lapatinib in the treatment of breast cancer

Drug Profile

10.1586/14737140.7.9.1183 © 2007 Future Drugs Ltd ISSN 1473-7140 1183www.future-drugs.com

Lapatinib in the treatment of breast cancerGerald M Higa and Jame Abraham†

†Author for correspondenceMary Babb Randolph Cancer Center, School of Medicine, West Virginia University, Morgantown, WV 26506, USATel.: +1 304 293 4229Fax: +1 304 293 [email protected]

KEYWORDS: EGFR, ErbB family, HER2, lapatinib, receptor tyrosine kinase, trastuzumab

Within the past 2 years, four separate groups have reported marked improvement in relapse-free survival when trastuzumab was added to adjuvant chemotherapy in patients with HER2-overexpressing breast cancer. These results add further credence to the relevance of this receptor as a tumor target. Despite the significant benefits observed in early and advanced HER2-positive breast cancer, overexpression of the receptor is still associated with a poorer prognosis and an increased risk of disease relapse, even in patients with primary operable disease. Besides cytotoxic chemotherapy, and possibly hormonal therapy, patients whose tumors exhibit resistance to trastuzumab have few molecular-targeted options available. Recently, lapatinib, a small molecule dual inhibitor of both HER2 and EGF receptors, has been developed to expand the options for treating HER-positive breast cancer.

Expert Rev. Anticancer Ther. 7(9), 1183–1192 (2007)

Breast cancer and chronic myelogenousleukemia have a common link in the devel-opment of molecular-directed therapies asthe estrogen receptor and the Bcr-Abl onco-protein, two of the most prominent tumortargets, were detected a few years apart fourdecades ago [1,2]. Although the commercialavailability of imatinib mesylate for thetreatment of chronic myelogenous leukemiais frequently considered as one of the mostsignificant therapeutic breakthroughs inclinical oncology over the last decade, suc-cessful translation of molecular conceptsinto clinical practice historically belongs totamoxifen in the management of hormone-dependent breast cancer. In retrospect, thebeneficial effects of anti-estrogen therapywas the precursor of all current attemptsaimed at identifying critical molecules thatregulate cancer cell growth and survival, andtesting novel therapies that inhibit themalignant process.

One other remarkable molecular discoveryrelates to the HER2/neu oncogene and geneproduct. Amplified or overexpressed inapproximately 20–25% of breast cancers,HER2-positivity has been correlated with ahigher risk of relapse, shorter time to disease

progression and poorer overall survival [3]. Inless than a decade, however, clinical trialshave consistently demonstrated that HER2 isalso important as a tumor target. Not onlyhas HER2-directed therapy, trastuzumab,been effective in patients with metastatic dis-ease, recent studies also demonstrated that atherapeutic cocktail of trastuzumab andstandard chemotherapy produced a markedimprovement in survival in patients withearly breast cancer [4,5]. Despite the encour-aging results, it is nonetheless sobering tonote that not all patients respond to trastuzu-mab, that metastatic disease eventuallyprogresses despite early benefits, and thateffective blockade is associated with a low buttangible increase in risk of cardiac complica-tions. Moreover, except for a few retro-spective reports of continued trastuzumabadministration beyond first progression, noother HER2-directed therapeutic option hadpreviously been available [6–9].

This review focuses on our increased,although by no means complete, understand-ing of the molecular basis of breast cancer. Atthe outset the authors acknowledge that, toas great an extent possible, information inthis exciting area of cancer therapeutics will

CONTENTS

Introduction to lapatinib

Clinical efficacy: advanced breast cancer

Tumor resistance

Safety & tolerability

Regulatory affairs

Conclusion

Expert commentary

Five-year view

Financial disclosure

Information resources

Key issues

References

Affiliations

For reprint orders, please contact [email protected]

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Higa & Abraham

1184 Expert Rev. Anticancer Ther. 7(9), (2007)

highlight a number of significant findings both past andpresent, although at times the reader may not find it as com-prehensive as they wish it to be. Nonetheless, this paper mergesconcepts related to two molecular targets and their signalingpathways with the rational application of lapatinib, a novelagent that has only recently been approved for clinical use inpatients with HER2-positive breast cancer that has progressedon prior trastuzumab therapy.

Introduction to lapatinibLapatinib (Tykerb®/Tyverb®, GlaxoSmithKline) is a potent,small-molecule inhibitor of the EGF receptor (EGFR;ErbB1) and HER2 (ErbB2) tyrosine kinases. The inhibitoryeffects, although reversible, result in blockade of receptor-mediated activation and propagation of downstream signal-ing involved in regulation of cell proliferation and survival(FIGURE 1). This is the first new (HER2-targeted) drug todemonstrate significant clinical benefits in patients withHER2-positive, advanced breast cancer progressing on previ-ous therapy that included trastuzumab, an anthracycline anda taxane [10].

PharmacologyEGFR (ErbB1) and HER2 belong to the ErbB family ofreceptor tyrosine kinases (RTKs), a homologous archival groupthat also includes HER3 and HER4. Molecularly, all membershave a short transmembrane region that connects the extracel-lular ligand-binding region to the intracellular kinase domain.The similarity, however, ends there, as differences in terms ofligand-specificity and intrinsic tyrosine kinase activity havebeen found [11]. Most notable are the three EGFR-specificgrowth factors (EGF, transforming growth factor-α andamphiregulin); the inability of endogenous ligands to bindHER2; and the total or marked attenuation of HER3 kinaseactivity [12].

Physiologically, the ErbB RTKs are known to contribute tothe development of a number of important organs and tissuesystems. In mammary tissue, each receptor has a differentfunction in gland development. Whereas EGFR promotesductal growth, signaling through HER2 contributes to lobu-loalveolar differentiation and lactation [13,14]. Pathologically,there is evidence that both receptors have a role in human neo-plasia. First, high levels of EGFR and HER2 have beenobserved in breast cancer as well as a number of other solidtumors [15]. Second, overexpression of EGFR leads to a trans-formed phenotype while amplification of the HER2 oncogeneor overexpression of the oncoprotein conveys tumor cellgrowth and survival advantages [16]. The significance of the lat-ter, especially, and its correlation with shortened disease-freeand overall survival led to the development of trastuzumab, aspecific targeted-inhibitor of this RTK [3,17].

Success of the molecular concept in practice was demon-strated in clinical trials of trastuzumab monotherapy in treat-ment-naive as well as extensively pretreated, HER2-positivemetastatic breast cancer patients [18,19]. Among 34 responders

who received prior chemotherapy, eight patients achievedcomplete tumor regression. Further proof that trastuzumabcould enhance the activity of cytotoxic chemotherapy wasobtained in two Phase II clinical studies [20,21]. Perhaps mostimportant was the pivotal Phase III trial, which demonstratedthat addition of targeted inhibition of HER2 to chemother-apy resulted in superior outcomes over chemotherapy alone inall clinical end points, including overall survival [22]. In addi-tion, as alluded to above, disease-free and overall survival ofpatients with early breast cancer is significantly improvedwith trastuzumab used either in sequence to or concomitantwith chemotherapy.

ChemistryExquisitely designed in vitro studies delineating the crystalstructure of the lapatinib–ErbB1 complex revealed that theconformation of inhibitor-bound EGFR is considerably differ-ent from the structure when bound by erlotinib [23]. Althoughboth tyrosine kinase inhibitors have high-binding affinities,receptor dissociation of lapatinib occurs much slower comparedwith erlotinib, a finding that correlates with prolonged down-regulation of tyrosine phosphorylation in tumor cells. Stoichio-metric studies of the interaction between lapatinib and theHER2 tyrosine kinase domain have not been published.

PharmacodynamicsThe relationship between lapatinib dosage and serum concen-tration with response and toxicity has been evaluated in aPhase I study. Of the 67 patients with highly refractory tumortypes, four subjects achieved a partial response (PR); stable dis-ease was reported in another 24 patients [24]. Notably, all thePRs occurred in patients with breast cancers that overexpressedHER2 and, except for one, also co-expressed EGFR. Tumorresponses appeared to correlate with median daily lapatinibdosages of 1200 mg and Cmin serum concentration between0.3 and 0.6 µg/ml, a range achievable with a dose of900 mg/day. Interestingly, these numbers correspond to theinhibitory effect on EGFR and HER2 kinase activity in vitro,although not with the incidence and severity of diarrhea andrash, the most frequent side effects [25].

These findings explain, in part, the rationale for continuousdaily dosing rather than intermittent pulse-dose administra-tion of the agent. However, maintenance of effective drug con-centrations may be equally important for another reason.Receptor endocytosis is regarded as the primary mechanismfor terminating ErbB signaling. While ligand-activated EGFRhomodimers undergo rapid cellular internalization and degra-dation, endocytosis of HER2 is not only markedly impaired,but also the heterodimeric partner is readily recycled back tothe cell surface [26,27].

Pharmacokinetics & metabolismFollowing oral administration, serum drug concentrationpeaks within 3–6 h. Currently, the precise metabolic andelimination pathways are not known, although it has been

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reported that lapatinib is metabolized, in part, by CYP3A4,CYP3A5 and, possibly, CYP2C8 [24]. Based on multidaystudies in patients given relatively small doses, steady-stateconcentrations were achieved by day 7, a timeframe some-what inconsistent with an apparent halflife of 7–11 h [28].

Even though a number of factors could impact drug clear-ance and considerable inter-individual variations may exist,the pharmacokinetics of lapatinib were similar in healthysubjects and patients with cancer. The authors’ findingssupport once-daily administration.

Figure 1. Simplified version of EGFR and HER2 signaling pathways. There are three possible dimers involving EGFR and HER2 only. Generally, ligand binding to the ectodomain promotes receptor dimerization and activation of the intracellular tyrosine kinase. The phosphorylated tyrosine residues serve as docking sites for a number of adaptor proteins (e.g., Shc and Grb2), thus propagating the cell signaling cascade. Notably, overexpression and formation of HER2 homodimers result in recruitment and activation of signaling molecules in the absence of ligand. Even more interestingly, HER2 can induce gene expression (e.g., COX-2) following nuclear translocation [61]. Signaling through the ErbB network affects cell cycle progression, cell growth, cytoskeleton rearrangement and cell survival.AP1: Activating protein 1; Bcl-XL: Antiapoptotic member of the Bcl family; EGFR: EGF receptor; ERK: Extracellular signal-regulated kinase; HIF1a: Hypoxia inducible factor 1α; MEK: Mitogen-activated protein kinase; mTOR: Mammalian target of rapamycin; P: Phosphorylated tyrosine residue; p70 S6K: Kinase associated with PI3K and AKT, which can promote cell survival and proliferation; TK: Tyrosine kinase.

Ligand-bound EGFR homodimer

HER2 transactivated by dimeric EGFRConsititutively activatedoverexpressed HER2 homodimer

EGFR

EGFR

HER2 HER2

Cell membraneEGFR

HER2

TKP

K-Ras

TKP

TK TKTK

K-Ras

TK

P

PP

P

Raf

ShcGrb2

SrcGrb2

COX-2

Src

Bcl-XL

p70S6K

NF-κB

PI3K

AKT

mTOR

p70S6K

MEK

ERK

Elk1/AP1

HIF1a

VEGF

Cyclin D1

Expert Review of Anticancer Therapy

Higa & Abraham


Clinical efficacy: advanced breast cancerTrastuzumab-refractory diseaseThe results of a Phase III clinical trial were recently published[10]. Originally designed to include 528 women with advanced,HER2-positive, trastuzumab- and chemotherapy-refractorybreast cancer, enrollment was terminated following a preplannedinterim analysis of safety and efficacy data by an independentmonitoring committee. Approximately 20 months after enroll-ment commenced, the data were locked on November 15, 2005,when the prespecified number of disease-progression events wasreported. At that time, 324 patients had been randomized (1:1)to capecitabine plus lapatinib (163) or capecitabine alone (161).Baseline characteristics of the subjects were similar in both treat-ment groups. On the basis of 121 events, 49 in the combinationand 72 in the monotherapy groups, a 51% reduction in risk ofdisease progression (time to progression [TTP], p < 0.001; one-sided p-value of 0.00004) favored the group receiving capecitab-ine and lapatinib. Median TTP was nearly twice as long withlapatinib added to capecitabine compared with capecitabinealone; 8.4 and 4.4 months, respectively. A secondary end point,progression-free survival, defined as the time from randomiza-tion to disease progression or death from any cause, was alsoimproved in the combination-therapy group (hazard ratio [HR]:0.47; 95% confidence interval [CI]: 0.33–0.67; p < 0.001). Thepreliminary status of these findings notwithstanding, furtherenrollment was halted at the point at which there was a totalaccrual of 399 patients.

Efficacy data of the entire cohort (n = 399) of patients treatedwere re-analyzed 4 months later [29]. Based on an independentreview, the median TTP was 27.1 and 18.6 weeks (p = 0.00013;HR: 0.57) and response rates were 23.7 and 13.9% for the lapat-inib combination arm and capecitabine monotherapy arm, respec-tively. These findings are similar to the assessment performed bythe investigators, which were 23.9 and 18.3 weeks for TTP(p = 0.00762; HR: 0.72) and a response rate of 31.8 and 17.4%for the two arms, respectively. In addition, progression in the CNSwas significantly lower with combination therapy compared withcapecitabine alone: 2 versus 11%, respectively (p = 0.0445).

Two additional issues further highlight the significance of thisstudy. First, that tumor cell expression of EGFR was not an eli-gibility criterion is especially notable since results from an earlierstudy of lapatinib suggested that clinical response may be higherin breast tumors that co-expressed EGFR and HER2 [24]. Sec-ond, since nearly two-thirds of the patients received trastuzu-mab (which has a reported halflife of 3–4 weeks) within the pre-vious 8 weeks, the provocative outcomes could be related tosynergism between residual trastuzumab levels and lapatinib [30].However, analysis of data in women who received lapatinib andprior trastuzumab (≤8 weeks versus >8 weeks) indicated that thecontribution of trastuzumab appeared to be minimal [31].

First-line therapyBecause of the clinical benefit achieved in the advanced diseasesetting, a number of studies have been undertaken to evaluate theefficacy of lapatinib as initial therapy in trastuzumab-naive

patients. Preliminary results of a Phase II study of lapatinibmonotherapy have been reported. In the first 40 patients whoreceived either 1000 or 1500 mg/day for at least 12 weeks, con-firmed PRs were achieved in 14 subjects, while another14 patients had stable disease [32].

At least three Phase III studies of lapatinib in combinationwith paclitaxel are ongoing (TABLE 1). In addition, and based onthe molecular finding that estrogen deprivation therapy upregu-lates the HER2 signaling pathway, a Phase III clinical trial com-paring an anti-aromatase agent with or without lapatinib inwomen with estrogen receptor-positive tumors, regardless ofHER2 status, is in progress. This study may provide proof ofconcept as well as a new practice standard.

Adjuvant therapyOne of the major tenets in oncology is if an agent is proveneffective in the advanced disease setting, clinical benefits arelikely to be seen in patients with early-stage cancer. However,an important caveat related to the drug’s adverse-effect profilemust be considered because, unlike metastatic disease, the goalof adjuvant therapy is cure. Thus, the development of delayedtoxicities such as congestive cardiomyopathy is an importantconsideration. While adjuvant therapy is generally of relativelyshort duration, anti-HER2 therapy may last up to 24 months.Nevertheless, the absence of symptomatic cardiac events inpatients enrolled in the EGF100151 study provides some evi-dence that lapatinib alone does not confer a high risk of devel-oping heart failure. Furthermore, an analysis of cardiac func-tion in a large cohort of patients treated with lapatinib either asmonotherapy or in combination with cytotoxic agents wasrecently presented [33]. Monitored by multigated radionuclideangiography or echocardiogram, 58 of the 3558 patients(1.6%) had confirmed decreases in left ventricular ejection frac-tion (LVEF). However, only seven of the 58 patients (0.2%)were symptomatic. In addition, nearly all of the patients withdecreased LVEF had medical or prior treatment histories thatcould have contributed to the cardiac event. While cardiacmonitoring is mandatory in patients receiving lapatinib, it isalso important to note that asymptomatic decreases in LVEFhave been reported to be two- to fourfold higher in the generalpopulation [34].

In conjunction with the Breast International Group (BIG),an ambitious Phase III trial named Adjuvant Lapatinib and/orTrastuzumab Treatment Optimization (ALTTO) is scheduledto commence enrollment in approximately mid-2007 (TABLE 1).In order to meet the primary end points of overall survival andTTP and have statistical power, a planned enrollment ofapproximately 8000 women with HER2-overexpressing earlybreast cancer is necessary. The enrolled subjects will be rand-omized to one of four treatment arms: trastuzumab for 1 year,lapatinib for 1 year, both agents for 1 year, or trastuzumab for3 months followed by lapatinib for 9 months. Chemotherapy isrequired though not prespecified. A second ‘adjuvant’ trial,Tykerb® Evaluation After Chemotherapy (TEACH), will com-pare lapatinib versus placebo for 1 year in women who have

Lapatinib


received prior adjuvant chemotherapy without trastuzumab.The interesting part of this trial is that the criteria do notspecify a timeframe from diagnosis to study entry as long asthe original tumor overexpressed HER2 and the patient istumor free by clinical assessment and radiographic imagingstudies. The primary end point is disease-free survival; overallsurvival, development of CNS disease and quality of life aresecondary end points.

Tumor resistanceDevelopment of drug resistance is a common characteristic ofadvanced cancers and can occur via a number of mechanisms.This notion is consistent with the observation that nearly allpatients with HER2-positive metastatic breast cancer who ini-tially responded to trastuzumab-based treatment appear tobecome refractory within 12 months [6]. Even more discourag-ing are relapses following adjuvant therapy with the antibody[4,5]. While it is common practice to discontinue the specifictherapy on which the tumor has progressed, preclinical andeven clinical evidence suggest that complete modification of thetreatment regimen may not be necessary. For example, in mice

developing trastuzumab-resistant tumors, adding a taxane totrastuzumab resulted in greater antitumor effects than taxanealone [35].

A circumstance that appears to bear some similarityoccurred in patients with advanced irinotecan-refractory coloncancer who were subsequently treated with the same drugsplus cetuximab [36]. Furthermore, it has been proposed thateven in patients with apparent trastuzumab-resistant tumors,clones of cells may retain trastuzumab sensitivity if a differentcytotoxic agent is used [37]. Based on this supposition, severalgroups have retrospectively evaluated the continued use oftrastuzumab after disease progression [6–9]. As mentioned pre-viously, with the addition of cetuximab in patients with iri-notecan-refractory colon cancer, further clinical benefit hasalso been observed with second-line trastuzumab in combina-tion with a different chemotherapy regimen in patients whosedisease progressed on trastuzumab.

Another aspect of resistance relates to the development ofbrain metastasis. Independent of other factors, positive HER2status alone has been associated with a higher risk of developingCNS involvement despite trastuzumab therapy [38,39]. This

Table 1. Breast cancer trials with lapatinib.

Design Key eligibility criteria Treatment schema End points

Metastatic breast cancer

Phase III, randomized, double-blind, placebo-controlled, 700 patients (EGF104383)

HER2+; no prior therapy for metastatic disease; trastuzumab therapy ≥12 months prior

Two-arm: paclitaxel + trastuzumab ± lapatinib

First: TTP; second: ORR

Phase III, randomized, double-blind, placebo-controlled, 424 patients (EGF104535), (EGF30001 similar)

HER2+; no prior therapy for metastatic disease; trastuzumab therapy ≥12 months prior

Two-arm: paclitaxel ± lapatinib First: clinical benefit rate; second: OS, PFS, TTF, RR

Phase III, randomized, double-blind, placebo-controlled, 1280 patients (EGF30008)

ER+ and/or PgR+; postmenopausal; no prior therapy for metastatic disease; aromatase inhibitor therapy ≥12 months prior

Two-arm: lapatinib ± letrozole First: TTP; second: RR, CBR, OS, 6-month PFS, time to and duration of response

Phase III, open-label, randomized, 270 patients (EGF104900)

HER2+; disease progression following two prior trastuzumab plus chemotherapy (taxane and anthracycline therapy regimens)

Two-arm: lapatinib ± trastuzumab First: PFS; second: OS, RR, CBR, time to and duration of response

Adjuvant breast cancer

Phase III, randomized, approximately 8000 patients (ALTTO)

HER2+; no prior therapy Four-arm: trastuzumab vs lapatinib vs trastuzumab + lapatinib vs sequential trastuzumab–lapatinib; chemotherapy will be given, but not specified

First: TTP; second: ORR

Phase III, randomized, double-blind, placebo-controlled, approximately 3000 patients (TEACH)

HER2+; completed adjuvant therapy, no prior trastuzumab therapy

Two-arm: lapatinib vs placebo First: DFS; second: OS, RFS, CNS occurrence

ALTTO: Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization; CBR: Clinical benefit rate; DFS: Disease-free survival; ER: Estrogen receptor; ORR: Objective response rate; OS: Overall survival; PFS: Progression free survival; PgR: Progesterone receptor; RR: Response rate; TEACH: Tykerb® Evaluation After Chemotherapy; TTF: Time to treatment failure; TTP: Time to progression.

Higa & Abraham


complication is presumably related, in part, to the poorer pen-etration of the antibody across the blood–brain barrier. Prelim-inary and updated results of a Phase II study suggest that asmall-molecule inhibitor of HER2 can access this sanctuarysite [40,41]. Analysis of the initial 104 patients with CNS diseasefollowing trastuzumab and cranial radiotherapy who were sub-sequently treated with lapatinib has been performed. Eightpatients achieved a PR; 17 (16.3%) additional patients hadvolumetric reductions of at least 20%, which persisted for amedian duration of 16 weeks. Further evidence of clinicalactivity in the CNS was seen in the Phase III study reportedabove [10,29]. Studies incorporating larger numbers of patientsmay show that the small molecule can decrease the risk of, oreffectively treat, CNS disease.

Perhaps, and not without regard for EGFR, targeting theintracellular kinase domain has been an effective therapeuticoption for patients with disease progressing on trastuzumab[10,32]. More intriguing, however, is whether two agents, eachpoised at two different HER2 molecular sites, are better thaneither agent given alone. This is indeed an important questionas mechanistic differences between the two classes of agentscould have significant clinical implications. To test this hypoth-esis, a trial (EGF104900) comparing lapatinib in combinationwith trastuzumab versus lapatinib alone in patients withadvanced breast cancer progressing on prior trastuzumab ther-apy is currently ongoing. The issue related to the mechanism(s)by which a small-molecule inhibitor of HER2 overcomestrastuzumab resistance will be discussed later.

Safety & tolerabilityAs important as efficacy, the relative safety and tolerability oflapatinib are important considerations in cancer therapy sinceeffects on quality of life are a principal concern regardless ofdisease stage. As such, and regardless of phase, a remarkablysimilar side-effect profile has been observed in all clinical tri-als of the drug. These findings further confirm that lapatinib,like other small molecule tyrosine kinase inhibitors, is reason-ably well tolerated with diarrhea, rash, nausea and fatigueamong the most frequently drug-related side effects reported.The incidence of diarrhea, dyspepsia and rash was higherwhen lapatinib was combined with capecitabine comparedwith fluoropyrimidine alone [10]. Although most of theseadverse events were grade 1 and 2, five deaths were alsoreported, two in the group receiving lapatinib plus capecitab-ine and three who were treated with capecitabine alone. Onewoman in the latter group developed diarrhea, vomiting andbowel obstruction, effects investigators attributed todrug-induced toxicity.

Cardiac events were also monitored as severe toxicityrelated, in part, to blockade of the HER2 signaling pathwayhas been reported [42,43]. Although addition of lapatinib wasnot associated with any symptomatic cardiac event resulting insubject withdrawal, the answer related to this issue is not finalas the possibility of selection bias and the relatively shortobservation period could impact future outcomes. Overall, the

addition of lapatinib to capecitabine did not result in a greaterincidence of severe adverse effects necessitating withdrawalfrom the study.

Regulatory affairsBased on the results of the pivotal Phase III study by Geyer et al.,the FDA, on March 13, 2007, approved the use of lapatinib incombination with capecitabine for patients with HER2-overex-pressing metastatic breast cancer progressing on previous anthra-cycline, taxane and trastuzumab therapy. A number of othercountries including Australia, Bahrain, Kuwait, Switzerland andVenezuela have also approved lapatinib for clinical use.

ConclusionThe approval of lapatinib for the treatment of trastuzumab-resistant advanced breast cancer can be viewed as a substantialtherapeutic advance. In some respects, results of the rand-omized Phase III study strengthen this perception, as lapatinibin combination with capecitabine significantly reduced the riskof disease progression and improved the overall response rate.Furthermore, the addition of lapatinib to chemotherapy wasnot related to increases in rates of adverse events or withdrawaldue to serious toxicity.

Another perspective, however, is that the dual kinase inhibitormay not be superior to the humanized antibody as there are nocomparative, head-to-head clinical trials of the two agents.While not offering definitive insight, an analogous, althoughnot identical, clinical trial was undertaken based on supra-addi-tive antitumor effects observed in elegant in vitro and in vivotumor models with the combination of a small molecule inhibi-tor of the EGFR tyrosine kinase plus trastuzumab [44,45].Designed to evaluate the efficacy of the identical combination asfirst- or second-line treatment in patients with advanced breastcancer, the study was discontinued because response rates wereno better, and time to disease progression was worse than anti-body alone. It should not be inferred from these observationsthat there is little or nothing to be gained by inhibiting EGFRin breast cancer. Although the disappointing outcomes may berelated to antagonistic pharmacologic and/or molecular mecha-nisms, the findings indirectly raise the question of how much oflapatinib’s effect can be attributed to inhibition of EGFR.

Because of the encouraging results of lapatinib in the advanced,disease- and treatment-progressive settings, it is intriguing tospeculate that incorporation of the drug in the adjuvant settingwill be as, if not more, beneficial than what has been observedwith trastuzumab. One important outcome relates to the devel-opment of brain metastasis; another will be to determine the effi-cacy of trastuzumab in primary lapatinib-resistant breast canceror in previously responding patients who develop disease progres-sion on lapatinib. An opportunity also exists to assess whethertargeting HER2 from the ‘outside’ and ‘inside’ simultaneouslyhas additive or perhaps even synergistic activity in patients withHER2-overexpressing breast cancers. Undoubtedly, this studywill have to be performed with extreme caution given previousfindings with the combination of gefitinib and trastuzumab.

Lapatinib


Finally, and clearly, clinical trials with lapatinib substantiatethe relative importance of HER2, confirm HER2 as a thera-peutic target and verify the accessibility of HER2 to inhibitionby small molecules.

Expert commentaryPerhaps of more academic than clinical interest is the issuerelated to the mechanism(s) by which lapatinib is able toovercome tumor resistance to trastuzumab. Identifying waysof overcoming resistance to targeted therapies should, theo-retically, be easier than to cytotoxic chemotherapy. Althoughthis may not be true, volumes of new information related tothe ErbB family members provide some, although often verylittle, insight. First, EGFR remains a conundrum in oncol-ogy. Although overexpressed in many solid tumors, criticaloncogenic signaling through EGFR alone may be of minorrelevance in breast cancer or may vary depending on hor-mone-sensitivity, nodal status, tumor grade or stage, or natu-ral history of the disease [46–48]. These beliefs are partiallysupported by early-phase clinical trials in breast cancer thatdemonstrated that neither monoclonal antibody- nor smallmolecule-mediated inhibition of EGFR was of significantbenefit [46,49,50].

Second, the consequences of ErbB receptor dimerization maybe of immense oncogenic significance in breast cancer.Although formation of ligand-bound complexes induces recep-tor oligomerization, heterodimers (especially HER2-containingcomplexes) appear to confer a more aggressive phenotype. Oneof the most convincing examples is the coupling of HER2 andHER3. While neither monomeric HER2 nor ErbB3 can sup-port linear signaling alone, it is both fascinating and disturbingthat this heterodimer has been shown to possess the mostpotent mitogenic and transforming properties [51]. Similarly,signaling through the EGFR–HER2 complex is more potentthan either homodimer alone [52]. Thus, while the very modestresponses observed in breast cancer may be due to the degree oftumor dependence on EGFR alone, reliance of oncogenic sign-aling through the functional interaction of EGFR and otherErbB receptors may be totally different. Analysis of mice bear-ing a breast cancer xenograft that co-expresses EGFR andHER2 revealed the formation of EGFR and full-length HER2(p185ErbB2). More importantly, phosphorylation of two keydownstream proteins was inhibited only when both receptorkinases were blocked. This finding provides a possible explana-tion for the efficacy of lapatinib in a tumor where trastuzumabhad little effect [53].

Molecularly, the importance of ErbB2 extends even furtheras the full-length protein (p185ErbB2) undergoes proteolytictruncation, resulting in a deceptively shortened receptor(p95ErbB2) with increased autokinase activity [54]. Clinically,elevated serum levels of the dissociated extracellular domainhave been correlated with a poorer response to therapy as wellas lymph node metastasis [55,56]. The presence of cleavedErbB2 is notable for two additional reasons. First, phos-phorylation of p95ErbB2 can be blocked by lapatinib, whereas

trastuzumab demonstrated no effect, and second, the truncatedreceptor preferentially dimerizes with ErbB3 [53]. Third, the bio-chemical mechanisms by which monoclonal antibodies andsmall molecules attenuate HER2 signaling may provide anexplanation for the effectiveness of lapatinib in patients who failtrastuzumab. Intriguingly, the answer may be related to EGFR.While formation of antibody–receptor complexes undergoesendocytosis and subsequent proteolytic degradation, specificinhibition of the EGFR tyrosine kinase has been shown, bothex vivo and in vivo, to affect heterodimer formation resulting inmarked impairment of HER2 signaling [44,57,58].

Finally, our understanding of the functional relevance ofEGFR in tumors that co-express HER2 and HER3 is incom-plete. Nonetheless, a number of molecular findings providesome clues to explain the efficacy of lapatinib, namely:

• The ability of gefitinib to inhibit heterodimeric transactivationof HER2 in cells that also express EGFR [44];

• In contrast to the modest antagonistic effects of aHER2-specific kinase inhibitor, formation of EGF-inducedsecondary heterodimers, such as HER2–HER3, can beprevented by an EGFR-specific kinase inhibitor [59,60];

• Inhibition of EGFR–HER2 crosstalk by targeting the EGFRkinase alone results in uncoupling of the HER2–HER3heterodimer [44].

Five-year viewAlthough EGFR and HER2 are among the oldest of postu-lated tumor targets, it has taken more than two decades toestablish molecular proof of concept. Despite the translationalachievement between laboratory and clinic with approval ofagents targeting ErbB1 and/or ErbB2, the expected concord-ance between signal inhibition and tumor eradication has, insome respects, been considerably overestimated. The apparentincongruence suggests that mere identification of trans-membrane receptors, regardless of their functional importance,grossly oversimplifies a signaling mainframe that is capable ofsupporting diverse information flow that ultimately controlscell destiny.

Despite the recent achievements in patients with HER2-over-expressing breast cancer, the ErbB story also exposes how aston-ishingly little is known about the complex signaling pathwaysinvolved in the regulation of tumor growth and survival. Thereality is that EGFR and HER2 are extraordinarily dynamicstructures as their respective genes are still malleable by the per-petual forces of mutation. As such, and as change is certain,both receptors will continue to evolve in unpredictable ways,necessitating, and even demanding, periodic re-examination ofexisting beliefs.

Financial disclosureThe authors have no relevant financial interests, includingemployment, consultancies, honoraria, stock ownership oroptions, expert testimony, grants or patents received or pending,or royalties related to this manuscript.

Higa & Abraham


Information resources• TYKERB Registration studies in breast cancer.

American Society of Clinical Oncology 2006.www.gsk.com

• American Society of Clinical Oncologywww.asco.org

• National Cancer Institute of the USA www.nci.nih.gov

• Trial number EGF104383, EGF20009Email: [email protected]

• Trial number EGF104535Email: [email protected]

• Trial number EGF30008, EGF104900, EGF105084Email: [email protected] or [email protected]

Key issues

• Patients with HER2-positive advanced breast cancer progressing on or refractory to trastuzumab therapy now have a legitimate treatment option with lapatinib.

• Identification of biomarkers that can be used a priori to select patients with breast and other solid tumors most likely to respond to lapatinib is needed.

• Further investigation of the clinical relevance of HER3 in HER2-overexpressing breast cancer is essential.

• Clinical results of lapatinib in the adjuvant setting are eagerly awaited.

• Clinical outcomes of lapatinib in tumors other than breast cancer are ongoing.

ReferencesPapers of special note have been highlighted as:• of interest•• of considerable interest

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•• Findings may alter approach to management of patients with early HER-overexpressing breast cancer.

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•• Findings may alter approach to management of patients with early HER-overexpressing breast cancer.

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• Data from a pivotal trial of a new dual kinase inhibitor in patients with HER-positive breast cancer progressing on trastuzumab therapy.

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• Important findings related to the crystal structure of EGFR.

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•• Excellent basic science study and presentation of data.

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Affiliations

• Gerald M Higa, PharmD

Associate Professor, Mary Babb Randolph Cancer Center, School of Pharmacy, West Virginia University, Morgantown, WV 26506, USATel.: +1 304 293 1461Fax: +1 30 293 [email protected]

• Jame Abraham, MD

Associate Professor, Mary Babb Randolph Cancer Center, School of Medicine, West Virginia University, Morgantown, WV 26506, USATel.: +1 304 293 4229Fax: +1 304 293 [email protected]

lapatinib in the treatment of breast cancer

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