The value of sorafenib trough levels in patients with advanced hepatocellular carcinoma–a substudy of the SORAMIC trial

Background: Sorafenib for advanced hepatocellular carcinoma (HCC) is dose adjusted by toxicity. Preliminary studies have suggested an association between plasma concentrations of sorafenib and its main metabolite (M2) and clinical outcomes. This study aimed to validate these findings and establish target values for sorafenib trough concentrations. Methods: Patients with advanced HCC were prospectively recruited within a multicenter phase II study (SORAMIC). Patients with blood samples available at trough level were included for this pharmacokinetic (PK) substudy. Trough plasma concentrations of sorafenib and its main metabolite (M2) were associated with sorafenib-related toxicity and overall survival (OS). Results: Seventy-four patients were included with a median OS of 19.7 months (95% CI 16.1–23.3). Patients received sorafenib for a median of 51 weeks (IQR 27–62) and blood samples were drawn after a median of 25 weeks (IQR 10–42). Patients had a median trough concentration of 3217 ng/ml (IQR 2166–4526) and 360 ng/ml (IQR 190–593) with coefficients of variation of 65% and 146% for sorafenib and M2, respectively. Patients who experienced severe sorafenib-related toxicity received a lower average daily dose (551 vs 730 mg/day, p =.003), but showed no significant differences in sorafenib (3298 vs 2915 ng/ml, p =.442) or M2 trough levels (428 vs 283 ng/ml, p =.159). Trough levels of sorafenib or M2 showed no significant association with OS. Conclusions: In patients with advanced HCC treated with sorafenib, the administered dose, trough levels of sorafenib or M2, and clinical outcomes were poorly correlated. Toxicity-adjusted dosing remains the standard for sorafenib treatment.