ISTANBUL, Turkey—The oral small-molecule lapatinib (Tykerb), a reversible dual tyrosine kinase inhibitor of HER1 (epidermal growth factor) and HER2 receptors (see mechanism of action image on page 1), produced clinical responses in some women with inflammatory breast cancer (IBC), a rare but aggressive form of the disease that is not usually detected by mammograms or ultrasound. Best responses were seen in patients who overexpressed HER2.
At the 31st Congress of the European Society for Medical Oncology (ESMO), Maureen Trudeau, MD, presented results of an international multicenter phase II trial aimed at identifying a tumor profile in IBC that was predictive of sensitivity to lapatinib (abstract 140 O). Results of a separate cardiac safety study of lapatinib (see box on page 25) were encouraging. “Lapatinib monotherapy is clinically active in heavily pretreated inflammatory breast cancer patients,” Dr. Trudeau said. “There was a 50% response rate in tumors overexpressing ErbB2 [HER2] and a 7% response rate in tumors expressing ErbB1 [HER1].”
Rare But Potent
Inflammatory breast cancer
primarily affects the skin of the
breast, which typically appears
red, swollen, inflamed,
and pitted like the skin of an
orange, said Dr. Trudeau,
head of the Division of Medical
Oncology/Hematology,
Sunnybrook Health Sciences Center,
University of Toronto, Canada. While
IBC affects only about 2% of the population,
she said, it is potent, with about
one-third of women presenting with
metastatic disease at initial diagnosis, and
only about half alive at 3 years. It also
strikes a younger population; most IBC
patients are less than 50 years old.
The current trial (EGF103009) was initiated based on preclinical and limited phase I data suggesting that patients with IBC might be particularly sensitive to the antitumor effects of lapatinib. For the study, women with relapsed or anthracycline- refractory IBC were stratified into two cohorts based on tumor biopsy results. One group of women (cohort A) comprised HER2 overexpressors (2/3+ IHC/FISH+), and the other group (cohort B) expressed HER1 but were HER2 non-overexpressors. More than 70% of patients had evidence of dermal-lymphatic invasion at diagnosis.
All patients received lapatinib 1,500 mg orally once daily. Investigators assessed response in the skin, via serial digital photographs, and also used RECIST criteria to evaluate potential sites of distant metastasis (liver, lung, brain) by CT. At presentation, response data were available in 47 patients who had reached day 56 of therapy. Among the 32 patients in the HER2-positive cohort A, 44% had a partial response to lapatinib and 6% a complete response. Among the HER1- positive/HER2-negative cohort B patients, 6.7% had a partial response.
Dr. Trudeau reported that lapatinib was well tolerated with GI and skin-related adverse events generally grade 1 or 2. One patient, however, had grade 3 cardiotoxicity and was withdrawn from the study. Five deaths occurred in the cohort, but they were the result of disease progression. Future studies of lapatinib in combination with other therapies are warranted for women with IBC, the researchers said Lapatinib has been submitted to the FDA for treatment of advanced or metastatic HER2-positive breast cancer in patients who have received prior therapy, including the HER2-targeting tyrosine kinase inhibitor trastuzumab(Drug information on trastuzumab) (Herceptin). (Lapatinib and trastuzumab have nonoverlapping mechanisms of action.) Dr. Trudeau's study was sponsored by GlaxoSmithKline.
