Lapatinib: a tyrosine kinase inhibitor with a clinical role in breast cancer

Lapatinib is a dual (ErbB-1 and ErB-2) receptor tyrosine kinase inhibitor (TKI) that was recently approved by the FDA for the treatment of advanced breast cancer. It shows synergy with trastuzumab, and has demonstrated clinical activity in trastuzumab-resistant tumour. This paper reviews the drug development of lapatinib from preclinical studies to the pivotal Phase III trial and ongoing clinical studies. Areas of interest include the advantages of small molecule TKIs versus antibodies in targeting HER receptors and the efficacy of lapatinib in the treatment of cerebral metastases. The surprisingly high response rate in inflammatory breast cancer raises the possibility of other novel predictive biomarkers. The potential for combination and sequencing with other biological and cytotoxic agents is both exciting and challenging.     

Lapatinib: a novel EGFR/HER2 tyrosine kinase inhibitor for cancer

Lapatinib is an oral dual tyrosine kinase inhibitor that targets epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor-2 (HER2), both frequently overexpressed in human cancer. Preclinical data have shown that lapatinib is a potent and selective inhibitor of the tyrosine kinase domain of EGFR and HER2, and tumor cells that overexpress these receptors are growth inhibited by lapatinib both in vitro and in vivo. Phase I clinical trials have shown that lapatinib is well tolerated, with mild diarrhea and rash the most frequent toxicities, and early evidence of clinical efficacy has been reported especially in HER2-positive breast cancer. Phase II studies have shown activity for lapatinib in trastuzumab-refractory breast cancer either alone or in combination with trastuzumab. When used as first-line monotherapy for advanced breast cancer, objective tumor responses have been seen in 28% of patients with untreated HER2-positive advanced breast cancer. An extensive phase III program in advanced breast cancer is now in progress both for refractory disease and as first-line therapy in combination with chemotherapy with and without trastuzumab, and with endocrine therapy. Phase II studies have also been conducted in a variety of other tumors, including renal cell cancer. Parallel biomarker studies are starting to elucidate predictive molecular phenotypes that may indicate likelihood of response to lapatinib, and these may direct future trials with this oral tyrosine kinase inhibitor.     

Lapatinib: the evidence for its therapeutic value in metastatic breast cancer

INTRODUCTION: Breast cancer is the most common cancer affecting women. Many patients ultimately progress to metastatic disease and optimal management of this disease remains a significant therapeutic challenge. Lapatinib, a dual tyrosine kinase inhibitor, is in clinical development for treatment of this disease. AIMS: The objective of this article is to review the published evidence for the treatment of metastatic breast cancer with lapatinib, and assess its therapeutic potential. EVIDENCE REVIEW: Most evidence has appeared in meeting abstract reports of phase I and II studies in healthy volunteers and cancer patients. Four studies have included patients with exclusively breast cancer. Complete and partial responses and stable disease has been reported in some patients. Emerging evidence indicates that complete and partial responses can be achieved in some patients with metastatic breast cancer. Lapatinib appears to be well tolerated in cancer patients and the maximum tolerated dose is in the region of 1800 mg/day. In addition, it has been used in combination with other cancer treatments. Five ongoing or planned phase II monotherapy and three phase III combination-therapy studies with lapatinib have been identified. OUTCOMES SUMMARY: The phase I and II studies reported to date have provided safety data and preliminary indications regarding efficacy. There is preliminary evidence that lapatinib can achieve objective response rates of 10-38% in patients with metastatic breast cancer. Patients with tumors overexpressing ErbB1 and/or ErbB2 are likely to benefit from lapatinib treatment.     

拉帕替尼联合曲妥珠单抗治疗HER2阳性乳腺癌的疗效观察

目的探讨拉帕替尼联合曲妥珠单抗治疗HER2阳性乳腺癌患者的临床效果。方法选取2011年1月—2014年3月在宝鸡市妇幼保健院接受治疗的261例乳腺癌患者,随机分为拉帕替尼组(82例)、曲妥珠单抗组(84例)和联合组(95例),3组患者中途各有3、2和1例停止治疗。拉帕替尼组口服拉帕替尼片,6片/次,1次/d;曲妥珠单抗组静脉注射注射用曲妥珠单抗,1次/周,前9周4 mg/kg,后9周2 mg/kg维持;联合组治疗方法是上述两组治疗方法的联用,3组均连续治疗18周。治疗后,观察3组患者临床疗效,同时比较3组治疗前后无进展生存率(PFS)、总生存期(OS)、中枢神经系统(CNS)转移情况、总反应率(ORR)、临床受益反应(CBR)以及不良反应变化情况。结果治疗后,拉帕替尼组治愈率为21.52%,控制率为51.90%;曲妥珠单抗组治愈率为24.39%,控制率为57.32%;联合组治愈率为45.74%,控制率为76.60%,3组治愈率比较差异具有统计学意义(P0.05),控制率比较差异具有统计学意义(P0.01)。治疗后,拉帕替尼组、曲妥珠单抗组和联合组的PFS分别为41、43、55个月,联合组PFS比拉帕替尼组和曲妥珠单抗组均显著延长,差异具有统计学意义(P0.05)。治疗后随访期间拉帕替尼组(72例)、曲妥珠单抗组(76例)和联合组(83例)的PFS分别为24、26、36个月,联合组的PFS比拉帕替尼组、曲妥珠单抗组的均显著延长,差异具有统计学意义(P0.05)。治疗后,拉帕替尼组、曲妥珠单抗组和联合组的CNS转移率分别为32.91%、29.27%、19.15%,联合组的CNS转移率明显低于拉帕替尼组和曲妥珠单抗组,差异具有统计学意义(P0.05)。拉帕替尼组、曲妥珠单抗组和联合组的ORR分别为56.96%、59.76%、76.60%,联合组ORR均高于拉帕替尼组、曲妥珠单抗组,差异具有统计学意义(P0.05)。拉帕替尼组、曲妥珠单抗组和联合组的CBR分别为43.04%、47.56%、69.15%,联合组的均高于拉帕替尼组、曲妥珠单抗组,差异具有统计学意义(P0.05)。联合组的不良反应发生率显著低于拉帕替尼组和曲妥珠单抗组,差异比较具有统计学意义(P0.05)。结论拉帕替尼联合曲妥珠单抗对HER2阳性乳腺癌患者具有较好的临床治疗效果,具有一定的临床推广应用价值。     

Lapatinib for breast cancer: a review of the current literature

Importance of the field: The identification of HER-2 expression as a predictive and prognostic marker revolutionized breast cancer. Trastuzumab, a humanized mAb, improves survival in both early and advanced HER-2 overexpressing breast cancer. However, many cancers either do not respond or develop resistance to this agent. Lapatinib is an oral tyrosine kinase inhibitor which has both HER-1 and -2 activities and has been licensed for use in recurrent breast cancer that overexpresses HER-2. Studies of lapatinib in early breast cancer are ongoing.

Areas covered in this review: A PubMed search was conducted using ‘lapatinib’ and ‘breast cancer’ as the key words. All published works up to July 2010 were reviewed. A manual review of abstracts presented at the ASCO Annual meeting and the San Antonio Breast Cancer Symposium was conducted for the last 2 years. In this review, we summarize the current knowledge of lapatinib and pose questions which need to be addressed as we further expand our knowledge of the HER-2 subtypes of breast cancer.

What the reader will gain: The reader will gain an up-to-date and comprehensive review of the current literature as it pertains to the safety and efficacy of lapatinib in the treatment of breast cancer.

Take home message: Lapatinib has provided an alternative for the treatment of advanced HER-2 overexpressing breast cancer and is currently being assessed in early disease.     

HER-2阳性早期乳腺癌辅助治疗的研究进展

人表皮生长因子受体-2(HER-2)阳性乳腺癌是具有较强侵袭性、预后较差的一类肿瘤,曲妥珠单抗抗Her-2靶向的问世,改变了Her-2阳性乳腺癌的预后.除了曲妥珠单抗这个药物,一系列抗Her-2靶向治疗药物的相继用于临床研究及治疗,包括小分子酪氨酸激酶抑制剂拉帕替尼、来那替尼;抗Her-2分子异源二聚化的药物帕妥珠单抗以及曲妥珠单抗-细胞毒性的共轭药物(T-DM1).本文就是对HER-2阳性早期乳腺癌的辅助治疗进行综述评价.     

Modulation of P-gp expression by lapatinib

Chemotherapy drug resistance is a major obstacle in the treatment of cancer. It can result from an increase in levels of cellular drug efflux pumps, such as P-glycoprotein (P-gp). Lapatinib, a growth factor receptor tyrosine kinase inhibitor, is currently in clinical trials for treatment of breast cancer. We examined the impact of co-incubation of chemotherapy drugs in combination with lapatinib in P-gp over-expressing drug resistant cells. Unexpectedly, lapatinib treatment, at clinically relevant concentrations, increased levels of the P-gp drug transporter in a dose- and time-responsive manner. Conversely, exposure to the epidermal growth factor (EGF), an endogenous growth factor receptor ligand, resulted in a decrease in P-gp expression. Despite the lapatinib-induced alteration in P-gp expression, use of accumulation, efflux and toxicity assays demonstrated that the induced alteration in P-gp expression by lapatinib had little direct impact on drug resistance.     

HER2阳性乳腺癌靶向治疗药物的临床研究进展

乳腺癌已成为全球最常见的癌症,人表皮生长因子受体2（HER2）阳性乳腺癌恶性程度较高,早期易复发和转移,总体预后较差。HER2阳性乳腺癌的治疗因靶向药物的不断问世而呈现更多可能,这类药物包括单克隆抗体（曲妥珠单抗、帕妥珠单抗）、酪氨酸激酶抑制剂（奈拉替尼、拉帕替尼、吡咯替尼、图卡替尼）、抗体药物偶联物（T-DM1、DS-8201）。对HER2阳性乳腺癌靶向治疗药物的最新临床试验结果进行综述,以期为该类乳腺癌的临床用药提供参考。     

Overcoming treatment resistance in HER2-positive breast cancer: potential strategies

Human epidermal growth factor receptor (HER)-2 overexpression or amplification occurs in about 20% of all breast cancers and results in a worse prognosis. Nevertheless, anti-HER2 treatments have recently been developed, resulting in dramatic improvements in the clinical outcome of patients with HER2-positive breast cancer. Trastuzumab has shown efficacy in early and advanced breast cancer treatment and lapatinib is currently approved for the treatment of advanced disease. Other anti-HER2 agents are being investigated. Mechanisms of resistance to trastuzumab treatment include crosstalk with heterologous receptors and amplification of HER2 signalling; amplification of the phosphoinositide 3-kinase (PI3K)/AKT pathway; alteration in binding of trastuzumab to HER2; and loss of HER2 expression. Proposed mechanisms of resistance to lapatinib involve derepression and/or activation of compensatory survival pathways through increased PI3K/AKT or estrogen receptor (ER) signalling. Several strategies to overcome resistance to anti-HER2 treatment are in different phases of development and include treatment with pertuzumab, T-DM1 and mammalian target of rapamycin (mTOR) inhibitors.     

Physiologically based pharmacokinetic model of lapatinib developed in mice and scaled to humans

Lapatinib is an oral 4-anilinoquinazoline derivative that dually inhibits epidermal growth factor receptor and human epidermal growth factor receptor 2 (HER2). This drug is a mere decade old and has only been approved by the FDA for the treatment of breast cancer since 2007. Consequently, the intricacies of the pharmacokinetics are still being elucidated. In the work presented herein, we determined the biodistribution of orally administered lapatinib in mouse plasma, brain, heart, lung, kidney, intestine, liver, muscle and adipose tissue. Using this data, we subsequently developed a physiologically based pharmacokinetic (PBPK) model of lapatinib in mice that accurately predicted the tissue concentrations after doses of 30, 60 and 90 mg/kg. By taking into account interspecies differences in physiology and physiochemistry, we then extrapolated the mouse PBPK model to humans. Our model predictions closely reflected lapatinib plasma pharmacokinetics in healthy subjects. Additionally, we were also able to simulate the pharmacokinetics of this drug in the plasma of patients with solid malignancies by incorporating a decrease in liver metabolism into the model. Finally, our PBPK model also facilitated the estimation of various human tissue exposures to lapatinib, which harmonize with the organ-specific toxicities observed in clinical trials. This first-generation PBPK model of lapatinib can be further improved with a greater understanding of lapatinib absorption, distribution, metabolism and excretion garnered from subsequent in vitro and in vivo studies and expanded to include other pharmacokinetic determinants, including efflux transporters, metabolite generation, combination dosing, etc., to better predict lapatinib disposition in both mouse and man.     

Synergistic interaction between trastuzumab and EGFR/HER-2 tyrosine kinase inhibitors in HER-2 positive breast cancer cells

Overexpression of HER-2 in breast cancer is frequently associated with expression of EGFR, and EGFR expression influences response to HER-2 inhibition. The aim of this study was to examine the effects of combining dual inhibition of EGFR and HER-2, using trastuzumab, gefitinib and lapatinib, in HER-2 overexpressing breast cancer cells. Combination proliferation assays were performed in two HER-2 positive breast cancer cell lines, SKBR-3 and BT-474. Trastuzumab combined with lapatinib was also tested in BT-474 xenografts. In proliferation assays, dual targeting with trastuzumab and gefitinib or lapatinib showed synergy or additivity in both SKBR-3 and BT-474 cells. Trastuzumab (10 nM) or gefitinib (5 μM) alone did not induce significant apoptosis, whereas lapatinib (0.75 μM) induced significant apoptosis in SKBR-3 cells. Trastuzumab combined with lapatinib further enhanced apoptosis induction. Trastuzumab (10 nM) and gefitinib (5 μM) induced apoptosis comparable to lapatinib alone (0.75 μM), suggesting that inhibition of both EGFR and HER-2 may be required to induce apoptosis in these cells. Pre-treatment with trastuzumab and gefitinib or lapatinib enhanced response to chemotherapy in vitro. The combination of trastuzumab and lapatinib also effectively blocked tumour growth in vivo. Dual targeting of EGFR and HER-2, by combining trastuzumab with EGFR/HER-2 tyrosine kinase inhibitors, may improve response in HER-2 overexpressing breast cancer cells that also express EGFR.     

Lapatinib and ixabepilone for the treatment of metastatic breast cancer

Breast cancer is the second leading cause of cancer death in women. Treatment options for advanced-stage disease, although numerous, remain suboptimal. Lapatinib and ixabepilone are two new agents approved by the United States Food and Drug Administration (FDA) in 2007 for the treatment of locally advanced breast cancer (LABC) or metastatic breast cancer (MBC). When added to the existing endocrine therapies-single--agent cytotoxic therapies and combination chemotherapy regimens--lapatinib and ixabepilone offer potential treatment strategies for disease that has become resistant to trastuzumab and the taxanes, respectively. Lapatinib is an oral dual tyrosine kinase inhibitor against members of the human epidermal growth factor receptor (HER) family (HER1 or epidermal growth factor receptor [EGFR], and HER2). It is indicated for combination therapy with capecitabine for the treatment of patients with HER2-overexpressing LABC or MBC whose disease has progressed after receiving previous treatment with an anthracycline, a taxane, and trastuzumab. Of note, lapatinib is the first FDA-approved tyrosine kinase inhibitor indicated for use in MBC. Ixabepilone, the first FDA-approved analog of the antimicrotubule agent epothilone B, is indicated as monotherapy for the treatment of LABC or MBC in patients whose tumors are refractory or resistant to anthracyclines, taxanes, and capecitabine. It is also indicated in combination with capecitabine for treatment of LABC or MBC that is resistant to anthracycline and taxane. Both lapatinib and ixabepilone are fairly well tolerated. The most common toxicities with lapatinib are diarrhea (65%) and hand-and-foot syndrome (53%), whereas peripheral neuropathy (62%), fatigue (56%), and neutropenia (54%) are most common with ixabepilone. Though the conventional standard end point of overall survival has not yet been assessed in clinical trials, these agents have been shown to improve surrogate markers of clinical benefit: progression-free survival and the related time to progression. Future clinical trials should focus on elucidation of optimal combination or sequential therapies, as well as patient-specific therapies based on tumor characteristics, such as biomarkers and tumor subtypes.     

EGFR和ErbB2双重酪氨酸激酶

拉帕替尼是一种人源2型表皮生长因子受体(HER2)和表皮生长因子受体(EGFR)双重酪氨酸激酶抑制剂,与卡培他滨联用治疗女性HER2阳性的乳腺癌。我们利用MEDLINE进行关键词为拉帕替尼的文献检索,对其药理作用、药动学、临床疗效及安全性,药物相互作用等进行综述。     

人类表皮生长因子受体-2在乳腺癌研究中进展

人类表皮生长因子受体-2（ human epidermal growth factor receptor-2, HER-2）是乳腺癌诊治过程中重要的预后指标和HER-2靶向药物的治疗指标。乳腺癌患者中约30％会出现HER-2的过表达,HER-2检测的目的就是鉴别出那些可以从HER-2靶向治疗中获益的人群。目前靶向治疗药物包括赫赛、拉帕替尼和T-DM1等。这些治疗可以大大提高HER-2阳性浸润性乳腺癌患者的生存期。所以选择适当的检测标准准确判读HER-2状态是乳腺癌患者预后判断以及制定有效治疗方案的先决条件,对乳腺癌的诊疗具有积极的指导作用。     

Human metabolism of lapatinib, a dual kinase inhibitor: implications for hepatotoxicity

Lapatinib (Tykerb, Tyverb) is an important orally active dual tyrosine kinase inhibitor efficacious in combination therapy for patients with progressive human epidermal receptor 2-overexpressing metastatic breast cancer. However, clinically significant liver injury, which may be associated with lapatinib metabolic activation, has been reported. We describe the metabolism and excretion of [(14)C]lapatinib in six healthy human volunteers after a single oral dose of 250 mg and the potential relationships between metabolism and clinical hepatotoxicity. Overall, elimination showed high intersubject variability, with fecal elimination being the predominant pathway, representing a median of 92% of the dose with lapatinib as the largest component (approximate median 27% of the dose). In plasma, approximately 50% of the observed radioactivity was attributed to metabolites. Analysis of a 4-h pooled plasma extract identified seven metabolites related by an N- and α-carbon oxidation cascade. Fecal metabolites derived from three prominent pathways: N- and α-carbon oxidation, fluorobenzyl oxidative cleavage, and hydroxypyridine formation. Several of the lapatinib metabolites can undoubtedly be linked to reactive species such as aldehydes or quinone imines. In addition to the contribution of these potentially reactive metabolites as suspects in clinical liver injury, the role of other disposition factors, including interaction with drug transporters, pharmacogenetics, or magnitude of the therapeutic dose, should not be discounted.     

Combining molecular targeted therapies: clinical experience

Approximately 20 molecular targeted therapies, mainly monoclonal antibodies and tyrosine kinase inhibitors, have been approved for the treatment of various cancers. They are being increasingly investigated in combination in clinical trials. We review the rationale for combining molecular targeted therapies and the results of clinical trials to date. There have been some exciting clinical results with some combinations, for example, lapatinib/trastuzumab or bevacizumab/trastuzumab in HER2-positive metastatic breast cancer, whereas other potential combinations have provided disappointment, for example, cetuximab or panitumumab in combination with bevacizumab/chemotherapy in first-line treatment of metastatic/advanced colorectal cancer. Therefore, at this point no general guidance to study such combinations can be derived.     

Lapatinib ditosylate: expanding therapeutic options for receptor tyrosine-protein kinase erbB-2-positive breast cancer

Receptor tyrosine-protein kinase erbB-2 (HER2)-positive breast cancer is a specific entity with an aggressive behavior. Trastuzumab, a monoclonal antibody targeting erbB-2 (HER2) deeply transformed the outcome in patients. Nevertheless, resistance to trastuzumab is still a major concern. Lapatinib ditosylate is an orally available, small molecule targeting the tyrosine activity of the HER2 receptor. Lapatinib as a single agent and in combination therapy showed interesting activity in trastuzumab-resistant advanced tumors. In addition, lapatinib use seemed suitable in recurrent locally advanced inflammatory breast cancer and brain metastases. More recently, the Neo-ALTTO (NeoAdjuvant Lapatinib and/or Trastuzumab Treatment Optimisation) trial showed that lapatinib in combination with trastuzumab and paclitaxel significantly improved the pathological complete response in a neoadjuvant setting. Several clinical trials are still ongoing and data that may change current clinical practice are awaited with much interest.     

Trastuzumab and chemotherapy after the treatment failure of lapatinib for HER2-positive metastatic breast cancer

We describe a patient with human epidermal growth factor receptor type 2 (HER2/c-erbB-2)-positive metastatic breast cancer who survived for approximately 6 years after the initiation of combination therapy with trastuzumab and varying types of chemotherapeutic agents. The patient was a 48-year-old postmenopausal female who underwent partial mastectomy with axillary node dissection for cancer of the right breast in March 1994. She developed lung metastases 2 years thereafter, but survived free of relapse for 8 years following chemotherapy and pulmonary lobectomy. The patient failed to respond to lapatinib, a HER1 (EGFR)/HER2 tyrosine kinase inhibitor, received during the course of her treatment but then again responded to subsequently administered trastuzumab. Primary treatment with trastuzumab and paclitaxel was initiated in April 2004 when the patient developed hepatic metastases 8 years after undergoing surgery for lung metastases. Long-term combination therapy with continued trastuzumab and a variety of chemotherapeutic agents was administered for 6 years without any significant adverse events. We discuss the treatment strategies for HER2-positive breast cancer and the role of lapatinib, a recently approved anticancer drug.     

Pharmacologic inhibition of mTOR improves lapatinib sensitivity in HER2-overexpressing breast cancer cells with primary trastuzumab resistance

Lapatinib, a dual EGFR/HER2 kinase inhibitor, is approved for use in patients with trastuzumab-refractory HER2- overexpressing breast cancer. Increased PI3K signaling has been associated with resistance to trastuzumab, although its role in lapatinib resistance remains unclear. The purpose of the current study was to determine if PI3K/mTOR activity affects lapatinib sensitivity. Reduced sensitivity to lapatinib was associated with an inability of lapatinib to inhibit Akt and p70S6K phosphorylation. Transfection of constitutively active Akt reduced lapatinib sensitivity, while kinase-dead Akt increased sensitivity. Knockdown of 4EBP1 also increased lapatinib sensitivity, in contrast to p70S6K knockdown, which did not affect response to lapatinib. Pharmacologic inhibition of mTOR using rapamycin or ridaforolimus increased lapatinib sensitivity and reduced phospho-Akt levels in cells that showed poor response to single-agent lapatinib, including those transfected with hyperactive Akt. Finally, combination mTOR inhibition plus lapatinib resulted in synergistic inhibition of proliferation, reduced anchorage-independent growth, and reduced in vivo tumor growth of HER2- overexpressing breast cancer cells that have primary trastuzumab resistance. Our data suggest that PI3K/mTOR inhibition is critical for achieving optimal response to lapatinib. Collectively, these experiments support evaluation of lapatinib in combination with pharmacologic mTOR inhibition as a potential strategy for inhibiting growth of HER2-overexpressing breast cancers that show resistance to trastuzumab and poor response to lapatinib.     

Lapatinib and obatoclax kill tumor cells through blockade of ERBB1/3/4 and through inhibition of BCL-XL and MCL-1

Prior studies in breast cancer cells have shown that lapatinib and obatoclax interact in a greater than additive fashion to cause cell death and do so through a toxic form of autophagy. The present studies sought to extend our analyses to the central nervous system (CNS) tumor cells and to further define mechanisms of drug action. Lapatinib and obatoclax killed multiple CNS tumor isolates. Cells lacking PTEN (phosphatase and tensin homolog on chromosome 10) function were relatively resistant to drug combination lethality; expression of PTEN in PTEN-null cells restored drug sensitivity, and knockdown of PTEN promoted drug resistance. On the basis of knockdown of ERBB1-4 (erythroblastic leukemia viral oncogene homolog 1-4), we discovered that the inhibition of ERBB1/3/4 receptors were most important for enhancing obatoclax lethality rather than ERBB2. In parallel, we noted in CNS tumor cells that knockdown of BCL-xL (B-cell lymphoma-extra large)and MCL-1 (myeloid cell leukemia-1) interacted in an additive fashion to facilitate lapatinib lethality. Pretreatment of tumor cells with obatoclax enhanced the lethality of lapatinib to a greater extent than concomitant treatment. Treatment of animals carrying orthotopic CNS tumor isolates with lapatinib- and obatoclax-prolonged survival. Altogether, our data show that lapatinib and obatoclax therapy could be of use in the treatment of tumors located in the CNS.