Pazopanib Exposure Relationship with Clinical Efficacy and Safety in the Adjuvant Treatment of Advanced Renal Cell Carcinoma.

PROTECT, a phase III, randomized, placebo-controlled study, evaluated pazopanib efficacy and safety in the adjuvant renal cell carcinoma setting. The relationship between pazopanib exposure (C) and efficacy and safety was evaluated. Evaluable steady-state blood trough concentrations were collected from 311 patients at week 3 or 5 (early C) and 250 patients at week 16 or 20 (late C). Pazopanib pharmacokinetic (PK) data were analyzed via a population model approach. Relationship between C or dose intensity and disease-free survival (DFS) was explored via Kaplan-Meier and multivariate analysis. Adverse events (AE) and AE-related treatment discontinuation proportions were summarized by C quartiles. Most (>90%) patients with early or late C data started on 600 mg. Mean early and late C overlapped across dose levels. Patients with higher early C quartiles achieved longer DFS (adjusted HR, 0.58; 95% confidence interval, 0.42-0.82; = 0.002). Patients achieving early or late C >20.5 μg/mL had significantly longer DFS: not estimable (NE) versus 29.5 months, = 0.006, and NE versus 29.9 months, = 0.008, respectively. Dose intensity up to week 8 did not correlate with DFS, consistent with population PK model-based simulations showing overlapping pazopanib exposure with 600 and 800 mg doses. The proportion of AE-related treatment discontinuation and grade 3/4 AEs, with the exception of hypertension, was not correlated to C In the adjuvant setting, higher pazopanib C was associated with improved DFS and did not increase treatment discontinuations or grade 3/4 AEs, with the exception of hypertension. .