Non-clear cell renal cell carcinoma (nccRCC) represents a heterogenous group of malignancies with varying degrees of clinical aggressiveness and response to different systemic therapies. As the characterization of subtypes of nccRCC continues to evolve, it is important to understand the evidence around systemic treatments used in advanced or metastatic stages of specific subtypes. Here, we review the literature on systemic therapies in nccRCC, with a focus on prospective trials that included patients with papillary renal cell carcinoma (RCC), chromophobe RCC, RCC not further classified/unclassified RCC, translocation RCC, collecting duct RCC, and renal medullary carcinoma. We also review emerging treatments for other molecularly defined subtypes of this disease.

Immune checkpoint inhibitors and antibody drug conjugate combinations have revolutionized the management of patients with advanced and metastatic urothelial carcinoma, offering unprecedented survival outcomes. These treatments are now moving into earlier stages of disease, including perioperative treatments for patients with muscle-invasive bladder cancer planning for curative-intent radical cystectomy. In this setting, there are now standard-of-care options for adjuvant immune checkpoint inhibitors with or without prior neoadjuvant chemotherapy, perioperative immune checkpoint plus cytotoxic chemotherapy combinations, and perioperative immune checkpoint inhibitor plus antibody drug conjugate combinations. This review will evaluate key clinical trials that led to modern standards of care involving these classes of drugs and highlight ongoing clinical trials that may further shift treatment paradigms for muscle-invasive bladder cancer. Key efficacy and toxicity considerations will be reviewed, and available evidence for biomarkers will be evaluated. As immune checkpoint inhibitors and antibody drug conjugates continue to demonstrate improved outcomes across the spectrum of bladder cancer treatment, understanding their role in the muscle-invasive disease state is crucial to managing patients with this condition.