Two phase-2 trials examine treatments for hepatocellular carcinoma

SAN DIEGO — Promising results of two phase-2 studies examining the effect of the tyrosine kinase inhibitors, sunitinib and lapatinib, on advanced hepatocellular cancer were presented this week at the 2008 Annual Meeting of the American Association for Cancer Research.

Although not as common in the United States as elsewhere, hepatocellular carcinoma rates are rising here, possibly due to increasing rates of hepatitis C and fatty liver disease, according to researchers.

The first study by Andrew X. Zhu, MD, PhD, and colleagues at Massachusetts General Hospital and Dana Farber Harvard Cancer Center found that treatment with sunitinib (Sutent, Pfizer) slows tumor growth and reduces the risk of metastasis.

“We observed preliminary antitumor activity in hepatocellular carcinoma patients,” Zhu said during an April 14 press briefing.

Thirty-four patients with unresectable or metastatic hepatocellular carcinoma were treated with 37.5 mg of sunitinib once daily for 28 days during a six-week cycle. One patient achieved partial response of 20 months duration and 17 (50%) achieved stable disease. The median progression-free survival was 3.9 months and the median overall survival was 9.8 months.

“In addition, we have consistently observed changes in several markers that are thought to be very critical for angiogenesis and some of these markers seem to be correlated with clinical outcomes,” Zhu said.

Stable disease with lapatinib

The second study, conducted by Tanois Bekaii-Saab, MD, assistant professor of hematology and oncology at The Ohio State University-James Cancer Hospital, and colleagues found that 31% of patients with hepatocellular carcinoma who were treated with lapatinib (Tykerb, GlaxoSmithKline) had stable disease, 8% of whom had stable disease for more than nine months.

This trial is novel in that it examined the effect of a dual inhibitor; lapatinib blocks the activity of both HER2/neu and EGFR.

“A previous clinical trial suggested interesting activity with blockade of EGFR alone,” Joseph Markowitz, MD, a researcher at the university, told HemOnc Today. “We thought that by blocking both EGFR and HER2 we would achieve improved efficacy.”

Lapatinib was administered orally to 26 patients with advanced hepatocellular cancer at 1,500 mg/day for a 28-day cycle. Median number of cycles was two, with a range of one to 14 or more cycles. Twenty percent of patients had received treatment prior to receiving lapatinib. The most common toxicities were diarrhea and nausea.

“This is a phase-2 trial with interesting activity. Further validation of this activity should be tested in a randomized, controlled study. We have conducted a number of correlative translational studies looking at mutational status of EGFR and HER2, as well as immunohistochemical markers for the downstream signaling of EGFR. This will hopefully help us figure out exactly why a certain subset of patients may have had a marked response,” Markowitz said. – by Leah Lawrence

The study by Zhu et al is a well conducted translational phase-2 trial with new and innovative clinical and biological knowledge. We are now seeing the evolution of antiangiogenic agents from single target agents to multitarget agents. We are seeing common and yet different biomarker activity with clinical implications leading to important further investigation and discovery.

– Christopher Willett, MD

Department of Radiation Oncology
Duke University Medical Center

For more information:

• Zhu AX. #LB-139.
• Markowitz J. #LB-306. Both presented at: 2008 Annual Meeting of the American Association for Cancer Research; April 12-16, 2008; San Diego.