more on lapatinib--who it works on,what cardiac risks,etc

[Lani]

Skin Rash Seemingly Predicts Response to Therapy

June 16, 2006 (Atlanta) — In an unexpected twist, researchers found that patients who developed a rash in response to treatment with lapatinib lived twice as long as those who did not. "I think this is a signal," lead author Ramesh Ramanathan, MD, from the University of Pittsburgh School of Medicine, Pennsylvania, told Medscape. "The rash may well be an early marker, but we have yet to identify predictive factors."

The small study, supported by the National Cancer Institute, was presented at the 42nd annual meeting of the American Society of Clinical Oncology. The researchers studied 49 patients with advanced liver, gallbladder, and bile duct cancers who were not candidates for surgery. "Traditional chemotherapy is difficult to administer in these patients, so we are evaluating the potential of molecularly targeted drugs such as lapatinib," Dr. Ramanathan said during an interview.

Predicting Cancer Growth and Identifying Patients Most Likely to Respond

Lapatinib is not yet available in the US, but its maker, GlaxoSmithKline, intends to market the product under the brand name Tykerb. The company plans to submit a regulatory file later this year or early in 2007. The product is a dual tyrosine kinase inhibitor of epidermal growth factor receptors ErbB1 and ErB2. "On the plus side," Dr. Ramanathan said, "lapatinib is an oral drug, easily administered, and with very mild toxicity."

But his group found that 20 patients developed a skin rash and that those who developed the irritation lived for an average of 10 months compared with 5 months for those who did not develop a rash. Patients were taking lapatinib 1500 mg per day.

“While we don’t yet know exactly why this has been reported here and in other studies, it has implications for predicting the growth of cancer and could be a method to identify patients with advanced cancer who would be most likely to respond to this treatment,” Dr. Ramanathan said.

Failed to Meet Study Objective

But the work did not achieve the study's objective of higher response. In its 2-stage design, where patients were stratified by tumor type, the study had a 90% power to detect a true response rate of 20% or higher.

After radiological assessment every 8 weeks, the researchers found no activity with lapatinib in gallbladder or bile duct cancer. Two patients with primary liver cancer had a partial response to treatment, and the disease was stabilized in an additional 17 patients. "Lapatinib activity in hepatocellular cancer is encouraging," the researchers note.

Despite disappointing results in gallbladder and bile duct cancer, lapatinib has shown promise in several tumor types. But researchers have also pointed to a possible cardiotoxic effect.

Potential Cardiotoxic Effect

Another group, also presenting findings at the meeting, looked at more than 2800 lapatinib-treated patients. In this GlaxoSmithKline-supported study, the researchers found that a decrease in left ventricular ejection fraction is rarely symptomatic and generally reversible. The incidence in their cohort was 1.3%. The investigators, led by Edith Perez, MD, from the Mayo Clinic in Jacksonville, Florida, note, "This is less than the 3% to 6% incidence of asymptomatic decreases observed in the general population."

Dr. Ramanathan told Medscape that his group tested ejection fractions but saw no evidence of the problem and found the product to be generally well tolerated.

J Clin Oncol. 2006;24(18 suppl):4010, 583.