Clinical

Optimal dosing of everolimus defined for advanced liver cancer

Last Updated: 2012-11-14 13:18:13 -0400 (Reuters Health)

By Robert Saunders

NEW YORK (Reuters Health) - Everolimus was more effective when given daily rather than weekly to patients with advanced hepatocellular cancer (HCC), and the maximum tolerated dose was 7.5 mg/day, in a phase I study in Taiwan.

Based on another finding from the study, the investigators also recommend that "prophylactic anti-viral therapy should be mandatory for HBsAg-seropositive patients" being treated with everolimus.

Dr. L.-T. Chen, with the National Institute of Cancer Research, National Health Research Institutes in Tainan, and colleagues explain in their online paper in Alimentary Pharmacology and Therapeutics that mTOR signaling is often upregulated in HCC, and the mTOR inhibitor everolimus has been shown to reduce the risk of HCC recurrence and new tumor development.

However, while an everolimus dose of 10 mg/day is recommended in treating other types of cancer, this may not be optimal in patients with impaired liver function because of reduced drug clearance. To investigate this issue, the team conducted a dose-escalation study in which 39 patients with locally advanced or metastatic HCC were randomly assigned to receive daily doses of 2.5, 5.0, 7.5 and 10.0 mg of everolimus, or weekly doses of 20, 30, 50 and 70 mg.

In the daily group, dose-limiting grade 3-4 toxicities occurred in one patient in each of the three lower dose levels and in two given the highest dose. In the weekly group, dose-limiting toxicities occurred in one patient receiving 30 mg and one receiving 70 mg. The authors therefore determined the maximum tolerated dose of everolimus to be 7.5 mg/day or 70 mg weekly.

However, while the study was not designed to assess efficacy, disease control rates were 71.4% in the daily arm and 44.4% in the weekly group.

"We did not expect weekly dosing would be associated with poorer efficacy before the initiation of the trial," Dr. Chen told Reuters Health via email. "We included the weekly dosing arm simply to compare the efficacy and toxicity profile of weekly and daily dosing schedule in HCC patients, a population whose underlying liver diseases may potentially alter the pharmacokinetics of everolimus."

Based on these results, the authors conclude, "The recommended everolimus dosing schedule for future hepatocellular carcinoma studies is 7.5 mg daily."

Four patients who were positive for hepatitis B surface antigen (HBsAg) exhibited a significant increase in serum HBV levels, along with grade 3-4 elevations in alanine transaminase (ALT). "Everolimus can cause HBV reactivation and hepatitis flare-up in HBsAg carriers," Dr. Chen commented. "Therefore, preemptive anti-HBV therapy is recommended for patients going to receive everolimus."

Meanwhile, the authors note, "The efficacy and safety of everolimus 7.5 mg daily is being compared with that of placebo, both given with best supportive care, in patients with advanced HCC that progressed after sorafenib or who are sorafenib intolerant in the ongoing international, randomized, phase 3 EVOLVE-1 trial."

SOURCE: http://bit.ly/SoBlic

Aliment Pharmacol Ther 2012.