Cabozantinib (C) exposure-response (ER) modeling of efficacy and safety endpoints as a function of clearance in patients (pts) with renal cell carcinoma (RCC).

Abstract

645 Background: C is approved for the treatment of advanced RCC after prior antiangiogenic therapy at 60 mg qd with dose reductions to 40 mg and 20 mg used to manage adverse events (AEs). In this study, ER analyses were used to evaluate the effect of C dose on progression-free survival (PFS) and safety endpoints at different apparent clearance (CL/F) values for pts in the phase 3 METEOR study (NCT01865747). Methods: Predicted steady-state C exposures were calculated for doses of 60, 40, and 20 mg in pts with CL/F values of 1.3, 2.23, and 3.3 L/hr; these values were based on population PK models and represent pts with low, average, and high CL/F, respectively. Time-to-event Cox proportional hazard ER models were used to characterize the relationship between predicted C exposure and the probability of PFS and 4 common C AEs: fatigue/asthenia (grade ≥3), palmar-plantar erythrodysesthesia (PPE; grade ≥1), diarrhea (grade ≥3), and hypertension (systolic BP > 160 mmHg or diastolic BP > 100 mmHg). Results: Among the 282 pts evaluated, predicted C CL/F values ranged from 0.51 to 7.24 L/hr. Predicted C exposure at the 60 mg dose ranged from 758 to 1923 ng/mL for representative pts with high and low CL/F (3.3 and 1.3 L/hr). A 60 mg dose for a high CL/F pt is predicted to yield C exposure similar to that of an average CL/F pt dosed at 40 mg (758 vs 748 ng/mL). At the 3 CL/F values evaluated, the hazard ratio (HR) for PFS modestly favored the 60 mg vs 40 mg dose, with the greatest impact on high CL/F pts (HR 1.13, 95% CI 1.10-1.16). 4 common C AEs are predicted to occur at lower rates at the 40 mg vs 60 mg dose; HRs ranged from 0.51-0.82 with the greatest effect in pts with low CL/F. Conclusions: Predicted C CL/F values and C exposures varied among pts with RCC in the METEOR study. ER models suggest that pts with high CL/F may have less favorable PFS outcomes at a starting dose of 40 mg vs the recommended 60 mg dose. Patients with low CL/F are predicted to have decreased rates of AEs at lower doses. Clinical trial information: NCT01865747. [Table: see text]