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

Purpose: PROTECT, a phase III randomized placebo-controlled study, evaluated pazopanib efficacy and safety in the adjuvant RCC setting. The relationship between pazopanib exposure (C_trough) and efficacy and safety was evaluated. Experimental Design: Evaluable steady-state blood trough concentrations were collected from 311 patients at week 3 or 5 (early C_trough), and 250 patients at week 16 or 20 (late C_trough). Pazopanib pharmacokinetic (PK) data was analyzed via a population model approach. Relationship between C_trough or dose intensity and disease-free survival (DFS) was explored via Kaplan-Meier and multivariate analysis. Adverse events (AEs) and AE-related treatment discontinuation proportions were summarized by C_trough quartiles. Results: Most (>90%) patients with early or late C_trough data started on 600 mg. Mean early and late C_trough overlapped across dose levels. Patients with higher early C_trough quartiles achieved longer DFS (adjusted hazard ratio [HR], 0.58; 95% CI, 0.42-0.82; P = 0.002). Patients achieving early or late C_trough >20.5 µg/mL had significantly longer DFS, not estimable (NE) vs 29.5 months, P = 0.006, and NE vs 29.9 months, P = 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 mg 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_trough. Conclusions: In the adjuvant setting, higher pazopanib C_trough was associated with improved DFS, and did not increase treatment discontinuations or grade 3/4 AEs with the exception of hypertension.

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