nccRCC histologic subtypes following systemic therapy.

Methods: A comprehensive literature search was conducted in PubMed and Cochrane Library from inception to July 2025. Studies reporting oncologic outcomes for patients with advanced nccRCC receiving systemic therapy were included. Quality assessment was performed using RoB 2 for RCTs and Newcastle-Ottawa Scale for non-randomized studies.

Results: Seventeen studies comprising 1,441 nccRCC patients were included. IO+TKI combinations demonstrated the most promising activity, with ORRs ranging from 29-60% and median PFS of 8.3-13.0 months. The SUNNIFORECAST trial showed that ipilimumab plus nivolumab significantly improved OS compared to standard of care (33.2 vs 25.2 months; HR 0.81), with pronounced benefit in PD-L1 CPS≥1 patients (HR 0.56). Single-agent pembrolizumab achieved ORR 26.7% and median OS 28.9 months, while nivolumab showed ORR 14.3% with no responses in PD-L1<5%. Pazopanib was the most active TKI monotherapy (ORR 28%, PFS 16.5 months). Papillary RCC was highly responsive to IO+TKI combinations (ORR up to 47%), while chromophobe RCC showed IO resistance (ORR 0-9.5%) but responded to everolimus plus bevacizumab (ORR 40%). Sarcomatoid features predicted high IO response rates (33-70%). Perioperative nivolumab showed no benefit in resected disease.

Conclusion: IO+TKI combinations and ipilimumab plus nivolumab represent preferred first-line regimens for advanced nccRCC. Histologic subtype, sarcomatoid features, and PD-L1 expression are critical determinants of treatment selection. Further randomized trials are needed for rare nccRCC subtypes