Abstract
PURPOSE: In the phase 3 CheckMate 9ER trial, intravenous nivolumab (240 mg every 2 weeks) plus oral cabozantinib (40 mg/day) improved progression-free survival (PFS) versus sunitinib as first-line therapy for advanced renal cell carcinoma (RCC). To support cabozantinib dosing with the combination, this exposure-response analysis characterized the relationship of cabozantinib exposure with clinical endpoints. METHODS: Dose modification was allowed with cabozantinib (holds and reductions) to manage adverse events (AEs). The population pharmacokinetics analysis was updated and used to generate individual predicted cabozantinib exposure measures. Kaplan-Meier plots and time-to-event Cox proportional hazard (CPH) exposure-response models characterized the relationship of cabozantinib exposure with PFS, dose modifications, and selected AEs. RESULTS: Kaplan-Meier plots showed no clear difference in PFS across cabozantinib exposure quartiles. Cabozantinib exposure did not significantly affect the hazard of PFS in the CPH base model nor in the final model. In contrast, baseline albumin and nivolumab clearance had a significant effect on PFS. There was no significant relationship between cabozantinib clearance and risk of dose modification, but a significant relationship was identified between cabozantinib exposure and Grade ≥ 1 palmar-plantar-erythrodysesthesia and Grade ≥ 3 diarrhea in the exposure-response analysis. CONCLUSION: To optimize individual cabozantinib exposure, these data support the dose modification strategies in CheckMate 9ER for cabozantinib in patients with advanced RCC when combined with nivolumab.