Sorafenib Benefits All Advanced HCC Subgroups but Not After TACE

ORLANDO, FL—Sorafenib was beneficial in one study of advanced hepatocellular carcinoma (HCC) patients, but failed to improve outcomes in another when given after transarterial chemoembolization (TACE), investigators reported at the 2010 Gastrointestinal Cancers Symposium.

In a subanalysis of the landmark international SHARP (Sorafenib HCC Assessment Randomized Protocol) trial, sorafenib was shown to be effective for HCC irrespective of baseline transaminase (ALT/AST), alpha-fetoprotein (AFP), and bilirubin levels. The study also showed that bilirubin levels are not appreciably affected by sorafenib treatment, reported Jean-Luc Raoul, MD, Centre Eugene Marquis, Rennes, France.

“Since hepatic function influences our treatment options, we examined the effect of sorafenib on hepatic function, as indicated by bilirubin levels, and performed subset analyses of SHARP according to baseline levels of ALT, AST, and AFP,” said Raoul.

The 605 patients in the trial were assessed according to whether they had normal or elevated transaminases and bilirubin. The analysis found that patients with elevated levels of ALT/AST, AFP, or bilirubin at baseline had shorter overall survival (OS) than those with normal levels of these markers. This was true across the subgroups, regardless of treatment; however, irrespective of baseline levels, sorafenib was effective and offered significant benefits over placebo, Raoul reported. In addition, bilirubin levels were not appreciably affected by treatment with the drug, although patients had a slight increase in bilirubin levels in cycle 2, he noted.

P

P

P

P

Sorafenib was associated with robust OS benefit in several subgroups. OS was 11.6 months with sorafenib versus 8.8 with placebo ( = .008) in patients with normal AST/ALT; 9.4 months versus 7.0 months ( = .009) in patients with elevated AFP; 11.1 months versus 9.1 months ( = .004) in patients with normal bilirubin; and 6.3 months versus 4.6 months ( = .058) in patients with moderately elevated transaminases, he reported.

Time to progression (TTP) and disease control rates followed a similar pattern, he reported. There were no notable differences in the safety profiles between patients with normal versus elevated transaminases.

P

“The study further supports the prognostic value of baseline AFT, AST/ALT, and bilirubin,” commented Anthony B. El-Khoueiry, MD, of the University of Southern California, who discussed the paper at the session. He said it is hard to make conclusions about the superiority of sorafenib in each subgroup, due to the small numbers of patients and the unplanned analysis, but the findings suggests that benefit is maintained in most patients, except perhaps those with elevated bilirubin, who showed only a trend for benefit ( = 0.099), he said.

2010 GI Symposium Abstract 129

Sorafenib after TACE: Less Benefit Shown

In contrast, in patients with unresectable HCC who responded to treatment with TACE, sorafenib did not significantly improve median TTP in a phase III multicenter study from Japan and South Korea.Kiwamu Okita, MD, of Shimonoseki Kohsei Hospital, Japan, said that most Japanese patients with advanced HCC are treated with TACE using gelatin sponge particles and chemotherapeutic agents. “Sorafenib has been shown to improve survival in HCC, therefore, we examined its benefit as an adjunct in patients who respond to TACE,” he said.

P

The study included 458 patients who responded to TACE and then were randomized to sorafenib 400 mg twice daily or placebo until progression. TTP was 5.4 months in the sorafenib arm and 3.7 months in the placebo arm, but this difference was not statistically significant ( = .252), he reported. OS was 29.7 months in the sorafenib arm, and has not been reached in the placebo arm.

Despite a lack of statistical significance, an exploratory subgroup analysis showed all subgroups favored sorafenib, with the exception of women treated with the drug.

P

Interestingly, a statistically significant benefit in TTP was shown in the South Korean cohort, whose median TTP has not been reached with sorafenib but was 5.5 months in the placebo arm, representing a 62% reduction in risk. No value is available for this analysis because it was unplanned and exploratory.

“The results of this trial do not impact ongoing investigations of sorafenib in patients with HCC, including the SPACE (Sorafenib or Placebo in Combination with TACE for Intermediate-Stage HCC) trial, or in studies in which sorafenib is administered in combination with TACE, rather than sequentially,” which may prove to be a more effective approach, said Okita.

2010 GI Symposium Abstract LBA128