New combination therapy may improve survival for advanced liver cancer patients

Abou-Alfa GK. JAMA. 2010;304:2154-2160.

The proportion of progression events in patients treated with doxorubicin/sorafenib combination therapy was half that of patients treated with doxorubicin and placebo, according to study results.

Previous study results have indicated that 400 mg sorafenib administered twice daily increased OS rates among patients with advanced hepatocellular carcinoma (HCC) and Child-Pugh class A disease, and that sorafenib with 60 mg/m² doxorubicin was well tolerated in patients with refractory solid tumors.

The current study is the first phase 2 or 3 analysis to examine the combination in patients with advanced HCC. The aim was to evaluate safety and efficacy outcomes for the doxorubicin/sorafenib combination as compared with doxorubicin alone in patients with advanced HCC and Child-Pugh class A disease.

Ninety-six patients from several countries participated in the double blind, phase 2 trial from April 2005 to October 2006. Eligible participants had advanced HCC, ECOG performance status of 0 to 2, Child-Pugh class A status and no prior systemic therapy.

Forty-seven patients received 60 mg/m² IV doxorubicin every 21 days, plus 400 mg oral sorafenib twice a day; 49 patients received the same doxorubicin regimen, plus placebo twice daily.

Encouraging results

There were 51 time-to-progression events overall; twenty-four occurred in the combination therapy group and 27 occurred in the placebo group.

Exploratory analysis results indicated that the risk for progression in the combination group was half the risk for progression in the placebo group (HR=0.5; 95% CI, 0.3-0.9). Competing risk analysis results indicated that the cumulative incidence of progression at the 4-month mark was 26% in the combination group (95% CI, 23-29) and 55% in the placebo group (95% CI, 53-57).

The median time to progression was 6.4 months in the combination group (95% CI, 4.8-9.2) and 2.8 months (95% CI, 1.6-5) in the monotherapy group.

There were 25 deaths in the combination group and 38 deaths in the placebo group. Patients in the combination group experienced a median OS time of 13.7 months (95% CI, 8.9-not reached) compared with 6.5 months in the placebo group (95% CI, 4.5-9.9). The HR for mortality risk in the therapy group was 0.49 (95% CI, 0.3-0.8) compared with the placebo group.

Of 70 PFS events overall, 32 occurred in the combination group and 38 occurred in the placebo group. PFS was 6 months (95% CI, 4.6-8.6) in the combination group and 2.7 months (95% CI, 1.4-2.8) in the placebo group. Exploratory analysis results indicated a 46% reduction in risk for progression in the combination group compared with the placebo group (HR=0.54; 95% CI, 0.3-0.8).

Tumor shrinkage occurred in 62% of combination therapy patients and 29% of placebo patients.

Grade 3 or 4 toxic events included fatigue, hand-foot skin reaction, diarrhea and neutropenia. Rates for these events were similar to those observed for the individual agents when administered as monotherapy.

Protocols and reaction

The primary endpoint — which was determined by independent review — was time to progression. Secondary endpoints included PFS, response rate and toxicity.

The trial was halted in the wake of an unplanned early analysis for efficacy performed by the independent review committee after complete accrual. At that point, two patients remained in the placebo group. Those patients were offered sorafenib.

The researchers said the results for the combination therapy are encouraging, but that “the degree to which this improvement may represent synergism between sorafenib and doxorubicin remains to be defined.”

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