OR WAIT null SECS
SAN ANTONIO -- The success of Herceptin (trastuzumab) in treating HER2-positive breast cancer has led to a search for other targeted therapies, researchers said here, and a range of so-called small molecules is in the pipeline.
SAN ANTONIO, Dec. 19 -- The success of Herceptin (trastuzumab) in treating some forms of breast cancer has led to a search for other targeted therapies, researchers said here, and a range of so-called small molecules is in the pipeline.
Herceptin is a monoclonal antibody that blocks the extracellular domain of the HER2 protein, noted Mark Pegram, M.D., of the UCLA School of Medicine, but the protein also has a cytoplasmic domain that can be targeted with small molecules.
Both forms of attacks have advantages and disadvantages, Dr. Pegram told an official satellite session at the San Antonio Breast Cancer Symposium. The session was sponsored by GlaxoSmithKline, which makes Tykerb (lapatinib), an investigational tyrosine kinase that is being used to target HER2.
One disadvantage of the small molecules, compared with Herceptin, is that they are less specific, Dr. Pegram said: Where Herceptin targets a specific part of the HER2 protein, tyrosine kinases can affect the cytoplasmic domains of many proteins.
On the other hand, he said, the small molecules can be given orally, rather than by injection, and they have a short half-life, unlike Herceptin which can last for several weeks.
Clinical use of the drugs - when the small molecules are available - will require physicians to balance the advantages and disadvantages, he said, and more research will be needed to understand how the medications should be employed.
One key question, he said, is whether the monoclonal antibodies and small molecules should be used singly or in combination.
In some patients, treatment with Herceptin leads to cardiac dysfunction, including reduced left-ventricular ejection fraction (LVEF), according to Edith Perez, M.D., of the Mayo Clinic in Jacksonville, Fla., but stopping treatment usually resolves the symptoms and allows re-treatment.
For that reason, she said, she and colleagues are studying the cardiac effects of Tykerb. In a meta-analysis of 3,558 patients, they reported earlier this year, they found that symptomatic or asymptomatic drug-related decreases in LVEF were seen in 0.2% and 1.6% of patients, respectively.
The changes were generally reversible, and non-progressive, she said.
Tykerb as a first-line therapy in HER2-positive breast cancer "appears to have similar activity" to first-line Herceptin, although the data is limited, said Eric Winer M.D., of the Dana-Farber Cancer Institute in Boston.
Data presented here from a first-line Tykerb monotherapy trial, using different doses of the drug, showed no complete responses, he said, but there were 32 partial responses (in 138 patients) and 71 cases of stable disease (24% and 51% respectively).
The findings are "promising and intriguing," he said, but added that treatment in the future will involve multiple biologic agents with or without chemotherapy, rather than monotherapy.
Another important biological target is the vascular endothelial growth factor (VEGF), which has been successfully targeted in HER2-negative breast cancer, as well as other malignancies, with the monoclonal antibody Avastin (bevacizumab), said Kathy Miller, M.D., of the Indiana University School of Medicine in Indianapolis.
As in the HER2 case, she said, a host of experimental small molecules are now being tested, including sunitinib, axitinib, and pazopanib. Some of these medications have already demonstrated efficacy in metastatic breast cancer, Dr. Miller said.
"This is a very fruitful area," she said, adding "there is much more to be gained by inhibiting the VEGF pathway." Like Drs. Winer and Pegram, she also suggested that combination therapy is the probable way forward.