Lapatinib Benefit Seen in Inflammatory Breast Cancer

November 1, 2006

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.

ISTANBUL, Turkey--The oralsmall-molecule lapatinib (Tykerb), a reversibledual tyrosine kinase inhibitor ofHER1 (epidermal growth factor) andHER2 receptors (see mechanism of actionimage on page 1), produced clinicalresponses in some women with inflammatorybreast cancer (IBC), a rare butaggressive form of the disease that is notusually detected by mammograms or ultrasound.Best responses were seen inpatients who overexpressed HER2.

At the 31st Congress of the EuropeanSociety for Medical Oncology (ESMO),Maureen Trudeau, MD, presented resultsof an international multicenterphase II trial aimed at identifying a tumorprofile in IBC that was predictive ofsensitivity to lapatinib (abstract 140 O).Results of a separate cardiac safety studyof lapatinib (see box on page 25) wereencouraging. "Lapatinib monotherapy isclinically active in heavily pretreated inflammatorybreast cancer patients," Dr.Trudeau said. "There was a 50% responserate in tumors overexpressing ErbB2[HER2] and a 7% response rate in tumorsexpressing ErbB1 [HER1]."

Rare But Potent
Inflammatory breast cancerprimarily affects the skin of thebreast, which typically appearsred, swollen, inflamed,and pitted like the skin of anorange, said Dr. Trudeau,head of the Division of MedicalOncology/Hematology,Sunnybrook Health Sciences Center,University of Toronto, Canada. WhileIBC affects only about 2% of the population,she said, it is potent, with aboutone-third of women presenting withmetastatic disease at initial diagnosis, andonly about half alive at 3 years. It alsostrikes a younger population; most IBCpatients are less than 50 years old.

The current trial (EGF103009) wasinitiated based on preclinical and limitedphase I data suggesting that patients withIBC might be particularly sensitive to theantitumor effects of lapatinib. For thestudy, women with relapsed or anthracycline-refractory IBC were stratified intotwo cohorts based on tumor biopsy results.One group of women (cohort A)comprised HER2 overexpressors (2/3+IHC/FISH+), and the other group (cohortB) expressed HER1 but were HER2non-overexpressors. More than 70% ofpatients had evidence of dermal-lymphaticinvasion at diagnosis.

All patients received lapatinib1,500 mg orally once daily.Investigators assessed responsein the skin, via serialdigital photographs, and alsoused RECIST criteria to evaluatepotential sites of distant metastasis(liver, lung, brain) by CT. Atpresentation, response data were availablein 47 patients who had reached day56 of therapy. Among the 32 patients inthe HER2-positive cohort A, 44% had apartial response to lapatinib and 6% acomplete response. Among the HER1-positive/HER2-negative cohort B patients,6.7% had a partial response.

Dr. Trudeau reported that lapatinibwas well tolerated with GI and skin-related adverse events generally grade 1or 2. One patient, however, had grade 3cardiotoxicity and was withdrawn fromthe study. Five deaths occurred in thecohort, but they were the result of diseaseprogression. Future studies oflapatinib in combination with othertherapies are warranted for women withIBC, the researchers said Lapatinib has been submitted to theFDA for treatment of advanced or metastaticHER2-positive breast cancer in patientswho have received prior therapy,including the HER2-targeting tyrosinekinase inhibitor trastuzumab (Herceptin).(Lapatinib and trastuzumab havenonoverlapping mechanisms of action.)Dr. Trudeau's study was sponsored byGlaxoSmithKline.