Unclear territory: navigating metastatic nonclear cell renal cell carcinoma

To summarize recent updates in the classification, clinical trial evidence, and evolving treatment strategies for nonclear cell renal cell carcinoma (nccRCC).

The 2022 WHO classification eliminated the type 1/2 papillary paradigm, refined molecularly defined tumors such as fumarate hydratase (FH)-deficient and anaplastic lymphoma kinase-rearranged RCC, while acknowledging indolent tumors like clear cell papillary renal cell tumors. Prospective and retrospective data increasingly support the use of immune checkpoint inhibitor (ICI)-based regimens, particularly ICI/ tyrosine kinase inhibitor (TKI) combinations. KEYNOTE-B61 and ARON-1 demonstrated consistent activity of pembrolizumab + lenvatinib across nccRCC subtypes, while the randomized SUNNIFORECAST trial validated ipilimumab + nivolumab as a first-line option with overall survival (OS) benefit over standard therapy. Subtype-specific approaches are also emerging: bevacizumab + erlotinib and sintilimab + axitinib showed high response rates in FH-deficient RCC, and prognostic tools such as VENUSS remain valuable for papillary RCC risk stratification. Despite progress, many studies remain limited by histologic heterogeneity and small sample sizes. Multiple ongoing trials, including ICONIC, SAMETA, and PAPMET2, are expected to further clarify optimal management strategies in 2026.

Therapeutic advances are reshaping the management of nccRCC, with IO/TKI regimens and histology-specific therapies showing promise. Continued integration of molecular classification, rare subtype-specific trials, and international collaboration will be essential to establish evidence-based treatment standards for this diverse and understudied population.