CONTEXT

In a randomized phase 3 trial, 400 mg of sorafenib twice daily prolonged overall survival of patients with advanced hepatocellular carcinoma (HCC) and Child-Pugh A disease. In a phase 1 study, sorafenib combined with doxorubicin, 60 mg/m(2), was well tolerated by patients with refractory solid tumors. The combination of sorafenib and doxorubicin in patients with advanced HCC has not been evaluated in a phase 2 or 3 trial.

OBJECTIVE

To evaluate the efficacy and safety of doxorubicin plus sorafenib compared with doxorubicin alone in patients with advanced HCC and Child-Pugh A disease.

DESIGN, SETTING, AND PATIENTS: In a double-blind phase 2 multinational study, conducted from April 2005 to October 2006, 96 patients (76% male; median age, 65 years [range, 38-82 years]) with advanced HCC, Eastern Cooperative Oncology Group performance status 0 to 2, Child-Pugh A status, and no prior systemic therapy were randomly assigned to receive 60 mg/m(2) of doxorubicin intravenously every 21 days plus either 400 mg of sorafenib or placebo orally twice a day. The date of the last patient's follow-up was April 2008.

MAIN OUTCOME MEASURE

Time to progression as determined by independent review.

RESULTS

Following complete accrual, an unplanned early analysis for efficacy was performed by the independent data monitoring committee, so the trial was halted. The 2 patients remaining in the placebo group at that time were offered sorafenib. Based on 51 progressions, 63 deaths, and 70 events for progression-free survival, median time to progression was 6.4 months in the sorafenib-doxorubicin group (95% confidence interval [CI], 4.8-9.2), and 2.8 months (95% CI, 1.6-5) in the doxorubicin-placebo monotherapy group (P = .02). Median overall survival was 13.7 months (95% CI, 8.9--not reached) and 6.5 months (95% CI, 4.5-9.9; P = .006), and progression-free survival was 6.0 months (95% CI, 4.6-8.6) and 2.7 months (95% CI, 1.4-2.8) in these groups, respectively (P = .006). Toxicity profiles were similar to those for the single agents.

CONCLUSIONS

Among patients with advanced HCC, treatment with sorafenib plus doxorubicin compared with doxorubicin monotherapy resulted in greater median time to progression, overall survival, and progression-free survival. The degree to which this improvement may represent synergism between sorafenib and doxorubicin remains to be defined. The combination of sorafenib and doxorubicin is not yet indicated for routine clinical use.

TRIAL REGISTRATION

clinicaltrials.gov Identifier: NCT00108953.