Systemic Therapies for the Management of Non-Clear Cell Renal Cell Carcinoma: What Works, What Doesn't, and What the Future Holds

Abstract

Non-clear cell renal cell carcinoma (nccRCC) is a broad term that refers to a diverse group of tumors, each with its own distinct biologic and therapeutic profile. The management of nccRCCs is often based on extrapolating data from clinical trials in the more common clear cell renal cell carcinoma, but our emerging prospective and retrospective clinical experience in nccRCC allows us to make more precise recommendations tailored to each histology. The systemic therapy options for metastatic nccRCC include targeted therapies such as tyrosine kinase inhibitors, immune checkpoint inhibitors, and, for specific rare subtypes, cytotoxic chemotherapy. Each nccRCC histology may respond differently to these regimens, which makes accurate pathologic diagnosis imperative. In the present review, we discuss the available clinical and biological data that can help guide systemic therapy recommendations for specific nccRCC subtypes.

Keywords: Chromophobe renal cell carcinoma; Collecting duct carcinoma; MiT family translocation renal cell carcinoma; Papillary renal cell carcinoma; Renal medullary carcinoma.

Figure 1.

Clinical and molecular features of distinct renal cell carcinoma subtypes. Abbreviations: BAP-1 = BRCA1 associated protein 1; MET = mesenchymal–epithelial transition factor; FH = fumarate hydrolase; HIF = hypoxia inducible factor; HLRCC = hereditary leiomyomatosis and renal cell carcinoma; MiT = microphthalmia transcription factor; mTOR = mammalian target of rapamycin; NF2 = neurofibromin 2; PI3K = phosphatidylinositol-3-kinase; pRCC = papillary renal cell carcinoma; PTEN = phosphatase and tensin homolog on chromosome 10; RCC= renal cell carcinoma; SDH = succinate dehydrogenase; TF = transcription factor; RHEB = ras homolog enriched in brain; VEGF = vascular endothelial growth factor; VHL=von Hippel-Lindau.

Figure 2.

Forest plots summarizing the responses to immune checkpoint–based therapies of papillary and chromophobe renal cell carcinomas.

Figure 3.

Immune cell infiltrates in renal cell carcinomas. Clear cell renal cell carcinomas contain more immune infiltrates than papillary renal cell carcinomas or especially chromophobe renal cell carcinomas. Immunotherapy strategies should aim to increase the number of activated antitumor immune cells, such as cytotoxic T lymphocytes (CTLs), in papillary and chromophobe renal cell carcinomas. On the other hand, renal medullary carcinoma and collecting duct carcinoma are highly inflamed tumors but contain a large number of immunosuppressive cells such as myeloid-derived suppressor cells (MDSCs) and regulatory T cells (T_regs), which may hinder the effectiveness of current immune checkpoint blockade strategies.