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aximizing Clinical Benefit With Trastuzumabichard Bell,a Shail Verma,b Michael Untch,c David Cameron,d and Ian Smithe

To optimize patient management in breast cancer a number of factors are considered,including hormone receptor and HER2 status. A feasible approach for women with lessaggressive, estrogen receptor/HER2-positive metastatic breast cancer is to consider tras-tuzumab (Herceptin; F. Hoffmann-La Roche, Basel, Switzerland) combined with endocrinetherapy. Randomized clinical trials are ongoing to assess the combination of trastuzumabwith aromatase inhibitors. In patients with aggressive HER2-positive metastatic breastcancer, trastuzumab/chemotherapy combination regimens are warranted. When adminis-tered first line in combination with a taxane, trastuzumab improves all clinical outcomeparameters, including survival, in such patients. Trastuzumab adds little to the toxicityprofile of taxanes, and trastuzumab combination therapy is associated with improvementsin quality of life when compared with chemotherapy alone. There is encouraging evidenceof improved efficacy when trastuzumab is combined with other cytotoxic agents withproven single-agent activity in breast cancer, including capecitabine (Xeloda; F. Hoff-mann-La Roche), gemcitabine, and vinorelbine. Trastuzumab is also being investigated aspart of triplet drug regimens. Trastuzumab has good single-agent activity in first-linetherapy. This is of relevance to women with HER2-positive disease who are not suitable for,or do not wish to receive, cytotoxic chemotherapy. The benefits noted with trastuzumab-containing regimens were documented in clinical trials where trastuzumab was given untildisease progression. A further rationale exists to continue trastuzumab beyond progres-sion. Data from retrospective reviews indicate that this strategy is feasible.Semin Oncol 31:35-44 © 2004 Elsevier Inc. All rights reserved.

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ptimizingreatment ofER2-Positiveetastatic Breast Cancerreast cancer represents a heterogeneous disease that canbe segregated into different subgroups based on a num-

er of prognostic and predictive parameters. Defining theptimal treatment options for individual patients, or groupsf patients, is paramount. Aggressive versus indolent, symp-

Andrew Love Cancer Centre, Geelong Hospital, Victoria, Australia.Ottawa Regional Cancer Centre, Ottawa, Ontario, Canada.Ludwig Maximilians University, Munich-Gro�hadern, Germany.Western General Hospital, Edinburgh, UK.Royal Marsden Hospital, London, UK.r Bell has received research grant support from F. Hoffmann-La Roche,

Amgen, Novartis, Sanofi, and Eli Lilly and is a paid consultant toF. Hoffmann-La Roche and Novartis. Drs Verma and Cameron havereceived research grant support from F. Hoffmann-La Roche. Dr Untchhas received research grant support from F. Hoffmann-La Roche, Am-gen, Novartis, BMS, and Pfizer.

ddress reprint request to Richard Bell, MD, Andrew Love Cancer Centre,

w70 Swanston St, Geelong 3220, Australia.

093-7754/04/$-see front matter © 2004 Elsevier Inc. All rights reserved.oi:10.1053/j.seminoncol.2004.07.020

omatic versus asymptomatic, and receptor-positive versuseceptor-negative disease influence treatment decisions. Forxample, determining HER2 status allows those patientsikely to benefit from trastuzumab to be identified. Similarly,etection of estrogen receptor (ER) and/or progesterone re-eptor-positive disease indicates patients whose disease maye responsive to endocrine therapies. These concepts andreclinical data support the evaluation of the combination ofrastuzumab with endocrine therapy for patients with HER2-ositive/ER-positive breast cancer. Both trastuzumab and en-ocrine therapies are well tolerated, targeted, can be admin-

stered over long periods of time, and show significantlinical benefits in their target patient groups. Such ap-roaches are of particular relevance in patients with less ag-ressive, ER/HER2-positive disease who may not require up-ront cytotoxic chemotherapy.

In patients with HER2-positive and aggressive ER-positiver ER-negative disease, combining trastuzumab with chemo-herapy may be warranted. Trastuzumab adds little to theoxicities of chemotherapy and is highly efficacious,1,2 and isherefore a useful combination partner. In preclinical exper-ments, trastuzumab shows additive and synergistic activity

hen combined with cytotoxic agents with known efficacy in

35

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36 R. Bell et al.

reast cancer, including the taxanes, paclitaxel and do-etaxel.3,4 Both taxanes have substantial single-agent activityn the treatment of metastatic breast cancer (MBC).5,6 Ran-omized trials have provided evidence for the superior out-ome associated with trastuzumab plus a taxane versus tax-ne alone.1,2 This combination is a commonly used regimenor women with HER2-positive MBC.

In some situations, a combined trastuzumab/chemother-py approach may not be optimal. This may be the case inatients with comorbidities, the elderly, or those who do notish to receive, or prefer to delay starting, cytotoxic treat-ent. For these patients, trastuzumab monotherapy provideswell-tolerated and effective treatment option. When re-

uired, the addition of chemotherapy to trastuzumab can beonsidered at a later time point, to exploit possible synergisticnteractions.

The duration of any given therapy is also determined by aumber of factors. In the adjuvant setting, current practice onreatment duration is based on evidence of efficacy obtainedrom clinical trials. These have established that prolongingherapy beyond six cycles of CMF (cyclophosphamide/meth-trexate/5-fluorouracil) for example, provides no additionalenefit. In the metastatic setting, it has been more difficult toetermine optimal treatment duration and the decision totop therapy is based generally on disease progression and/oroxicity. Endocrine therapy is well tolerated and so diseaserogression is the major determinant of timing of cessation ofreatment. Cytotoxic chemotherapy is often associated withoxicity of a cumulative nature (ie, cardiotoxicity with an-hracyclines; neurotoxicity with taxanes) and therefore bothrogression and toxicity limit treatment duration with thesegents. Patient choice also plays a part in these decisions,ith many women preferring to continue the treatment they

re tolerating for as long as possible. Trastuzumab is cur-ently given at least until disease progression. However, theres emerging evidence that suggests that continuing trastu-umab treatment beyond progression, while changing thehemotherapy combination partner, is a feasible strategy anday produce clinical benefit.

ombiningrastuzumab withndocrine Therapyor Long-term Treatmentptimal therapy for ER-positive, HER2-positive tumors has

et to be determined. However, clinical evidence supportshe feasibility of combining trastuzumab with endocrineherapies. Although preclinical studies show an inverse rela-ionship between HER2 expression and quantitative ER sta-us,7 clinical studies show that approximately 50% of HER2verexpressing breast cancers are ER- and/or progesteroneeceptor-positive.8,9 Trastuzumab is effective in HER2-posi-ive breast cancer regardless of ER status,2,8,10 but HER2 pos-tivity predicts a relative resistance to endocrine therapy,11

articularly tamoxifen.12 There is evidence that this is caused

y “crosstalk” between the HER2 and ER intracellular signal- p

ng pathways,13,14 and that HER2 signaling stimulates thestrogenic, proliferative (agonist) effect of tamoxifen.15 Thisppears to be mediated by mitogen-activated protein (MAP)inase, which catalyses autophosphorylation of both the ER

tself and some of its coactivators. In ER-positive breast can-er, this results in hormone-independent proliferation,hich is insensitive to, and may be enhanced by, tamoxifen.rastuzumab has been shown to reverse the agonistic effect of

amoxifen in HER2-positive cell lines.16

Aromatase inhibitors such as letrozole have a different mech-nism of action from tamoxifen. The results of a comparativetudy in the primary systemic (neoadjuvant) setting showed thatetrozole is more active than tamoxifen in patients with ER-ositive, HER1- and/or HER2-overexpressing tumors. In thistudy, 15 of 17 patients (88%) with HER1- and/or HER2-posi-ive disease responded to letrozole versus four of 19 (21%) re-ponding to tamoxifen. Responses to letrozole and tamoxifenere similar in patients with ER-positive and HER1/HER2-neg-

tive disease (54% v 42%, respectively).12 In view of this re-ained sensitivity to aromatase inhibitors in the subgroup ofR-positive tumors that overexpress HER2, randomized clinical

rials are now investigating the combination of trastuzumabith aromatase inhibitors.

rastuzumab plus Letrozolestudy of trastuzumab combined with letrozole (2.5 mg daily)

n 26 patients with ER/progesterone receptor-positive and im-unohistochemistry (IHC) 2�/3� or fluorescence in situ hy-

ridization-positive MBC has recently been reported (data pre-ented at 26th Annual San Antonio Breast Cancer Symposium003).17 In 22 evaluable patients, 27% responded; a clinicalenefit (overall response rate [ORR] plus stable disease) waschieved in 64%. The median time to progression (TTP) was 31eeks. Only one patient developed grade 3/4 toxicity. This was

ardiomyopathy and followed doxorubicin/paclitaxel pretreat-ent and left chest wall irradiation. These data are encouraging,

lthough the patient numbers are small and the study includedatients with IHC 2� tumors.A large (n � 300), international, randomized first-line trial of

rastuzumab plus letrozole in ER-positive MBC (MO16722;LEcTRA) with tighter HER2 inclusion criteria (IHC 3� or flu-rescence in situ hybridization-positive) is ongoing. Patients willeceive either single-agent letrozole (2.5 mg daily) or letrozolelus trastuzumab at the standard schedule (4 mg/kg loadingose followed by 2 mg/kg weekly), both administered until dis-ase progression. The primary endpoint is TTP; secondary ob-ectives include ORR, clinical benefit rate, duration of responseDR) and overall survival (OS).

rastuzumab plus Anastrozolerial BO16216 is a randomized comparison of anastrozole (1g daily) with and without trastuzumab given at the standard

chedule in patients with no prior chemotherapy for MBC andHC 3� and/or fluorescence in situ hybridization-positive, ER-ositive disease. Patients may have received prior treatment withamoxifen for MBC, but it must be stopped at least 1 day beforentering the trial. Treatment is until disease progression or for 2ears, when eligible patients can enter an extension phase. The

rimary study endpoint is progression-free survival; secondary

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Maximizing clinical benefit with trastuzumab 37

bjectives include safety, clinical benefit rate, ORR, OS, and-year survival. Trial recruitment (n � 202 total) was completed

n May 2004. Results of this trial are expected in early 2005.

rastuzumablus Taxanes

rastuzumab with Paclitaxelhe pivotal phase III trial (H0648g) of trastuzumab plus che-otherapy was conducted in a total of 469 patients with HER2-ositive MBC who had not previously received chemotherapyor metastatic disease.1 Of these, 188 who had previously re-eived anthracyclines in the adjuvant setting were given pacli-axel 175 mg/m2 either alone (n � 96) or in combination withrastuzumab administered at the standard schedule (n � 92).hemotherapy was repeated every 3 weeks for at least six cycles.he primary study endpoint was TTP. Secondary endpointsere ORR, DR, time to treatment failure, and OS.The trial included patients with HER2 overexpression at the

� and 3� levels, as assessed by IHC in a central laboratory.ubgroup analyses identified that greatest clinical benefits withrastuzumab are achieved in patients whose tumors stronglyverexpress HER2 (ie, IHC 3�) and/or show HER2 gene am-lification,1,18 with a 90% concordance between these selectionriteria.18 In patients with IHC 3� tumors, the addition of tras-uzumab to paclitaxel improved outcomes in terms of ORR,TP, DR, and time to treatment failure (Table 1). Median OSlso increased from 17.9 months to 24.8 months (Table 1).1,18

his survival advantage was observed despite 72% of the pa-ients initially randomized to single-agent chemotherapy subse-uently crossing over to receive trastuzumab following diseaserogression. Patients receiving trastuzumab also showed im-rovements in quality of life (QOL) when compared with thoseeceiving chemotherapy alone.19 The combination of trastu-umab plus paclitaxel has been further investigated in other,hase II, studies. These have used a 3-weekly or weekly pacli-axel regimen. Reported response rates range between 36% to1% (Table 2).20-30

rastuzumab With Docetaxelollowing the positive results from the trastuzumab plus pacli-axel pivotal trial, several studies have investigated trastuzumab

able 1 Trastuzumab Combination Pivotal Trial (H0648g) Clin-cal Outcomes (Immunohistochemistry 3� Subgroup)1,18

Trastuzumab �Paclitaxel(n � 68)

PaclitaxelAlone

(n � 77)

edian TTP (mos) 7.1 3.0RR (%) 49.0 17.0edian DR (mos) 10.9 4.6edian TTF (mos) 6.7 2.8edian OS (mos) 24.8 17.9

bbreviations: TTP, time to progression; ORR, overall response rate;DR, duration of response; TTF, time to treatment failure; OS,overall survival.

ombined with docetaxel. The results of phase II trials in a total i

f 343 patients, with docetaxel administered weekly or-weekly, are encouraging. Reported response rates range be-ween 44% to 70% (Table 2).20,31-41

A randomized trial was initiated to investigate the efficacy andafety of trastuzumab plus docetaxel versus docetaxel alone, asrst-line therapy (M77001). In total, 188 patients with HER2-ositive (IHC 3� and fluorescence in situ hybridization-posi-ive) MBC were enrolled into the trial. Two patients in the com-ination arm did not receive study drug and were excluded.2

ocetaxel was administered at a dose of 100 mg/m2 every 3eeks, and trastuzumab weekly according to the standard

chedule until disease progression. Patients progressing on do-etaxel alone could cross over to receive trastuzumab at thenvestigators’ discretion. The primary study endpoint was ORR;econdary endpoints were safety, TTP, time to treatment failure,R, 1-year survival, and OS. Approximately 70% of patients inoth arms had received adjuvant chemotherapy, including an-hracyclines in 64% and 55% of those receiving trastuzumab/ocetaxel and docetaxel alone, respectively.The 12-month cut-off data were presented by David Cam-

ron at the 4th European Breast Cancer Conference2 andhowed that the addition of trastuzumab to docetaxel signifi-antly improved all clinical outcomes (Table 3), including OSFig 1). Subgroup analyses conducted retrospectively showedhe combination resulted in superior responses compared withocetaxel alone for all parameters examined. A further retro-pective analysis looked at the Kaplan-Meier survival plots ofatients who, upon progression, crossed over from the do-etaxel-alone arm to receive trastuzumab. These data includedt least 48% of 94 patients randomized into the single-agentocetaxel arm. The Kaplan-Meier plots showed a trend suggest-

ng that OS was greater in patients who received trastuzumabollowing docetaxel compared with those who did not crossver to receive trastuzumab (median OS, 24.5 v 19.1 months,espectively). These data should be interpreted with cautionecause of a potential selection bias. The best median OS of 30.5onths was seen in the patients receiving the combination up-

ront.As discussed elsewhere in this supplement the combination

f trastuzumab and docetaxel was generally well tolerated.42

rastuzumab added a small and manageable component to theoxicity profile of docetaxel alone. Hematologic toxicities re-orted as serious adverse events, which are common with do-etaxel treatment, were increased (not statistically significant) inhe combination arm compared with the single-agent arm, butere manageable.In summary, two randomized trials are now mature and pro-

ide clear evidence of the clinical benefits, in particular in-reased survival, when trastuzumab is used in combination withtaxane as first-line treatment of HER2-positive MBC.

rastuzumabn Combinationith Other Chemotherapy

rastuzumab plus Capecitabineapecitabine monotherapy shows consistently high activity

n MBC, with a favorable safety profile that includes minimal

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able 2 Response Rates to Trastuzumab plus Chemotherapy

Study Chemotherapy Regimen nResponse Rate

(%)

aclitaxelToi et al, 200220 175 mg/m2 every 3 weeks 12 67Leyland-Jones et al, 200321 175 mg/m2 every 3 weeks 32 59Robert et al, 200422* 175 mg/m2 every 3 weeks 95 36Fountzilas et al, 200123* 90 mg/m2 weekly 33 62Krasna et al, 200124 80 mg/m2 weekly 15 67Seidman et al, 200125 90 mg/m2 weekly 36 81Janku et al, 200226 80 mg/m2 weekly 17 59Gasparini et al, 200327* 80 mg/m2 weekly 43 74John et al, 200328 90 mg/m2 weekly 77 69Christodoulou et al, 200329 70 or 90 mg/m2 weekly 26 62Gori et al, 200430 60-90 mg/m2 weekly 25 56ocetaxelKuzur et al, 200031 75 mg/m2 every 3 weeks 16 44Toi et al, 200220 60 mg/m2 every 3 weeks 14 57Bauer-Kosinska et al, 200332 100 mg/m2 every 3 weeks 18 55Montemurro et al, 200433 75 mg/m2 every 3 weeks 42 67Tabei et al, 200434 70 mg/m2 every 3 weeks 40 70Raab et al, 200235* 100 mg/m2 every 3 weeks or 35 mg/m2 weekly 24 63Meden et al, 200136 35 mg/m2 weekly 12 50Esteva et al, 200237 35 mg/m2 weekly 30 63Schwartz et al, 200238* per investigator’s discretion 63 51Raaf et al, 200439 33 mg/m2 weekly 17 59Takao et al, 200440 40 mg/m2 weekly 35 62Tedesco et al, 200441 35 mg/m2 weekly 26 50apecitabineBangemann et al, 200053 1,250 mg/m2 twice weekly (days 1-14) every 3 weeks 16 50inorelbineBurstein et al, 200155 25 mg/m2 weekly 40 75Bernado et al, 200256* 25 mg/m2 weekly 35 84Jahanzeb et al, 200257* 30 mg/m2 weekly 40 78Burstein et al, 200358* 25 mg/m2 weekly 55 68Papaldo et al, 200359 25 mg/m2 weekly 32 47Bayo et al, 200460 25 mg/m2 weekly 46 66Untch et al, 200461* 30 mg/m2 weekly 69 59emcitabineO’Shaughnessy et al, 200266 1,200 mg/m2 (days 1 & 8) every 3 weeks 38 32Christodoulou et al, 200367 1,000 mg/m2 (days 1, 8 and 15) every 3 weeks 28 36riple combinationsCarboplatin/paclitaxel

Yardley et al, 200269* AUC 2/70 mg/m2 weekly 61 66Perez et al, 200370* AUC 2/80 mg/m2 weekly 53 78Perez et al, 200370* AUC 6/200 mg/m2 every 3 weeks 43 50Robert et al, 200422* AUC 6/175 mg/m2 every 3 weeks 93 52

Epirubicin/docetaxelVenturini et al, 200371* 75/75 mg/m2 weekly 45 69

Gemcitabine/paclitaxelMiller et al, 200272* 1,200 mg/m2 (days 1 & 8)/ 175 mg/m2 every 3 weeks 45 62

nthracyclinesEpirubicin/cyclophosphamide

Untch et al, 200473* 60/600 mg/m2 26 6290/600 mg/m2 25 64

Liposomal doxorubicinTheodoulou et al, 200274 60 mg/m2 3-weekly 37 58

Liposomal doxorubicin/paclitaxelBaselga et al, 200475* 50 mg/m2 weekly/80 mg/m2 3-weekly 54 92

First-line treatment.

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Maximizing clinical benefit with trastuzumab 39

yelosuppression and alopecia.43-50 In combination with do-etaxel, capecitabine improves survival over docetaxellone.51 With respect to HER2-positive disease, capecitabinend trastuzumab have at least additive activity in vivo.52

aken together, these factors provide a rationale for combin-ng trastuzumab with capecitabine.

Preliminary data are available from a pilot study. Heavilyretreated patients with advanced HER2-positive breast can-er received oral capecitabine 1,250 mg/m2 twice daily onays 1 to 14 of a 3-weekly schedule combined with the stan-ard weekly schedule of trastuzumab.53 Capecitabine plusrastuzumab achieved objective responses in eight of 16 pa-ients (50%) and disease stabilization in a further six patients38%), providing a clinical benefit rate of 88%. Mean TTPas 7 months. The most common adverse events were hand-

oot syndrome and gastrointestinal toxicities. There was nolopecia or grade 3/4 myelosuppression.

These findings indicate the trastuzumab/capecitabineombination is feasible and well tolerated, and warrants fur-her investigation. Six phase II studies of the combinationegimen alone or as part of a triplet combination are nowlanned or ongoing. This includes a large trial of capecitabineith or without trastuzumab following disease progressionn trastuzumab (MO17038) and a randomized trial of tras-uzumab plus docetaxel with or without capecitabineMO16419, the CHAT study).

rastuzumab plus Vinorelbineinorelbine is active in MBC54 with a favorable safety profilend low toxicity, making it an attractive combination partner.t has shown synergy with trastuzumab in vitro.3 A number oflinical trials of trastuzumab at the standard schedule com-ined with vinorelbine (25 or 30 mg/m2) have shown that theombination is highly active. Response rates of 47% to 84%ere observed55-61 (Table 2). In a small study by Papaldo et

l59 patients with HER2-negative disease were given vinorel-ine alone while those with HER2-positive disease wereiven trastuzumab plus vinorelbine. The ORRs were 28%nd 47% for patients with HER2-negative and HER2-positiveisease, respectively. This suggests that combining trastu-umab with chemotherapy can overcome the expectedoorer prognosis of patients with HER2-positive diseaseompared with HER2-negative disease. In patients with IHC

able 3 Efficacy Summary for Patients Treated With Trastu-umab plus Docetaxel versus Docetaxel Alone2

Outcome

Trastuzumab �Docetaxel(n � 92)

DocetaxelAlone

(n � 94)P

Value

RR (%) 61.0 34.0 .0002R (median, mos) 11.4 5.1 .0011TP (median, mos) 10.6 5.7 .0001S* (median, mos) 30.5 22.1 .0062

OTE. Intent-to-treat population, 12-month cut-off data.bbreviations: ORR, overall response rate; DR, duration of re-

sponse; TTP, time to progression; OS, overall survival.Kaplan-Meier estimate.

� disease, response rates are reported to be higher than in m

he total (IHC 2�/3�) population.56 Complementary safetyrofiles result in a well-tolerated regimen.

rastuzumab plus Gemcitabineingle-agent gemcitabine is well tolerated in MBC and asso-iated with response rates of up to 37% when used as first/econd-line therapy.62-65 Two preliminary clinical trials ofrastuzumab plus gemcitabine, in patients previously treatedor MBC, have shown promising response rates and medianTP of 32% and 6.7 months66 as well as 36% and 7.8onths.67 This combination has been associated with prom-

sing median survival times of 10.2 months66 and 18.7onths,67 respectively, although patient numbers are small

n � 38 and n � 28). Tolerability was found to be generallyood, with no unexpected side effects.

rastuzumab in Triplet Combinationshe combination of more than two agents is an establishedpproach in cancer therapy and has the potential to furthermprove response rates and increase survival. Trastuzumabriplet combinations showed enhanced activity in HER2reast cancer cell lines4,68 and several such triplet combina-ions are currently under investigation or have been reportedn clinical trials. These include combinations with carbopla-in and paclitaxel,22,69,70 epirubicin and docetaxel,71 or gem-itabine and paclitaxel.72 The ORRs ranged between 50% to8% (Table 2). The trial by Robert et al22 is randomized andompares trastuzumab plus paclitaxel with or without theddition of carboplatin. In the total patient population (IHC� and 3�) the triplet combination achieved a significantlyuperior response rate when compared with trastuzumablus paclitaxel alone (52% v 36%, respectively; P � .04).esponse rates were improved in patients with IHC 3� dis-ase (57% and 37%, respectively; P � .03) compared withhe total (IHC 2�/3�) population. Median TTP was signifi-antly improved with the addition of carboplatin to trastu-umab plus paclitaxel (10.7 v 7.0 months; P � .02). MedianS was longer in the triplet combination group comparedith the doublet arm (36 months v 32 months; P � .49).gain, better survival was seen in the patients with IHC 3�isease compared with the total population (42 months v 29onths, respectively; P � .29).In the randomized triplet combination trial comparing

igure 1 Estimated OS in patients treated with trastuzumab plusocetaxel versus docetaxel alone.2 Intent-to-treat population, 12-

onth cut-off. Documented crossover � 48%.

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40 R. Bell et al.

rastuzumab plus docetaxel with and without the addition ofapecitabine (MO16419), the primary endpoint is ORR andecondary endpoints include progression-free and OS, DR,nd safety.

rastuzumab plus Anthracyclineshe anthracyclines are among the most commonly used an-

icancer agents for MBC. In the randomized combinationrial, H0648g, the combination of trastuzumab and anthra-yclines (mainly doxorubicin) was highly efficacious,1 butas associated with an increased risk of congestive heart

ailure that prevented its inclusion in the current trastu-umab license. Several studies are ongoing to investigate theardiac safety of trastuzumab with anthracyclines with lessardiotoxic potential than doxorubicin, including epirubicinnd liposomal formulations of doxorubicin. Initial resultsrom these trials indicate acceptable safety profiles,42,73 andncouraging response rates (Table 2).73-75 The HERCULESrial (M77003), for example, is investigating trastuzumabith epirubicin (E; 60 or 90 mg/m2) and cyclophosphamide

C; 600 mg/m2). Results from 75 patients have shown highesponse rates (62% and 64% for trastuzumab plus EC60 andC90, respectively) and a low incidence of cardiacvents.42,73 The trial continues enrollment.

rastuzumab Monotherapylinical trial evidence indicates that trastuzumab is active asrst-line monotherapy in HER2-positive MBC. A phase IIandomized multicenter trial of trastuzumab monotherapyH0650g) was conducted in 114 women who had not previ-usly received chemotherapy for metastatic disease.76 Theedian duration of survival in the total population, which

ncluded some patients with IHC 2� disease, was 24.4onths. This compares favorably with median survival times

f 16.2 to 19.1 months observed with first-line anthracyclinese,77-79 and 15.6 to 22.2 months with taxane use.77,79 TheRR to trastuzumab monotherapy in patients with IHC 3�isease was 35%. This ORR is similar to clinical trial responseates of 36% to 41% observed with anthracyclines77,79 and5% to 34% with taxanes.77,79 It should be remembered thathese reference results were seen in an unselected patientopulation (HER2-positive and -negative), while results withrastuzumab were achieved in a selected patient group with aarticularly poor prognosis (ie, patients with HER2-positiveisease). When stable disease for more than 6 months was

ncluded as a form of response, 48% of patients receivingrastuzumab monotherapy obtained clinical benefit fromrastuzumab.76 Health-related QOL was assessed in 74 pa-ients who completed the QOL questionnaire at baseline andt least one subsequent time point. In the majority of patientsOL improved or was maintained.76,80 In summary, thesendings show that trastuzumab monotherapy is a feasible,ctive, and useful treatment option for HER2-positive MBC,

roviding clinical and QOL benefit. a

reatment Beyondisease Progression

n reported clinical trials, including the pivotal trialsH0649g and H0648g) and the recently reported random-zed trial of docetaxel with or without trastuzumabM77001), the significant clinical benefits were achievedhen trastuzumab was administered at least until diseaserogression in accord with trial design.1,2,81 While there are,s yet, no randomized trial data addressing the issue of con-inuing trastuzumab following progression, a number of ret-ospective studies have provided valuable insight.

HER2 positivity is stable and is maintained throughout theourse of the disease,82 and results in enhanced HER2 signal-ng. HER2 signaling plays an important role in tumor devel-pment and growth, and is associated with aggressive diseasend a poor prognosis.83-87 Preclinical data suggest that con-inuous suppression of HER2 signaling helps control tumorrowth, with trastuzumab withdrawal resulting in rapid tu-or regrowth.68 Moreover, there is no definitive evidence in

hese systems that resistance to trastuzumab develops withrolonged exposure.88 In addition, safety data indicate that

ong-term administration of trastuzumab does not appear toe associated with any significant safety issues. The adversevents seen with trastuzumab plus chemotherapy combina-ions are generally those related to the chemotherapy. Theres no evidence of any cumulative toxicity from chronic expo-ure to trastuzumab.

Retrospective analyses from reported clinical trials showhat patients can respond to subsequent lines of treatmentith trastuzumab beyond initial progression. This provides

t least the proof of principle for continued exploration of these of trastuzumab and is discussed below.In an extension study of the pivotal phase III trial

H0648g),1 93 of the 235 patients treated with trastuzumablus chemotherapy (anthracycline/cyclophosphamide oraclitaxel) received further trastuzumab-containing treat-ent on progression. Approximately three quarters of pa-

ients (76%) received trastuzumab plus chemotherapy (pac-itaxel, vinorelbine, docetaxel, 5-fluorouracil, cisplatin,yclophosphamide, doxorubicin, or gemcitabine) and oneuarter (24%) received trastuzumab monotherapy.89 TheRR was 11%, the clinical benefit rate was 22%, and DR was.7 months. Responses to trastuzumab combination therapyn � 8) were seen, as well as responses to monotherapy (n �). The incidence and nature of adverse events in the exten-ion study were similar to those in the pivotal trial; the inci-ence of cardiac dysfunction was only 2%. No new adversevents were seen with prolonged treatment of up to 40�onths.Retrospective evidence of the clinical benefits of continu-

ng trastuzumab beyond disease progression is provided bywo reported analyses of patient files. In the first, data wereollected on 105 patients.90 Patients had received at least tworastuzumab-containing regimens for MBC. Data were lim-ted to patients receiving trastuzumab alone or with a taxane

s the first trastuzumab-containing regimen. The ORR and

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Maximizing clinical benefit with trastuzumab 41

TP to the first and second trastuzumab-containing regimensere similar (Fig 2; Table 4). Median survival from the startf the first trastuzumab regimen was 29.0 months (95% con-dence interval: 22.7 to 56.0).The second retrospective analysis included 80 patients, of

hom 91% had IHC 3� disease. Patients had received up toeven consecutive trastuzumab-containing regimens.91 A to-al of 32 responses were seen. Response rates were compara-le for at least three subsequent regimens after progressionn the first trastuzumab treatment: 24%, 14%, and 19%,espectively. Time to disease progression was also compara-le on the second, third, and fourth trastuzumab retreat-ents: 5.2, 3.5, and 4.9 months, respectively.The two retrospective analyses show that some patients

an respond repeatedly to a trastuzumab-containing regi-en; one third of patients responding to an initial trastu-

umab regimen had a second response.90 Furthermore, theyndicate that patients who fail a trastuzumab regimen canespond to subsequent lines of trastuzumab-containing treat-ent. In the first study, nine of 21 patients responding to

econd-line trastuzumab had not responded to the first-linef treatment.90 In the second study, four patients who pro-ressed while on second-line trastuzumab responded to fur-her regimens.91

n Ongoing Prospective Studyhe above data suggest that trastuzumab retains activity andonfers clinical benefit beyond disease progression, and thathanging chemotherapy while continuing trastuzumab cane an effective approach. The question of trastuzumab treat-ent beyond progression is currently being addressed in a

andomized study in more than 60 centers in Germany and

igure 2 Response rates to trastuzumab treatment beyond progres-ion: a case review from 105 patients.90 ND, not done.

able 4 Time to Progression for First and Second Lines of Tr

TrastuzumabRegimen

First Regimen

No. ofPatients

MeWee

Monotherapy 27 2Taxane 45 2Vinorelbine ND

bbreviations: TTP, time to progression; ND, not done.

Not reached at time of analysis.

ustria (MO17038). A total of 438 patients who have pro-ressed on trastuzumab plus a taxane are randomized toapecitabine (2,500 mg on days 1 to 14 of each 3-weeklyycle) with or without trastuzumab (each 3-weekly dose: 8g/kg loading followed by 6 mg/kg) both given until diseaserogression. The long half-life of trastuzumab complicateshe analysis of such studies, as the washout period for tras-uzumab overlaps with subsequent therapy.

ummary:ntegrating Knowledgeo Optimize Patient Carehe treatment of MBC depends on a number of factors, in-luding disease stage, receptor (ER and/or HER2), and per-ormance status as well as prior therapy. In light of the clinicalenefits achieved with trastuzumab, it should be considered

n the management plan of patients with HER2-positiveBC.Women with ER-positive tumors are currently given en-

ocrine therapy, such as tamoxifen or aromatase inhibitors.he optimal therapy for women whose tumors are both ER-nd HER2-positive has yet to be established. However, thevidence presented in this review provides a strong rationaleor combining trastuzumab with aromatase inhibitors for pa-ients with ER- and HER2-positive disease. Randomized trialsre ongoing to determine the clinical benefit associated withhis combination of targeted therapies.

Two randomized clinical trials have shown the superiorityf the combination of trastuzumab plus a taxane comparedith taxane alone. This benefit includes improved survivalith little addition to the toxicity profile of the taxane alone.onsequently, taxanes are considered the combination part-er of choice for use with trastuzumab. However, treatmentlgorithms are changing. Agents such as taxanes are nowore commonly used in the adjuvant setting, limiting theirse in MBC. Alternative regimens will be required for thoseatients who relapse with advanced disease, having beenreated with standard therapies in the adjuvant setting.

For women who have received prior adjuvant taxane ther-py, this combination regimen may still be of relevance ifore than 1 year has elapsed between the end of taxane

reatment and time of relapse. If the time lapse is less than 1ear, the alternate taxane or other chemotherapy partnersay be considered for use with trastuzumab. To this end,

mab-Containing Therapy90

Second Regimen

TP,ange)

No. ofPatients

Median TTP,Weeks (Range)

3) 10 30.5 (18-68)20 24 (3-72)33 26 (3-108)

astuzu

dian Tks (R

3 (3-74 (0*)

ND

twhtcaowacctdM

ieataTwc

wtphstiu

Haadpam

R

1

1

1

1

1

1

1

1

1

1

2

2

2

2

2

2

42 R. Bell et al.

rastuzumab has been investigated in combination regimensith chemotherapy other than taxanes. Phase II clinical trialsave provided promising data that combination regimens ofrastuzumab with standard chemotherapy for MBC, such asapecitabine, vinorelbine, and gemcitabine, are feasible andctive. These regimens have been shown to be effective with-ut compromising tolerability. The combination of agentsith different modes of action allows targeting of different

spects of the disease process. Combining more than oneytotoxic agent with trastuzumab may provide additionallinical benefits. Data from ongoing trastuzumab combina-ion trials, including triplet combinations, will help furtherefine the optimal treatment for women with HER2-positiveBC.Trastuzumab monotherapy is a useful option that has sim-

lar efficacy to current single-agent standard treatment strat-gies, and has a favorable safety profile with QOL benefits. Inddition, the demonstrated clinical benefits associated withrastuzumab use are noteworthy in a patient population with

particularly poor prognosis (ie, HER2-positive disease).rastuzumab may therefore be the preferred option foromen who are not suitable for, or do not wish to receive,

ytotoxic chemotherapy.Current evidence shows that trastuzumab has activity

hen used beyond disease progression. The lack of cumula-ive toxicity allows this strategy. Changing the chemotherapyartner while continuing trastuzumab beyond progressionas been clearly shown to result in objective tumor re-ponses. This can occur even in patients who did not respondo their first line of trastuzumab therapy. A randomized trials in progress to further determine the efficacy and clinicaltility of this strategy.Trastuzumab offers benefit to most clinical scenarios in

ER2-positive MBC. Therapy should always be tailored tochieve the best therapeutic ratio in each individual patientnd, where possible, therapeutic decisions should be evi-ence-based. The evidence from reported clinical trials sup-orts the use of trastuzumab in a wide variety of situationslone, in combination with hormonal agents, and with che-otherapy in doublets and triplets.

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