Tolerability in patients receiving trastuzumab with or without chemotherapy

Annals of Oncology 12 (Suppi. 1): S63-S68, 2001. © 2001 Kluwer Academic Publishers. Printed in the Netherlands.

Symposium article Tolerability in patients receiving trastuzumab with or without chemotherapy L. Gianni Division of Medical Oncology A, Islituto Nazionale Tumori, Milan, Italy

Summary

Introduction

The human epidermal growth factor receptor-2 (HER2) protein is overexpressed in up to 30% of metastatic breast cancers, which almost invariably arises from amplification of the HER2 gene [1-3]. HER2 overexpression is correlated with more aggressive breast cancer and poor prognosis (including decreased survival duration) in patients with both node-negative and -positive breast cancer [2-5]. There is also direct evidence that HER2 is an oncogene, playing a key role in the aggressive course of breast cancer [6, 7]. HER2 overexpression therefore provides a logical and accessible target for monoclonal antibody therapy that should result in selective pharmacologic effects and be devoid of the adverse effects of cytotoxic chemotherapeutic agents. Murine monoclonal antibodies were generated against epitopes of the HER2 receptor protein and showed therapeutic potential in animal models [8]. However, long-term administration of murine monoclonal antibodies in humans was restricted because of the human immunologic response to murine protein. Thus, one of the most potent murine monoclonal antibodies, 4D5, was humanized using genetic engineering techniques to insert the antigen-binding region of 4D5 into a human IgG framework [9], generating trastuzumab (Herceptin®). The drug showed potent anti-tumor activity in preclinical studies [10, 11]. This led to progression to a human clinical trial program for trastuzumab in patients with metastatic breast cancer to establish not only its efficacy, but also to determine its tolerability and safety. This report summarizes the safety profile of

Key words: adverse events, cardiotoxicity, Herceptin" metastatic breast cancer, safety, trastuzumab

trastuzumab as revealed so far during its clinical trial program. Safety of trastuzumab Preliminary phase I and II clinical trials To date, published data on the clinical development of trastuzumab in breast cancer have consisted of a series of phase I, II and III trials, which have been invariably conducted in patients with HER2-positive metastatic disease. Initial phase I studies were primarily conducted to determine the safety of escalating doses of trastuzumab in patients with refractory breast cancer (reviewed in Shak et al. [12]). These studies were conducted in relatively small numbers of patients (15-17 per trial) using single or weekly i.v. doses of trastuzumab (10-500 mg) administered either as monotherapy or in combination with cisplatin (50 or 100 mg/m2 weekly). Trastuzumab was well tolerated at all doses: grade 3 and 4 adverse events were few and included those that would be expected in this patient population. When used in combination with cisplatin, the severity and frequency of adverse events were similar to those expected with cisplatin alone. No antibodies to trastuzumab were detected and no unexpected intolerance was encountered, which allowed progression to phase II clinical trials [12]. Two open-label, phase II clinical trials were performed to determine the preliminary anti-cancer activity and safety of trastuzumab given at 250 mg initial dose followed by 100 mg weekly i.v. for 8-10 doses as a single

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One of the major expectations from the use of humanized monoclonal antibodies in cancer therapy has been that of exploiting the specificity and sensitivity of the immune system to achieve selective therapeutic effects devoid of the often severe toxicity caused by chemotherapy. The tolerability of trastuzumab (Herceptin®) as it emerged from the trials where the drug was used as a single agent or in combination with chemotherapy largely confirmed that expectation. Adverse events most frequently encountered include mild-to-moderate, transient effects related to administration of the first dose of

trastuzumab. The incidence of severe or serious adverse effects attributable to trastuzumab was low. However, the occurrence of cardiac toxicity that was unexpectedly high, especially in patients previously or concomitantly treated with anthracyclines, could not be predicted on the basis of the putative mechanism of action of the antibody. The safety profile of trastuzumab is discussed here with a particular focus on cardiotoxicity and the issues relating to patient management during trastuzumab therapy.

64

Pivotal phase Hand III clinical trials

Table I Adverse events, including those not related to treatment, occurring in ^ 1 % of 213 patients treated with at least one dose of trastuzumab during the pivotal monotherapy trial. a Adverse event

Pain Asthenia Fever Nausea Chills Headache Diarrhea Dyspnea Abdominal pain Chest pain a

Number of patients (%) Any adverse event

Severe adverse event

103(48) 97 (46) 81 (38) 77 (36) 7-7-(-36)56 (26) 55 (26) 49 (23) 47 (22) 44(21)

17(8) 6(3) 2(1) 2(1) 5(2) 4(2) 3(1) 10(5) 4(2) 3(1)

Cardiac adverse events are not included.

and there were no grade 4 abnormalities: 9% experienced at least one grade 3 hepatic laboratory abnormality and Safety data were collected in a phase II trial of trastuzu- 4% experienced grade 3 hematologic abnormalities. Of mab as a single agent [17] and in the phase III trial of note, trastuzumab was not associated with standard trastuzumab combined with chemotherapy [18] in patients chemotherapy-associated adverse effects such as vomitwith metastatic breast cancer. Trastuzumab was adminis- ing, hair loss and myelosuppression [17]. tered i.v. as an initial 4 mg/kg dose over 90 minutes In the pivotal phase III trial, a total of 469 patients followed by 2 mg/kg over 30 minutes weekly until disease were randomized to receive either chemotherapy alone progression. (n = 234) or trastuzumab + chemotherapy (n = 235) [18]. In the single-agent trial 222 patients were enrolled Trastuzumab was administered according to the same and 213 went on to receive at least one dose of trastuzu- schedule as in the preceding study. For those patients mab. It should be stressed that the patients had a who had not previously received an anthracycline particularly poor presentation at study entry, as this has (n = 281), chemotherapy consisted of either doxorubicin an impact on interpretation of the tolerability of trastu- 60 mg/m2 or epirubicin 75 mg/m2 plus cyclophosphazumab. Disease-free interval was < 12 months in 37% of mide 600 mg/m2 (AC) administered as an i.v. bolus or patients; 70% had liver or lung disease, 68% had received infusion for up to two hours. Paclitaxel 175 mg/m2 two previous chemotherapy regimens for metastatic dis- administered by i.v. infusion over three hours, was given ease, 26% had received prior high-dose chemotherapy to those who had already received adjuvant anthracywith stem cell or bone marrow rescue, almost all had cline (n - 188). Each chemotherapy was repeated every received anthracyclines (94%), and two-thirds (67%) three weeks for a maximum of six cycles. Paclitaxel was had received taxanes. Adverse events, including those administered with dexamethasone, diphenhydramine not related to treatment, that occurred in > 10% of plus cimetidine premedication. Trastuzumab infusion patients are shown in Table 1. The commonest events was administered on an outpatient basis and immediwere related to the first infusion, and included fever, ately prior to chemotherapy if administration was on the chills, pain, asthenia, nausea, vomiting, and headache. same day. As in the other pivotal study, the commonest These were generally mild to moderate in intensity and adverse events were mild-to-moderate chills and fever in could usually be treated with temporary interruption of about 40% of patients, most often related to first-dose infusion or by treatment with acetaminophen, diphen- administration and usually managed with symptomatic hydramine, and/or meperidine. These infusion-related treatment. Less frequent infusion-related signs and effects occurred infrequently during subsequent adminis- symptoms were nausea, vomiting, pain, headache and tration of trastuzumab. Severe adverse events were rare dizziness. Such adverse events were rarely severe. No and only two patients were withdrawn from treatment episodes of anaphylaxis occurred and one patient expe(one because of atherosclerotic heart disease clearly rienced moderate hypertension which resolved without unrelated to therapy, and another because of an anaphy- treatment. No patients developed detectable levels of lactoid reaction during administration of the first dose). neutralizing antibodies against trastuzumab. The inciUnexpectedly, nine patients had a significant reduction dence of infection was higher in patients who received in cardiac ejection fraction, of whom six were sympto- trastuzumab plus AC than in those who received AC matic (see later for details). One patient developed anti- alone (47% vs. 29%). However, these infections were bodies to trastuzumab after the end of therapy. World usually of minor clinical significance, consisting of mild Health Organization grade 3 laboratory abnormalities to moderate upper respiratory tract infections (72% of were rare during treatment before disease progression, all infection events), catheter infections (9%), viral syn-

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agent (n = 46) [13, 14] and in combination with cisplatin 75 mg/m2 i.v. on days 1, 29 and 57 (« = 39) [15, 16]. Patients continued therapy if they demonstrated stable disease or minor, partial or complete response. Adverse events associated with trastuzumab were infrequent, and usually mild or moderate, transient, and manageable. The most common events were fever and chills related to first-dose administration. Toxicity was assessed using the modified National Cancer Institute Common Toxicity Criteria. Grade 3 or 4 toxicity, which is commonly associated with cytotoxic chemotherapy, was only rarely associated with trastuzumab. Antibodies to trastuzumab were not detected. Based on this safety and favorable preliminary efficacy, the clinical trial program progressed to pivotal clinical trials in large numbers of patients, in which doses were determined in mg/kg instead of fixed doses.

65 Table 2. Serious adverse events occurring in >2.5% of patients receiving AC ± trastuzumab in the pivotal phase 111 combination trial.a

Table 3. Summary of CREC retrospective identification of patients with cardiac dysfunction in trastuzumab clinical trials.

Adverse event

Clinical trial (« = 1024)

Number of patients with cardiac dysfunction (« = 97)

Pivotal comparative study Single-agent studies Extension study Expanded access study Phase II trastuzumab + cisplatin study

60 14 11 11 1

Fever Sepsis Pneumonia 1

Events (%) Trastuzumab + AC (n = 143)

AC (n = 135)

23 7 3

16 6 2

Cardiac adverse events are not included. Table 4. Details of cardiac dysfunction in single-agent studies of trastuzumab.

Cardiac adverse events

Cardiac adverse events observed in trastuzumab trials were unexpected and prompted increased safety surveillance after four serious cases of congestive heart failure were reported. An independent, blinded Cardiac Review and Evaluation Committee (CREC) was formed to assess the safety of trastuzumab in the above-mentioned trials by retrospectively reviewing all records related to the patients. The point of this increased safety surveillance needs to be stressed as this detailed analysis can only be applied to the present studies and cannot be used to make comparisons with data in literature. The CREC definition of cardiac dysfunction included signs and symptoms of congestive heart failure (e.g., S3 gallop, tachycardia, dyspnea, orthopnea) and cardiomyopathy characterized by a decrease in cardiac ejection fraction that was global or more severe in the septum. A significant decrease in cardiac ejection fraction was defined as a decrease of > 10% (or ^ 5% if symptomatic) to < 55%. The severity of cardiac dysfunction was graded according to New York Heart Association (NYHA) functional classification 1, 2, 3 and 4. The application of NYHA classification is infrequent in oncology literature and this is an additional reason for avoiding comparison with evaluations of drug-induced cardiac effects from different published investigations and different drugs. The CREC reviewed 1024 records retrospectively_and found 97 patients with cardiac dysfunction^ lable 3). The majority of these cases were in the previously described pivotal phase III comparative trial [18]. More details of cardiac dysfunction in the single-agent studies are provided in Table 4. The percentage of patients with cardiac dysfunction varied from l%-6% in the singleagent studies. The majority of patients had prior exposure

Baselga etal. (1996) (» = 46) Number of patients with cardiac dysfunction (%) Median prior doxorubicin exposure (mg/m2) NYHA severity (%) Class 1 Class 2 Class 3 Class 4 Not evaluable Number of deaths due to cardiac dysfunction

3(7) NE

Cobleigh etal. (1999) (n = 213)

Extension studya (« = 79)

10(5)

1(1)

328

240

0 0 2 0 4

1 1.5 1 0.5 1

1 0 0 0 0

2

1

0

a

Extension study comprising patients initially treated in pivotal comparative study. Abbreviation: NE - not evaluable.

to doxorubicin, which would appear to be a probable predisposing factor to cardiac dysfunction. It is important to note that once cardiac dysfunction had been identified in clinical trials of trastuzumab, patients started to receive standard medical treatment for cardiac dysfunction. This resulted in a decline in the severity of NYHA classification and was possibly responsible for the very few deaths reported in the overall clinical experience with trastuzumab. In the pivotal single-agent, phase II trial [17], cardiac events were recorded in 4.7% of patients. However, cardiac status was stable in six of eight patients with cardiac dysfunction who continued to receive trastuzumab, and cardiac dysfunction improved after standard medical therapy in most cases. In the phase III trial of trastuzumab plus chemotherapy [18], cardiac dysfunction was diagnosed by the CREC in 27% of patients receiving trastuzumab and AC, 7% in those receiving AC alone, 11% in those receiving trastuzumab plus paclitaxel, and 1% in those receiving paclitaxel alone (Tables 5 and 6). There were two cardiac-related deaths, one each in the groups receiving trastuzumab plus AC and AC alone. Furthermore, administration of trastuzumab was discontinued because of cardiac dysfunction in 8% of all study patients receiving trastuzumab, and the condition improved in 80% of patients following standard medical manage-

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drome (3%) and other infections (16%). Indeed, the incidence of sepsis, fever and pneumonia were evenly distributed across treatment groups, whether or not the patients received trastuzumab (Table 2). Likewise, abnormal laboratory test values were evenly spread across treatment groups. The most noted and unexpected adverse event occurring with trastuzumab was cardiac dysfunction (see later).

66 Table 5 Details of cardiac dysfunction in the pivotal phase III combination study of trastuzumab.

6 3 7 9 2

10(7)

2 1 1.5 1.5 1

10(11)

4 3 2 0 2

rate

80-

cti

§

60-

c

3

1(1)

CareJiac dys

38 (27)

Paclitaxel (« = 95)

0 0 0 1 0

ment. This reduction is also reflected in the reduction of NYHA class 3 and 4 dysfunction following treatment (Table 6). Discussion Congestive heart failure and a decrease in cardiac systolic function are the primary clinical characteristics of anthracycline toxic effects on the heart [19]. It was therefore expected that cardiac dysfunction would be higher in the trastuzumab plus AC group than in the trastuzumab plus paclitaxel group, as was the case. It is also well established that clinical cardiotoxicity of doxorubicin is rare at low cumulative doses, but becomes increasingly more likely as the cumulative dose increases [20, 21]. In the previously discussed trastuzumab studies, the majority of patients had received doxorubicin either previously or concomitantly with trastuzumab, often at relatively high cumulative doses (Figure 1). Preliminary information suggests that decreased cardiac systolic function is a clinical characteristic of cardiotoxicity observed in trials of trastuzumab given either as a single agent or in combination with chemotherapy. A number of hypotheses can be put forward to explain the cardiotoxicity. The simplest would be that trastuzumab has inherent cardiac toxicity similar to that caused by anthracyclines. As for anthracyclines, this would be an independent toxicity. In favor of this view would be the observation of altered cardiac systolic function in a small percentage of patients treated with single-agent trastuzumab. No mechanistic explanation is available for such an independent cardiotoxicity. A second hypothesis would be that trastuzumab amplifies the effects of anthracyclines on the heart through an additive or synergistic effect. In keeping with this hypothesis, the addition of trastuzumab to AC was associated with a significantly higher incidence of cardiotoxicity than observed in the patients treated with AC alone. Importantly, the cardiac events observed in the patients treated with AC plus trastuzumab had a sudden increase after a cumulative dose of 360 mg/m2 of doxorubicin (Figure 1)

40-

20-

0-

0

250 500 750 1000 1250 1500 Cumulative anthracycline (mg/m2)

— Anthracycline + Herceptin* — Anthracycline 80g> 60-

40-

20-

0-

0

100 200 300 400 500 600 Cumulative anthracycline (mg/m2)

Figure 1. Panel (a) shows the rate of risk of cardiac dysfunction of any seventy in the group of patients treated with paclitaxel or paclitaxel plus trastuzumab with respect to the cumulative dose of anthracyclines. Panel (b) shows a similar relationship for the patients who received either AC or AC plus trastuzumab (Herceptin®). (Reproduced with permission from F. Hoffmann-La Roche Ltd, unpublished data.)

according to a pattern that was also observed for ACtreated patients, and is consistent with the known doserelated appearance of anthracycline-induced cardiotoxicity. However, anthracycline cardiotoxicity is attributed to a biochemical oxidative stress in myocardial cells that involves the disruption of iron trafficking and complex alterations of energy metabolism [22]. Currently, there is no explanation as to how trastuzumab would amplify such a mechanism and increase the inherent cardiotoxicity of AC. In vitro evidence indicates that expression of HER2 receptors may play a role in myocardial adaptation to physiologic stress or injury [23], although it is unknown whether this involves overexpression of HER2 to a sufficient degree that it might potentially be affected by the administration of trastuzumab. Finally, the cardiac toxicity of trastuzumab could represent an observational artifact due to the serial prospective clinical and instrumental monitoring of cardiac function that is common nowadays in many clinical trials in oncology. Such an observational artifact would be a possibility in studies of single-agent trastuzumab, but it is unlikely in

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Number with cardiac dysfunction (%) NYHA severity of initial event (%) Class 1 Class 2 Class 3 Class 4 Not evaluable

Trastu(n = 135) zumab + paclitaxel («=91) AC

Cardi ac dysf unction r

Trastuzumab + AC (n - 143)

— Paclitaxel + Herceptin" - - Paclitaxel

67 Table 6 Summary of cardiac adverse events in trastuzumab clinical trials. Events (%)

Cardiac dysfunction NYHA class 3-4 (initial) NYHA class 3-4 (post-treatment) Death due to cardiac dysfunction

Trastuzumab + AC (n = 143)

AC (n = 135)

Trastuzumab + paclitaxel (n=91)

Paclitaxel (n = 95)

Single-agent Trastuzumab (n = 338)

27.0 16.0 6.0 0.7

7.0 3.0 0.7 0.7

12.0 2.0 0 0

1.0 1.0 0 0

4.0 3.0 1.5 0.9

Conclusions Clinical trials have shown trastuzumab therapy is well tolerated. The most frequent side effects are mild-tomoderate, transient effects such as fever, chills, pain and nausea, which can be more of an inconvenience than an adverse effect. They are usually encountered with the first infusion of trastuzumab and can be easily treated by temporary discontinuation of infusion or with the use of simple symptomatic treatment. Trastuzumab was not associated with the serious dose-limiting toxicity that is usually associated with cytotoxic chemotherapy, e.g., hair loss, mucositis, myelosuppression, nerve damage, which frequently have a major impact on patient quality of life and/or compromise the patient's willingness to continue with therapy. Severe adverse events were infrequently associated with trastuzumab administration, with the only serious adverse event being cardiac dysfunction,

especially in combination with anthracyclines. However, with standard medical treatment, the cardiotoxicity is manageable. Ongoing studies should determine the nature of the cardiotoxicity of trastuzumab and the influence of previous therapy with anthracyclines and other cardiotoxic agents. Note The author has not reported any financial relationships with companies whose products are mentioned in the text.

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the phase III combination trial that showed a significantly higher incidence of toxicity when trastuzumab was combined with AC. Although current data indicate that trastuzumab can lead to cardiac dysfunction, this adverse event is reversible with standard medical management in the majority of affected patients. Moreover, with medical management there is rarely any deterioration in cardiac function with further trastuzumab therapy. Nevertheless, focused surveillance, including cardiac monitoring and baseline determination of left ventricular ejection fraction, is recommended for all patients receiving trastuzumab until more information on the influence of trastuzumab on cardiac functioning is available. Prior exposure or concurrent exposure to high cumulative doses of doxorubicin appears to be a predisposing risk factor for trastuzumab-induced cardiotoxicity, and age > 60 years may also be a predisposing factor. It is not yet known whether different anthracyclines (doxorubicin vs. epirubicin) affect the incidence of cardiotoxicity in trastuzumab-treated patients. Further studies are required to determine the mechanistic basis of this cardiotoxicity and this needs to ensure that the pharmacokinetics of doxorubicin, cyclophosphamide and paclitaxel are not altered by the presence of trastuzumab. Such studies are ongoing.

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Correspondence to: L. Gianni, MD Division of Medical Oncology A Istituto NazionaleTumori Via Venezian 1 20133 Milan Italy E-mail: [email protected]

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