Prevalence and clinical impact of actionable genomic alterations in non–clear cell renal cell carcinoma: A review of NGS-based trials and real-world data.

Abstract

556 Background: Non–clear cell renal cell carcinoma (nccRCC) comprises biologically diverse subtypes with limited evidence guiding systemic therapy. The role of next-generation sequencing (NGS) in identifying actionable targets and informing precision-based approaches remains incompletely defined. This study summarizes prospective and retrospective data on the prevalence of targetable genomic alterations and the clinical impact of molecularly guided treatment strategies in nccRCC. Methods: A structured review of phase II–III trials and translational datasets incorporating NGS or molecular profiling in nccRCC (papillary, chromophobe, translocation, FH-deficient, and SDH-deficient subtypes) was performed. Studies were included if they reported (1) the prevalence of actionable alterations or (2) outcomes associated with targeted therapy. Results: Across nine studies (≈1,100 evaluable patients), actionable genomic alterations were identified in ~25–40% of nccRCC cases, with marked variability by subtype. Papillary RCC commonly demonstrated MET activation (mutation, amplification, or chromosome 7 gain) in ≈40%, with treatment responses mainly in MET-driven tumors. In PAPMET/SWOG-1500, cabozantinib was superior to sunitinib irrespective of MET status, underscoring the need for integrated molecular selection. FH-deficient RCC was almost uniformly associated with germline FH mutations; in the phase II study by Srinivasan et al., bevacizumab plus erlotinib achieved an objective response rate (ORR) of 64–72% and median PFS > 20 months. Chromophobe RCC frequently harbored mTOR-pathway alterations (TSC1/2, MTOR) in 20–25%, with reported responses to everolimus. Translocation RCC, driven by TFE3/TFEB fusions (~5% of RCC), demonstrated the best outcomes with immune checkpoint inhibitor (ICI)–TKI combinations. SDH-deficient RCC typically involved germline SDH mutations (most commonly SDHB); though evidence remains limited, overlap with the VHL pathway supports the rationale for TKI therapy. Conclusions: Actionable genomic alterations occur in approximately one-third of nccRCC, most frequently involving MET and mTOR pathways. Comprehensive NGS testing should be considered across all non–clear cell subtypes to identify MET-, FH-, mTOR-, and SDH-driven disease, refine targeted therapy selection, and enable biomarker-driven clinical trial enrollment.