Bevacizumab and erlotinib appeared to improve survival in hepatocellular carcinoma

Randomized, phase-2 trial may have made results clearer.

The results of a recent single-arm, phase-2 study suggest that bevacizumab and erlotinib could be an alternative to sorafenib for treating hepatocellular carcinoma, but the trial design could make evaluating the results difficult.

A team of researchers from M.D. Anderson Cancer Center reported the results in the Journal of Clinical Oncology. They assigned 40 patients with advanced liver cancer to 150 mg oral erlotinib (Tarceva, OSI Pharmaceuticals) daily and 10 mg/kg bevacizumab (Avastin, Genentech) on days one and 15 of a 28-day cycle.

The primary endpoint was 16-week PFS, and 62.5% of patients met that target. Median PFS was 39 weeks (95% CI, 26-45 weeks) and median OS was 68 weeks (95% CI, 48-78 weeks).

“Single-arm studies are very difficult to interpret,” said Josep M. Llovet, MD, professor of research at University of Barcelona and director of the hepatocellular carcinoma research program at Mount Sinai School of Medicine. He wrote an accompanying editorial in the Journal of Clinical Oncology.

“For instance, in this study, I realize that the outcome of 15.7 months is important. The problem is, what are we comparing this 15.7 months with? Are we comparing it with the control arm of the phase-3 sorafenib (Nexavar, Bayer) trial where the median survival was 7.9 months? If the target populations are the same and we can do this comparison, the outcome is outstanding.”

Llovet was part of a team of experts convened by the American Association for the Study of Liver Disease who published guidelines in 2008 calling for randomized, phase-2 trials to evaluate potential treatments for hepatocellular carcinoma.

“When analyzing the patients who were included in this study, I realized that 35% were not at an advanced stage of the disease. These patients present a better outcome even without treatment,” he told HemOnc Today. “The only way to control for that is with a randomized, phase-2 study. You would have a control arm with which to compare — same target population, same center and same investigator. Then you will have a clearer answer.”

Llovet said the results of the study are worthy of evaluation in a phase-3 study. But he could not determine if the survival results were a function of the natural history of the study population or evidence of the effectiveness of bevacizumab and erlotinib.

“I think it’s a combination of both,” he said. “The combination of bevacizumab and erlotinib looks effective, but in order to understand if it’s better than the standard of care, sorafenib, we need a phase-3 study. I personally need additional data in terms of phase-3 data in order to identify the advantage of the combination and as a result of patients being at intermediate stage.” – by Jason Harris

J Clin Oncol. 2009;doi:10.1200/JCO.2008.18.3301.