Figlin Views Combination Therapy as the Key to Durable Responses in RCC

Robert A. Figlin, MD, FACP

Robert A. Figlin, MD, FACP, is an internationally recognized leader in genitourinary oncology and founder of the Kidney Cancer Program at Cedars-Sinai Medical Center in Los Angeles. He joined Cedars Sinai in 2010 as the Stephen Spielberg Family Chair in Hematology/ Oncology. He also is a professor of Medicine and Biomedical Sciences, and deputy director of the Samuel Oschin Comprehensive Cancer Institute.

OncLive: How has our understanding of the genomics of kidney cancer evolved in the past decade?

What are the central genetic events underlying the development of the major types of kidney cancer, and how is our genomic understanding informing the development of targeted therapies?

In an interview with OncLive, Figlin discusses how the genomics of kidney cancer have evolved over recent years.Figlin: With the identification of mutations in the VHL gene and subsequent TCGA analysis of both clear cell and non-clear cell histologies, we have a better understanding of possible targets and the effects of small-molecule inhibitors against these targets. This has in part explained the rapid regulatory approval of agents in this disease that have led to improvements in progression-free and overall survival when compared with prior non-targeted therapy.Clear cell RCC has the major driver: mutations, hyper methylations, or loss of heterozygosity of the VHL gene and its downstream effects on other targets.

What are the most promising therapeutic strategies emerging from these studies?

What are the most significant unanswered questions or challenges in the field?

Recent evidence suggests that BAP1, PBRM1, and SETD2 are prevalent in more than 10% of specimens but as yet are not druggable and in the clinic. Papillary RCC has been defined by abnormalities of MET for type 1 tumors and CDKN2A, SETD2, TFE3 fusions and others in type 2 tumors. These findings should facilitate more specific development strategies for these tumors.While targeted therapies have been developed against known targets in RCC, there is a parallel strategy that is addressing checkpoint inhibition, with the recent approval of checkpoint inhibitors. This exemplifies the close interaction between the mutational status of tumors and their potential responsiveness to immune-based therapies.Our success over the past decade has led to significant improvement in PFS and OS but as yet the absence of durable unmaintained remissions. Efforts to extend these observations by combining agents that target mutations in combination with immune oncology agents offer the opportunity for significant additional benefit. Additionally, identifying mechanisms of resistance that can be exploited in drug development such as cabozantinib, which inhibits VEGFR, Axl, and MET, may offer such a possible solution.