LAPATINIB FAILURE IN HCC

September 14, 2009 — Results from a phase 2 trial of lapatinib (Tykerb) in liver cancer were disappointing, with benefit seen only in a small subgroup of patients who developed a rash while taking the drug. The results are reported in the September 15 issue of Clinical Cancer Research.

Lapatinib was tested in hepatocellular cancer because one of its actions is to inhibit epidermal growth-factor receptor (EGFR), which is thought to be important in this disease. However, lapatinib also inhibits EGFR type 2 (HER2/neu), a pathway that is important in breast cancer, and lapatinib is currently approved for use in breast cancer patients who are being treated with capecitabine (Xeloda).

Currently, the standard treatment for liver cancer is sorafenib (Nexavar). This drug, like lapatinib, is an inhibitor of tyrosine kinase, but it inhibits a different set of pathways, including Raf kinase, platelet-derived growth factor, vascular endothelial growth factor, and the c-kit receptor for stem-cell factor.

No Objective Responses, But Benefit in Small Subgroup

The study tested lapatinib in 26 patients with advanced inoperable hepatocellular carcinoma. Patients received oral lapatinib 1500 mg each day for 28 days. A median of 2 cycles were administered (range, 1–14). The most common adverse effects were diarrhea (reported by 73% of patients), nausea (45%), and rash (42%), but the researchers report that the drug was well tolerated.

Median progression-free survival was 1.9 months, which the researchers describe as "uninteresting." However, the median overall survival was 12.6 months, which is "one of the highest reported in the literature," they note. But this may be partially explained by the use of sorafenib after disease progression in 40% of the patients, they add, noting that sorafenib has a known survival advantage in hepatocellular carcinoma.

No patient had an objective response. However, a small subgroup of patients showed some benefit from the drug. Ten patients (40%) had stable disease as their best response, and 6 (23%) had stable disease that lasted for more than 120 days.

Patients who developed a skin rash had a borderline statistically significant longer survival than patients who did not have a rash (16.2 vs 8.7 months, P = .07). This effect has also been seen with EGRF inhibitors in a variety of other cancers, the researchers note.

"Our findings suggest a potential benefit from EGFR inhibition," said lead author Tanios Bekaii-Saab, MD, medical director of gastrointestinal oncology at the Ohio State University Comprehensive Cancer Center in Columbus, in a press release.

"Overall, though, we were certainly hopeful that lapatinib would be more active and were somewhat disappointed by the results," Dr. Bekaii-Saab said.

Nevertheless, the study provides important information about the relevance of these signaling pathways in liver cancer, according to Samuel Ho, MD, an editorial board member of Clinical Cancer Research. Dr. Ho is chief of gastroenterology at the VA San Diego Healthcare System, and professor of medicine at the University of California, San Diego.

"The results support the fact that hepatocellular carcinomas are clinically and biochemically heterogenous, and that certain subsets of hepatocellular carcinoma may respond differently than others, suggesting that larger trials with patients more likely to respond may show a definite survival benefit," Dr. Ho said in a statement.

"However, this study failed to find a marker that could differentiate between tumors that may or may not be expected to respond," Dr. Ho pointed out. But it is unlikely that 1 marker alone would be predictive; multiple markers would make "more sense," given the complexity of the biology involved, he added.