Sorafenib in advanced melanoma: a critical role for pharmacokinetics?

Abstract

Background: Inter-patient pharmacokinetic variability can lead to suboptimal drug exposure, and therefore might impact the efficacy of sorafenib. This study reports long-term pharmacokinetic monitoring of patients treated with sorafenib and a retrospective pharmacodynamic/pharmacokinetic analysis in melanoma patients.

Patients and methods: Heavily pretreated patients with stage IV melanoma were started on sorafenib 400 mg twice daily (bid). In the absence of limiting toxicity, dose escalation of 200 mg bid levels was done every 2 weeks. Plasma sorafenib measurement was performed at each visit, allowing a retrospective pharmacodynamic/pharmacokinetic analysis for safety and efficacy.

Results: In all, 19 of 30 patients underwent dose escalation over 400 mg bid, and 28 were evaluable for response. The overall disease control rate was 61% (95% confidence interval (CI): 42.6-78.8), including three confirmed responses (12%). Disease control rate and progression-free survival (PFS) were improved in patients with high vs low exposure (80% vs 32%, P=0.02, and 5.25 vs 2.5 months, P=0.005, hazard ratio (HR)=0.28 (95% CI: 0.11-0.73)). In contrast, drug dosing had no effect on PFS. In multivariate analysis, drug exposure was the only factor associated with PFS (HR=0.36 (95% CI: 0.13-0.99)). Diarrhoea and anorexia were correlated with drug dosing, while hypertension and hand-foot skin reaction were correlated with drug exposure.

Conclusions: Although sorafenib had modest efficacy in melanoma, these results suggest a correlation between exposure and efficacy of sorafenib. Therefore, dose optimisation in patients with low exposure at standard doses should be evaluated in validated indications.

Conflict of interest statement

FG has worked as paid consultant for Bayer Healthcare and Pfizer. OM has worked as paid consultant for Roche. The other authors declare no conflict of interest.

© 2012 Cancer Research UK

Figures

Figure 1

Effect of dose escalation on inter patient sorafenib AUC (mg l−1 h−1). A total 119 AUCs from 29 patients are represented. Wilcoxon’s P-value: *<0.05, **<0.005, NS >0.05.

Figure 2

Effect of dose escalation on intra patient sorafenib AUC (mg l−1 h−1). Median AUCs from 19 patients are represented. In red: increased exposure; in orange: stable exposure; in green: decreased exposure.

Figure 3

Investigator-assessed tumour regression (i.e., maximum change from baseline in target lesions diameter). (n=27) Patients with RECIST progressive disease are indicated by an asterix. Clear grey: AUCmax <100 mg l−1 h−1; dark grey: AUCmax⩾100 mg l−1 h−1.

Figure 4

PFS probability according to maximal exposure to sorafenib (AUCmax). Dot line: patients with AUCmax −1 h−1/ solid line: patients with AUCmax⩾100 mg l−1 h−1.