Pazopanib exposure-response assessment as adjuvant therapy for patients with localized or locally advanced renal cell carcinoma (RCC) following nephrectomy.

Abstract

4564 Background: PROTECT was a Phase 3 randomized placebo-controlled study to evaluate pazopanib efficacy and safety as adjuvant RCC treatment. The starting dose was 800 mg daily, which was reduced to 600 mg in an attempt to improve tolerability. Pazopanib trough concentrations (Ctrough) were collected from 358 patients at the 600-mg starting dose at two timepoints (Week 3/ 5 and Week 16/20). This analysis characterized the relationship between Ctrough and efficacy and safety endpoints. Methods: The relationship between pazopanib Ctrough and disease-free survival (DFS) was explored by Cox regression analysis. DFS of pazopanib Ctrough quartiles was explored using Kaplan-Meier plots. Exposure-safety relationship was explored via summaries of all grade adverse events (AEs), grade 3/4 (G3/4) AEs, and AE-related treatment discontinuation by Ctrough quartiles. Results: The geometric mean (geo-CV%) of Ctrough at 600-mg dose was 31.4 (57%) µg/mL and 25.3 (70%) µg/mL for Week 3/5 and Week 16/20, respectively. At Week 16/20, Ctrough values overlapped among patients receiving 400-, 600-, and 800-mg doses. Cox regression analysis showed pazopanib Ctrough at Week 3/5 as a significant covariate for DFS after adjusting for TNM staging and Fuhrman Nuclear grading (HR: 0.58, 95% CI, 0.42, 0.82; p = 0.002). Longer DFS was observed in higher Week 3/5 Ctrough quartiles (median DFS by quartile—Q1: 41.89 months, Q2-Q4: median DFS not reached). Incidence of all-grade AEs, as well as G3/4 hypertension, increased as Ctrough increased. Treatment discontinuation due to hypertension among pazopanib-treated subjects was low (3.1% vs < 1% in the placebo group). Ctrough was not correlated to G3/4 ALT increase. Incidence of other G3/4 AEs plateaued at higher Ctrough. No relationship was observed between Ctrough and treatment discontinuation due to AEs. Conclusions: Pazopanib Ctrough levels in PROTECT were consistent with levels associated with efficacy in the advanced setting. Higher pazopanib Ctrough correlated with longer DFS. Higher pazopanib exposure did not increase the incidence of G3/4 AEs, with the exception of hypertension, which was adequately controlled and managed. Clinical trial information: NCT01235962.