Breast cancer is a heterogeneous disease in terms of its natural history and response to various modalities of treatment. It has been known since the early 1990's that the presence of Her2 neu over-amplification is associated with a more aggressive tumour phenotype and a worse prognosis (1). The Her2 neu gene is one of a family of four transmembrane growth factor receptors. There are similarities between each of these four receptors, namely the presence of an extracellular ligand binding domain, a single transmembrane domain and an intracellular tyrosine kinase domain.

Following activation of the erbB receptors, these receptors undergoing hetero- or homodimerisation. Subsequently a cascade of downstream pathways are activated following initiation of phosphorylation and signal transmission results in gene transcription that ultimately impacts on cell division, apoptosis, adhesion, migration or further differentiation (2).

Currently, it is thought that up to 20% of breast cancers have Her2 neu over-amplification. It is clearly established that the use of trastuzumab (Herceptin) has an important role in the treatment of these cancers; both in the metastatic and adjuvant setting. This agent is a monoclonal antibody which specifically binds with the Her2 neu receptor resulting in downstream inhibition of tumour cell growth (3).

Despite the efficacy of trastuzumab (Herceptin), most patients will develop resistance to this drug eventually in the metastatic setting and some patients receiving this agent in the adjuvant setting will develop recurrence. Lapatinib (Tykerb) is a small molecule tyrosine kinase that exhibits dual inhibition of both Her2 neu and epidermal growth factor receptor (EGFR or Her1).

Lapatinib is an orally active agent which works intracellularly to target the tyrosine kinase domain of both Her2 neu and EGFR. Upon binding to the adenosine triphosphate (ATP) binding site of the kinase, the downstream activation of P13K and Akt are inhibited. This inhibition is dose dependent and several in vitro studies have demonstrated a greater potency of Lapatinib inhibition towards ErbB1 and ErbB2 compared with many other agents. The homodimerisation of ErbB1 and heterodimerisation between ErbB1 and ErbB2, suggests that theoretically an agent capable of inhibiting signalling of both these processes, may be more effective than inhibition of either tyrosine kinase alone. Further, preclinical studies have demonstrated increased expression of other growth factor receptors (insulin-like growth factor receptor 1, vascular endothelial growth factor receptor 1, transforming growth factor-α receptor). The complex interaction between these various transmembrane growth factor receptors may suggest that dual inhibition by an intracellularly active agent may have greater therapeutic benefit then solely targeting the extracellular domain of a single receptor (4).

Phase I studies have been conducted using Lapatinib in pre-treated women with Her2-positive metastatic breast cancer. Patients in these studies had uniformly received trastuzumab prior to disease progression and results show that there is a lack of cross resistance with trastuzumab. It is recognised that women receiving trastuzumab therapy for metastatic breast cancer may develop CNS diseases despite ongoing response in extra-cranial metastatic sites. It is thought that monoclonal antibodies such as trastuzumab have a low likelihood of penetrating the blood brain barrier in levels sufficient to treat intracerebral disease. A further possible advantage of Lapatinib is the finding that other small molecule tyrosine kinase inhibitors have the ability to penetrate the blood brain barrier, particularly in the presence of altered the blood-tumour barrier associated with brain metastases (5~7).

EGF10009 evaluated 42 patients with solid tumours including six patients with breast cancer. Patients received Lapatinib at doses ranging between 1,250 to 1,500 mg/d in combination with Paclitaxel 135~225 mg/m². Although tolerability of this combination was the primary focus of the study, partial response was achieved in three breast cancer patients, with stable disease in one patient. The most common non-haematological toxicity seen in this study included grade 1 or 2 diarrhoea, neuropathy, rash, fatigue and arthralgia.

Metastatic breast cancer patients who experienced disease progression following first or second-line trastuzumab therapy, were evaluated in EGF20002. Of 41 patients reported in an interim analysis, the objective response rate of 46.3% was considered extremely encouraging.

In study EGF20009, patients with Her2-positive locally advanced or metastatic breast cancer were treated with two dose levels of Lapatinib. Preliminary results demonstrated partial response rate of 35%, with a similar proportion of patients achieving stable disease.

Safety results from Phase I studies indicate that Lapatinib administered orally is generally well tolerated in doses ranging up to 1,800 mg daily. The majority of adverse events were either grade I or II. These included diarrhoea, skin rash, fatigue, anorexia, nausea and vomiting. With respect to serious adverse effect, dyspnoea, dehydration and neutropenia have been reported. To date three episodes of interstitial pneumonitis have been reported, although a definite causal relationship to Lapatinib has been difficult to confirm. As of January 2005 there is an overall incidence of 1.4% of patients experiencing a decrease in left ventricle ejection fraction (5).

The first Phase III randomised clinical trial evaluating Lapatinib and Capecitabine versus Capecitabine alone was first presented at ASCO 2006 (8). The protocol was designed to include women with progressive Her2 neu-positive locally advanced or metastatic breast cancer who had received prior treatment with anthracycline, taxane, and trastuzumab. Patients were stratified according to disease site and stage of disease. Time to tumour progression based on intention-to-treat was the primary endpoint; with secondary endpoints including overall survival, progression-free survival, overall response rate, clinical benefit and toxicity. Enrolment was planned for a total of 528 patients to achieve a 90% power to detect a 50% increase in median time to progression, estimated to be three months for patients receiving capecitabine alone to 4½ months in those receiving combination therapy.

The clinical development of Lapatinib highlights the importance of translational research, where tumour cell targeted therapy can be logically developed for clinical benefit. The availability of Lapatinib as second-line therapy is extremely encouraging as the majority of Her2 neu-positive breast cancers initially responding to trastuzumab therapy will become resistant. The toxicity profile of this oral tyrosine kinase agent is generally acceptable, although evaluation of the impact of gastrointestinal side-effects and skin toxicity on quality of life is needed, especially if used for prolonged periods. Future studies will need to evaluate this agent compared to Trastuzumab as first-line therapy, the potential increase benefit of combining with agents, identifying other endocrine, cytotoxic and biological agents, that can be used in combination with Lapatinib and most importantly, the optimal way of incorporating this drug into the adjuvant setting.