Lapatinib: A novel approach to inhibit EGFR(ErbB1)/HER2(ErbB2)

SY04-01 Lapatinib is a potent, oral, small molecule dual inhibitor of both EGFR (ErbB1) and HER2 (ErbB2) tyrosine kinases (TK) and is currently being investigated in breast cancer and other solid tumors. Lapatinib has shown promising activity against HER2-positive breast cancers that have been previously treated with trastuzumab, and has proven efficacy in combination with capecitabine against HER2-positive breast cancer. EGFR and HER2 are transmembrane TK receptors that are often overexpressed or altered in a variety of neoplastic tissues. EGFR and HER2 activate cell signaling pathways, including MAP kinase/Erk and PI3 kinase/Akt, leading to cell growth and survival. Overexpression of EGFR/HER receptors in human cancers correlates with poor clinical prognosis and reduced overall survival. The central role of these TK in carcinogenesis is the basis for the antitumor activity of lapatinib. The HER/Erb family of growth factor receptors are multi-domain proteins with an extracellular ligand binding domain, a transmembrane domain, and an intracellular TK domain. The structure of bound TK inhibitor/Erb appears to influence the biological activity of the TK inhibitor, including inhibitor off-rate and receptor selectivity. The crystal structure of EGFR bound to lapatinib demonstrates that lapatinib binds to the adenosine triphosphate (ATP) binding cleft in a manner similar to that of other quinazoline TK inhibitors; however, there are significant differences in the orientation of the NH2- and COOH-terminal lobes, the COOH-terminal tail and the C helix. The ATP binding cleft of lapatinib/EGFR is in a relatively closed conformation, whereas the ATP binding cleft of erlotinib/EGFR is in a more open conformation. Furthermore, lapatinib exhibited reversible, non-covalent inhibition of EGFR and HER2, with a very slow dissociation rate (half-life >300 minutes), which was considerably longer than that of erlotinib and gefitinib (EGFR inhibitors, half-life for EGFR In preclinical studies, lapatinib induces reversible cytostatic or cytotoxic effects, depending on the tumor cell type and experimental model. Synergistic interactions were observed for several cytotoxic and targeted agents in combination with lapatinib, including capecitabine, docetaxel, trastuzumab, Akt inhibitors and IGF-1R inhibitors. In human tumor cell lines, lapatinib inhibits phosphorylation of EGFR and HER2 in a time- and dose-dependent manner. In addition, lapatinib decreases phosphorylation of downstream markers, such as Erk1/2, Akt, FKHRL1 and Bad to varying degrees, depending on the cell line. Lapatinib is particularly active in HER2-overexpressing and trastuzumab-conditioned breast cancer cells in vitro. The development of lapatinib to date has largely been in refractory breast cancer. In phase I clinical studies, lapatinib caused dose-related inhibition of EGFR and/or HER2 phosphorylation, or decreased phosphorylation of downstream signaling cascade components (Erk1/2 and Akt). A phase I trial of trastuzumab plus lapatinib (EGF10023) in heavily pretreated breast cancer patients with HER2 overexpression showed a 26% response rate for the combination in patients in the dose escalation part of the study; all of the responders had progressed on trastuzumab containing regimens prior to enrollment. Preclinical and phase I results lead to 5 phase II/III studies investigating the role of lapatinib in refractory advanced/metastatic HER2-positive breast cancer that progressed following therapy with trastuzumab. The pivotal lapatinib trial submitted to the FDA for approval involved patients with HER2-positive advanced or metastatic breast cancer who had progressed on trastuzumab, anthracyclines and taxanes and were randomized to receive capecitabine alone or capecitabine plus lapatinib (EGF100151). Time to progression nearly doubled when patients were administered the combination of lapatinib plus capecitabine compared with capecitabine alone (8.4 months vs 4.4 months, respectively; P=.00004). Several phase II/III clinical trials are investigating the role of lapatinib in the first-line setting in advanced/metastatic breast cancer. Clinical trials combine lapatinib with a taxane, with or without trastuzumab, and another trial is underway in combination with letrozole for post-menopausal women with hormone receptor-positive metastatic disease. Data from a first-line monotherapy lapatinib phase II trial (EGF20009) in HER2 amplified, locally advanced or metastatic breast cancer, demonstrated a response rate of 24% across treatment groups with a 6-month progression-free survival rate of 43%. Clinical benefit was also shown with the combination of lapatinib and paclitaxel as neoadjuvant therapy in patients with newly diagnosed inflammatory breast cancer (IBC), a rare and particularly aggressive form of breast cancer (EGF102580) affecting 1% to 6% of the population. The study showed that 77% of patients whose tumors overexpressed HER2, responded to lapatinib, with 10% of patients achieving a complete response. Of the 21 patients who completed surgery at data analysis, 14% of all patients or 17% of patients with HER2 overexpressing tumors (3/18) had a complete pathological response. In addition, 80% of the five patients whose tumors expressed EGFR but did not overexpress HER2 had a partial response. These results may represent a major development in the neoadjuvant treatment of IBC, a disease that has been notoriously difficult to treat. The most common adverse events with lapatinib are grades 1 or 2 diarrhea, grades 1 or 2 rash, fatigue and gastrointestinal symptoms. The cardiotoxicity profile of lapatinib is an important consideration as HER2 inhibitors have the potential to affect cardiac function. In addition, most patients with HER2-positive breast cancer receive anthracyclines and/or trastuzumab which are known cardiotoxic regimens. The incidence of laboratory (LVEF) or clinical signs of cardiac dysfunction associated with lapatinib, however, is rare, and is largely reversible. In the preliminary analyses of lapatinib clinical trial population involving 3127 patients, symptomatic or asymptomatic decreases in LVEF were very low; symptomatic cardiac events were 0.1% and asymptomatic LVEF decreases were 1.3%, regardless of prior exposure to trastuzumab or anthracycline. The promising activity of lapatinib against trastuzumab refractory tumors and its potential activity against brain metastasis has led to the development of two large clinical trials with lapatinib. TEACH will be the first phase III study to investigate whether adjuvant treatment with lapatinib improves disease-free survival in women with early-stage HER2-positive breast cancer who have completed chemotherapy treatment and are currently without disease. The TEACH trial will be conducted at approximately 450 clinical research sites globally and approximately 3,000 women who have not previously received trastuzumab will be enrolled. ALTTO (Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization) will be the largest clinical trial yet for lapatinib, involving 8,000 women with early breast cancer. The trial compares lapatinib versus trastuzumab alone or in combination, concurrent or sequential following chemotherapy in the adjuvant treatment of patients with HER2 overexpressing and/or amplified breast cancer. Biomarkers have been studied in the lapatinib breast cancer clinical trials including testing for HER2 and EGFR status in the tumor and protein biomarker expression to assess the molecular phenotypes that predict response to lapatinib as a single agent or in combination with other anti-cancer agents. In EGF100151, HER2 status by FISH was significantly associated with lapatinib response (P=.005). Detectable levels of circulating EGFR and HER2 extracellular domain (ECD) are associated with the worst prognosis, but may also be a marker for increased response to lapatinib therapy. Patients with high baseline HER2 ECD serum levels have a shorter PFS with capecitabine alone. Addition of lapatinib to capecitabine significantly improves PFS regardless of baseline HER2 ECD levels. No such correlations were observed for EGFR (either in tumor by IHC or serum by EGFR ECD). In IBC (EGF102580), predictors of response to lapatinib were HER2 and high expression of IBC-related genes (e.g., RhoC, E-cadherin). Of note, high expression of IGF-1R and PTEN deficiency that have been previsously associated with trastuzumab resistance did not preclude a clinical response to lapatinib. Additional work is ongoing to better define the relationship of underlying genetic aberrations (i.e., PI3K mutations) and transcriptional profiles to single-agent and combination-therapy activity of lapatinib. Lapatinib, through its potent, selective, and reversible dual mechanism of EGFR/HER2 inhibition, has proven to be efficacious in the clinical setting; ongoing and future studies will both reinforce and define its role in the treatment of EGFR/HER2-positive breast cancer as well as other solid tumors.