Systemic Therapy for Non–Clear Cell Renal Cell Carcinoma

Treatment options for metastatic clear cell renal cell carcinoma (ccRCC) have evolved markedly over the past decade, with multiple targeted therapies approved for the disease. In contrast, little improvement has been made in the management of metastatic non–clear cell RCC (nccRCC). Non–clear cell disease is an umbrella term that encompasses multiple biologically distinct entities, including but not limited to papillary, chromophobe, and sarcomatoid RCC. To date, prospective studies have largely explored treatments for ccRCC (e.g., VEGF- and mTOR-directed therapies) in trials that aggregate non–clear cell histologies. However, the studies do not acknowledge the varying biology of each non–clear cell subtype. Emerging studies in nccRCC should examine individual histologies and apply biologically relevant therapies. An example of this is SWOG 1500, a randomized phase II study that will compare a VEGF-inhibitor to one of three MET-directed therapies in patients with metastatic papillary RCC. Until the biologic diversity of nccRCC is appreciated, outcomes are likely to remain dismal.