Cabozantinib in Combination with Immunotherapy for Advanced Renal Cell Carcinoma and Urothelial Carcinoma: Rationale and Clinical Evidence

Abstract

The treatment landscape for metastatic renal cell carcinoma (mRCC) and urothelial carcinoma (mUC) has evolved rapidly in recent years with the approval of several checkpoint inhibitors. Despite these advances, survival rates for metastatic disease remain poor, and additional strategies will be needed to improve the efficacy of checkpoint inhibitors. Combining anti-VEGF/VEGFR agents with checkpoint inhibitors has emerged as a potential strategy to advance the immunotherapy paradigm, because VEGF inhibitors have immunomodulatory potential. Cabozantinib is a tyrosine kinase inhibitor (TKI) whose targets include MET, AXL, and VEGFR2. Cabozantinib has a unique immunomodulatory profile and has demonstrated clinical efficacy as a monotherapy in mRCC and mUC, making it a potentially suitable partner for checkpoint inhibitor therapy. In this review, we summarize the current status of immunotherapy for mRCC and mUC and discuss the development of immunotherapy-TKI combinations, with a focus on cabozantinib. We discuss the rationale for such combinations based on our growing understanding of the tumor microenvironment, and we review in detail the preclinical and clinical studies supporting their use.

Immune Checkpoint Inhibitors in the Treatment of Renal Cancer: Current State and Future Perspective

“…Combination strategies may overcome the resistance to immunotherapy through the immunomodulatory properties of VEGF-TKI inhibitors such as the increase in effector T-cell infiltration and decrease in inhibitory cell subpopulations, which could turn the cold tumors hot. In this setting, cabozantinib seems a promising partner for ICIs and is actually under investigation in clinical trials [56][57][58].…”

Cabozantinib in combination with atezolizumab versus sorafenib in treatment-naive advanced hepatocellular carcinoma: COSMIC-312 Phase III study design

“…There are a number of proposed mechanisms for primary resistance to ICI monotherapy that highlight the complex interplay between immune tolerance and response within the tumor microenvironment [26]. Overexpression of immunosuppressive factors by tumor and non-tumor cells may maintain immune tolerance via 'alternative' pathways outside of current ICI targets.…”

“…Circulating VEGF and VEGF within the tumor microenvironment also have immunosuppressive effects [26,29]. Tumor cells release VEGF, which can increase the number and function of immunosuppressive cells, including T regulatory cells, MDSCs and tumor-associated macrophages.…”

“…In addition to the VEGF pathway, preclinical studies have described the immunomodulatory activity of other cabozantinib targets, including MET and the TAM family of receptor kinases (Figure 1) [26,32,33]. Inhibition of these targets has been shown to promote an immune-permissive tumor microenvironment in preclinical models.…”

Notch3 is involved in the proliferation of renal cancer cells via regulation of cell cycle progression and HIF‑2α

“…Renal cell carcinoma (RCC) is a complex, multifaceted malignant disease comprising different and specific entities, with over two-thirds of all cases being clear cell RCC (ccRCC) (1). Of all ccRCCs cases, 60-80% are considered to be associated with the biallelic inactivation of the Von Hippel Lindau (VHL) gene, which causes aberrant accumulation of hypoxia-inducible factor (HIF) (2).…”