In Brief

From OncoLog, January 2007, Vol. 52, No. 1

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Lapatinib Shows Promise for Inflammatory Breast Cancer

In a multicenter and international clinical trial of the experimental biological agent lapatinib, researchers have discovered that it is active against inflammatory breast cancer (IBC), an aggressive and often lethal form of the disease.

Massimo Cristofanilli, M.D., associate professor in the Department of Breast Medical Oncology at M. D. Anderson Cancer Center, reported the findings of the international phase II trial at the San Antonio Breast Cancer Symposium in December.

IBC is a fast growing cancer. According to Dr. Cristofanilli, only 40% of women with IBC will survive five years. Until now, no therapies specific to IBC have been studied in multicenter clinical trials. Therefore, no proven therapies—standard or experimental—currently exist for women with IBC.

“We did this phase II study because lapatinib is one of the few drugs that has shown any activity in phase I studies in patients with recurrent IBC. It appeared that this agent could become the first to offer hope for women newly diagnosed with the disease,” said Dr. Cristofanilli, the study’s principal investigator.

Lapatinib is an epidermal growth factor receptor (EGFR) and HER2neu tyrosine kinase inhibitor. An experimental drug that has shown promise in patients with metastatic HER2- positive breast cancer in whom trastuzumab (Herceptin) has failed, the oral agent blocks the activity of the HER2 protein as well as EGFR by binding to the part of the protein found inside breast cancer cells, explained Dr. Cristofanilli.

The study reports that 30 of the 35 patients, or 86%, had a clinical response (defined as a 50% or greater reduction in tumor size) to the lapatinib chemotherapy drug regimen. Just as interesting and important is the finding that 25% to 30% of the patients receiving lapatinib alone responded in the first two weeks, said Dr. Cristofanilli.

“With lapatinib, we finally have a drug on which to build effective therapy—we just have to refine the most effective way to use it,” said Dr. Cristofanilli.

Further studies are planned with lapatinib that will likely include the agent in combination with different chemotherapy regimens.

New Molecule Targets Leukemia

Researchers at M. D. Anderson Cancer Center report that a novel multi-kinase inhibitor, MK-0457 (VX-680), is clinically active against multiple target mutations in two types of leukemia and myeloproliferative disorders and produces few side effects.

Francis J. Giles, M.D., professor in the Department of Leukemia at M. D. Anderson, presented the phase I/II trial data at the annual meeting of the American Society of Hematology in December.

According to Dr. Giles, the study of 44 patients, conducted at M. D. Anderson and Duke University Medical Center, showed the first clinical activity of a kinase inhibitor against the T315I BCR-ABL mutation found in chronic myeloid leukemia and acute lymphocytic leukemia. In addition, the trial showed the first activity against the JAK-2 mutation found in myeloproliferative disorders.

The findings could potentially lead to effective treatments for diseases resistant to imatinib (Gleevec), nilotinib (Tasigna), and dasatinib (Sprycel). The T315I mutation is known to be responsible for the aggressive biological growth cycle and resistance to these drugs.

Dr. Giles reported that patients on the study experienced minimal side effects, such that no maximum tolerated dose was defined. Mild side effects included lowering of white blood cell counts, hair loss, nausea, and inflammation of the mouth.

“This drug produces clinical and biologic activity where we have not seen it before—in T315I-positive chronic myeloid and acute lymphocytic leukemias and JAK-2-positive myeloproliferative disorders,” Dr. Giles said.

“While we went into this trial to determine the safety and dosage of the drug, it became apparent quite quickly that the drug was very well tolerated and showed a clinical response not only in patients but in terms of pharmacodynamics,” said Dr. Giles. “As a result, we ended the phase I aspect of the trial earlier than anticipated and moved into phase II with a range of different doses. We are quite hopeful that this drug will ultimately prove to be clinically beneficial for this segment of patients, but additional research will be needed.”

Though chronic myeloid leukemia, acute lymphocytic leukemia, and myeloproliferative disorders are relatively rare cancers, they are very aggressive and often fatal after standard therapy fails, said Dr. Giles. For the subset of leukemia patients who have the T315I mutation or for patients with myeloproliferative disorders with the JAK-2 mutation—about 10% of patients with the respective diagnoses—there are no therapies available to specifically attack these key mutations.

“This is a relatively small population that can potentially benefit from the drug, but for those who have these mutations, this research opens the door to a tremendous option for them,” said Dr. Giles.

Dr. Giles and his team are planning an international phase II study of MK-0457 in patients with the T315I mutation.

For more information on this topic or for questions about M. D. Anderson’s treatments, programs, or services, call askMDAnderson at (877) MDA-6789.

Other articles in OncoLog, January 2007 issue:

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