Introduction
renal cell carcinoma, death, genitourinary malignancies, RCC
RENAL CELL CARCINOMA, RCC
Over the last decade, improved understanding of the angiogenic and immunogenic biology of renal cell carcinoma (RCC) has led to development of tyrosine kinase inhibitors (TKI) that target the vascular endothelial growth factor receptor (VEGFR) and immune checkpoint inhibitors that target the programmed cell death 1 (PD-1) and cytotoxic T lymphocyte antigen 4 (CTLA-4) receptors [The cabozantinib tablet formulation (CabometyxGiven its immunomodulatory activity, cabozantinib is being evaluated in combination with immune checkpoint inhibitors as part of its clinical development. The combination of cabozantinib with nivolumab (a PD-1 immune checkpoint inhibitor antibody) showed promising preliminary antitumor activity in a phase 1 study in patients with advanced genitourinary malignancies, providing a rationale for the combination [In the phase 3 CheckMate 9ER trial (NCT03141177), nivolumab plus cabozantinib significantly improved progression-free survival (PFS) compared with sunitinib (hazard ratio [HR] 0.51, 95% confidence interval [CI] 0.41–0.64; Here, we describe a cabozantinib exposure–response analysis based on efficacy and safety data from patients with RCC administered nivolumab plus cabozantinib in CheckMate 9ER. A population pharmacokinetics (PopPK) analysis of cabozantinib was updated and used to generate individual predicted cabozantinib exposure measures for the exposure–response analyses. The objective was to characterize the relationship of cabozantinib exposure with efficacy and safety endpoints and to investigate the effects of selected covariates on the exposure–response relationship of cabozantinib with efficacy.