Immune Checkpoint Inhibition in Advanced Non-Clear Cell Renal Cell Carcinoma: Leveraging Success from Clear Cell Histology into New Opportunities

SIMPLE SUMMARY: Kidney cancer has many forms, which fall under the overall term, renal cell carcinoma. Clear cell renal cell carcinoma is by far the most common type, and all other renal cell carcinomas are categorized as non-clear cell renal cell carcinoma. Patients with non-clear cell renal cell carcinomas unfortunately tend to fare worse and have fewer treatment options. We are now beginning to understand non-clear cell tumors better, including what drives these tumors to grow and spread. With this improved understanding, we can design more effective therapies. The current treatments include drugs that activate the immune system to recognize and destroy cancer cells, which is termed immunotherapy. There are many active clinical trials using immunotherapy either alone or in combination with other drugs to improve the lives of patients with non-clear cell carcinomas. ABSTRACT: Renal cell carcinoma (RCC) is a histologically heterogeneous disease with multiple subtypes. Clear cell RCC (ccRCC) represents the most common histology and has thus been easiest to study in clinical trials. Non-clear cell RCC (nccRCC) represents about 25% of RCC tumors, with fewer treatment options available, compared to ccRCC, and with poorer outcomes. Non-clear cell RCC tumors are histologically diverse, with each subtype having distinct molecular and clinical characteristics. Our understanding of nccRCC is evolving, with a gradual shift from treating nccRCC as a single entity to approaching each subtype as its own disease with unique features. Due to the scarcity of patients for study development, trials have predominantly combined all nccRCC subtypes and re-purposed drugs already approved for ccRCC, despite the decreased efficacy. We are now in the early stages of a potential paradigm shift in the treatment of nccRCC, with a rapid development of clinical studies with a focus on this subset of tumors. Investigators have launched trials focused on the molecular drivers of tumorigenesis using targeted therapies. Harboring the immunogenicity of some nccRCC subtypes, and based on promising retrospective studies, clinicians have also devised multiple trials using immune checkpoint inhibitors (ICIs), both alone or in combination with targeted therapies, for nccRCC subtypes. We highlight the promising completed and ongoing studies employing ICIs that will likely continue to improve outcomes in patients with nccRCC and propose future potential immunotherapeutic avenues.