PROTECT, a phase III randomized placebo-controlled study, evaluated pazopanib efficacy and safety in the adjuvant RCC setting. The relationship between pazopanib exposure (Ctrough) and efficacy and safety was evaluated.
Evaluable steady-state blood trough concentrations were collected from 311 patients at week 3 or 5 (early Ctrough), and 250 patients at week 16 or 20 (late Ctrough). Pazopanib pharmacokinetic (PK) data was analyzed via a population model approach. Relationship between Ctrough 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 Ctrough quartiles.
Most (>90%) patients with early or late Ctrough data started on 600 mg. Mean early and late Ctrough overlapped across dose levels. Patients with higher early Ctrough quartiles achieved longer DFS (adjusted hazard ratio [HR], 0.58; 95% CI, 0.42-0.82; P = 0.002). Patients achieving early or late Ctrough >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 Ctrough Conclusions: In the adjuvant setting, higher pazopanib Ctrough was associated with improved DFS, and did not increase treatment discontinuations or grade 3/4 AEs with the exception of hypertension.
Clinical cancer research : an official journal of the American Association for Cancer Research. 2018 Jan 12 [Epub ahead of print]
Cora Sternberg, Frede Donskov, Naomi B Haas, Christian Doehn, Paul Russo, Mohamed A Elmeliegy, Guillaume Baneyx, Hiya Banerjee, Paola Aimone, Robert J Motzer
San Camillo and Forlanini Hospitals ., Department of Oncology, Aarhus University Hospital, Denmark., Abramson Cancer Center and the Division of Hematology & Oncology, Perelman School of Medicine, University of Pennsylvania., Department of Urology, Urologikum Lübeck., Surgery- Urology service, Memorial Sloan Kettering., Oncology Clinical Pharmacology, Novartis (United States)., Novartis Pharmaceuticals., Department of Medicine, Memorial Sloan Kettering Cancer Center.