Current Options for RCC with Divergent Histology

How to cite: McGregor B. Current Options for RCC with Divergent Histology. Grand Rounds in Urology. November 13, 2025. Accessed Mar 2026. https://grandroundsinurology.com/current-options-for-rcc-with-divergent-histology/

Summary

Bradley McGregor, MD, FASCO, Director of Clinical Research, Lank Center of Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, provides an overview of systemic treatment options for renal cell carcinoma (RCC) with divergent histology, emphasizing that these tumors represent biologically distinct diseases. Dr. McGregor reviews how advances in pathology, genomics, and clinical trial design are reshaping treatment selection for these rare and challenging RCC subtypes.

He notes that earlier trials grouped divergent histologies together. Trials such as ESPN and ASPEN established sunitinib as a modestly effective standard of care but failed to account for the biologic heterogeneity within these tumors. Dr. McGregor emphasizes that contemporary pathology now provides far more granular classification.

Papillary RCC is discussed in detail, with focus on the PAPMET trial, which demonstrated superior progression-free survival and objective response rate with cabozantinib compared with sunitinib. The presentation highlights the shift away from papillary subtyping toward molecular drivers, noting that mesenchymal-epithelial transition (MET) inhibition is not universally effective across histologically defined papillary disease. Data from SAVOIR and other MET-driven studies support the selective use of MET inhibitors in genomically defined populations.

Dr. McGregor reviews compelling data in fumarate hydratase-deficient RCC, a disease space in which bevacizumab plus erlotinib demonstrates particularly high response rates and prolonged progression-free survival. This regimen is emphasized as a preferred option for patients with hereditary leiomyomatosis and RCC.

The role of immunotherapy is examined across divergent histologies. Single-agent pembrolizumab demonstrates activity in papillary and unclassified RCC but limited efficacy in chromophobe disease. The randomized SUNNIFORECAST trial shows improved 12-month overall survival with nivolumab plus ipilimumab compared with standard care, with responses observed across histologic subtypes, including chromophobe RCC.

Combination immunotherapy and tyrosine kinase inhibitor (TKI) regimens are reviewed, including cabozantinib plus nivolumab and lenvatinib plus pembrolizumab. These combinations demonstrate objective response rates of around 50% across multiple divergent histologies, including chromophobe and translocation-associated RCC.

Dr. McGregor emphasizes that combination therapy is increasingly becoming the standard of care for divergent histology RCC, while future progress will depend on genomically driven trials rather than histology alone.

About the 32nd Annual Perspectives in Urology: Point Counterpoint conference: Presented by Program Chair and Grand Rounds in Urology Editor-in-Chief E. David Crawford, MD, this conference brought together leading experts in urology, medical oncology, and radiation oncology to discuss and debate the latest topics in genitourinary cancers, primarily prostate cancer and bladder cancer. This interactive conference offered topical lectures, pro/con debates, interesting case presentations, interactive panel discussions, and interactive audience and faculty networking.