Lapatinib: new opportunities for management of breast cancer

Abstract

Approximately 20% of new diagnosed breast cancers overexpress the human epidermal growth factor receptor 2 (EGFR2), also known as erythroblastic leukemia viral oncogene homolog 2 (ERBB2) protein, as a consequence of ERBB2 gene amplification, resulting in a poor prognosis. Clinical outcome can be substantially improved by ERBB2-targeted therapy. Lapatinib is a potent, orally bioavailable small molecule that reversibly and selectively inhibits epidermal growth factor receptor (EGFR1 or ERBB1) and ERBB2 tyrosine kinases. Lapatinib binds the adenosine triphosphate-binding site of the receptor's intracellular domain to inhibit tumor cell growth. This review summarizes the pharmacology, pharmacokinetics, efficacy, and tolerability of lapatinib, and reviews both Food and Drug Administration-approved and investigational uses of lapatinib in breast cancer therapy. The drug is generally well tolerated in patients, with diarrhea and rashes being the most common (usually mild or moderate) adverse effects. Unlike trastuzumab, lapatinib has infrequent adverse effects on cardiac function. Lapatinib has substantial activity for advanced ERBB2-positive breast cancer, particularly in combination with capecitabine, following progression after anthracyclines, taxanes, and trastuzumab. Lapatinib combined with capecitabine yielded significant improvements in time to progression and response rate compared with capecitabine alone. This drug can also be combined with letrozole for the treatment of postmenopausal women with ERBB2-positive breast cancer, for whom hormonal therapy is indicated. Lapatinib has shown early promise in treatment of central nervous system metastasis and is being further evaluated in various clinical settings.

Potency and plasma protein binding of drugs in vitro—a potentially misleading pair for predicting in vivo efficacious concentrations in humans

“…For a few drugs for which therapeutic dose AUCs had been reported in patients, we used the reported AUCs rather than the above equation to calculate the C u_ss.avg . This information was available for erlotinib and lapatinib (epidermal growth factor receptor [EGFR] inhibitors, reported in research articles [34]), dasatinib, ponatinib, nilotinib and bosutinib (BCR-ABL inhibitors, reported in the investigators' brochure or on labels), phenytoin and carbamazepine (antiepileptics, known target concentrations available from therapeutic drug monitoring [5]).…”

Novel Adamantanyl-Based Thiadiazolyl Pyrazoles Targeting EGFR in Triple-Negative Breast Cancer

“… 10 Lapatinib is a quinazoline-based small-molecule inhibitor of the EGFR, which has been approved for the treatment of metastatic TNBC. 11 Gefitinib, erlotinib, cetuximab, and panitumumab are also the approved drugs targeting the EGFR for the treatment of various types of cancers. 12 Therefore, EGFR inhibitors may provide substantial clinical benefit for patients with TNBC.…”

PATRI, a Genomics Data Integration Tool for Biomarker Discovery

“…Lapatinib [ 35 ] is a dual EGFR and ERBB2 inhibitor, currently approved in the clinics for the treatment of ERBB2 amplified breast cancers in combination with capecitabine or letrozole [ 64 ]. In our analysis, ERBB2 kinase gene amplification and overexpression were correctly identified by PATRI within a group of lapatinib sensitive versus resistant breast cancer cell lines ( Figure 3(a) ) tested in our labs.…”