RCC Histologies: Clear Cell vs Non–Clear Cell


Clinical insights from a leader in kidney cancer research on the differences between clear cell and non–clear cell renal cell carcinoma.


Robert J. Motzer, MD: Classically, renal cell carcinoma [RCC] from the standpoint of a medical oncologist has been divided into 2 main categories, and we refer to that as the clear cell and then non–clear cell groups. Clear cell RCC has emerged as the predominant cell type. It comprises probably 80% of patients diagnosed with RCC or who develop metastasis. And so the field and therapeutics have been dominated by studies looking at clear cell RCC. In addition, there has been a better understanding of the cause of clear cell RCC from a standpoint of basic biology, with initially a high level of angiogenesis associated with this tumor leading to antiangiogenesis therapy, and then the discovery of the VHL gene and its role in antiangiogenesis. And so that has led to therapies that target the VHL gene or its downstream effect, and they have been very successful, as well as immunotherapy.

The other group, non–clear cell RCC, has comprised a spectrum of histologies, is less well characterized, less common, and it’s been difficult to conduct trials for specific non–clear cell histologies as well as to find targets for our therapeutics. Originally, non–clear cell renal cell carcinoma comprised papillary, type 1, type 2, chromophobe, and other rare histologies. This was largely based on familial forms that were identified for these types of tumors, as well as some genetic considerations that went into classification and morphology. But we recognize now, as time goes on, there's more and more of this heterogeneous group of tumors. And so now there is a translocation-associated RCC. There was what used to be medullary carcinoma, but now it’s SMARCB1-associated tumors, collecting duct cancers, and there are many different cell types.

This challenge really has been with regard to classification, rarity, and defining underlying biology and targets. For the most part, the treatments that have been used from the standpoint of the medical oncologist have been those that have been extrapolated over from clear cell cancers, the tyrosine kinase inhibitors, and, more recently, the immunotherapy. Some of those have shown promising activity, one of which is cabozantinib. Cabozantinib has been used either alone or in combination with an IO therapy, with nivolumab. IO [immuno-oncology] therapies, monotherapy, [and] pembrolizumab as a single agent have shown promising activity in some of the non–clear cell histologies. And then more recently there were data for lenvatinib plus pembrolizumab in patients with these various non–clear cell histologies.

For the most part, overall, the response rate and the success is lower than in clear cell. We really have an unmet need to identify better therapy. But there is some activity and some benefit to patients with cabozantinib alone, cabozantinib plus nivolumab, lenvatinib plus everolimus for some patients, particularly chromophobe tumors, or with the more recent data showing lenvatinib and pembrolizumab. Those are different programs that we consider in that population of patients.

Transcript is AI-generated and edited for clarity and readability.

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