Endocrine-Related Cancer (2002) 9 75—85
`
`The development and clinical use of
`trastuzumab (Herceptin)
`
`M Harries and I Smith
`
`Breast Unit, The Royal Marsden Hospital and Institute of Cancer Research, Fulham Rd, London SW3 6JJ, UK
`
`(Requests for offprints should be addressed to M Harries; Email: mark.harries@rmh.nthames.nhs.uk)
`
`Abstract
`
`HER-2 is a member of the c-erbB family of receptor tyrosine kinases and is overexpressed by 20—
`30% of human breast cancers. HER-2 overexpression is an independent adverse prognostic factor
`and may also predict for response to both chemotherapy and endocrine agents. Trastuzumab is a
`humanised monoclonal antibody that binds with high affinity to the extracellular domain of HER-2. In
`HER-2—overexpressing preclinical models trastuzumab has been shown to have a marked
`antiproliferative effect and demonstrates synergy with a number of cytotoxic drugs. Several phase II
`and phase III clinical trials have now been performed in patients with advanced breast cancer that
`overexpress HER-2. Trastuzumab was initially shown to be active and well tolerated as a single agent
`in heavily pretreated women. Subsequently, studies of first-line treatment for metastatic breast cancer
`have demonstrated an improvement in survival for trastuzumab when used in combination with either
`paclitaxel or an anthracycline—cyclophosphamide regimen compared with chemotherapy alone.
`Unexpectedly,
`the combination of
`trastuzumab and the anthracycline-containing regimen was
`associated with a significant incidence of cardiac dysfunction. The benefit of trastuzumab is generally
`confined to patients whose tumours have gene amplification as detected by fluorescence in situ
`hybridisation (FISH) and this is tightly associated with immunohistochemical (IHC) staining at the
`highest (3+) level. A small number of patients have IHC 2+ tumours together with FISH evidence
`of gene amplification and may also derive benefit from treatment. Trastuzumab has also been shown
`to be effective when used as first-line monotherapy for advanced breast cancer. Trials to date have
`employed trastuzumab in a weekly schedule, but there is emerging evidence that a three-weekly
`regimen may be as effective. Trastuzumab has shown encouraging activity when used with other
`agents including docetaxel and vinorelbine. The combination of trastuzumab, docetaxel, and platinum
`salts also appears to be very active. The role of trastuzumab as adjuvant therapy for early breast
`cancer is being tested in a number of large randomised trials.
`
`Endocrine-Related Cancer (2002) 9 75—85
`
`Introduction
`
`and an assessment of current clinical trials to define further
`
`the background to
`the optimal usage of this agent. First,
`the discovery of the HER-2 target and the preclinical vali-
`dation of antibody therapies directed against
`it will be
`
`presented.
`
`In recent years a number of the molecular pathways respon-
`sible for tumorigenesis have been identified (Hanahan &
`Weinberg 2000). With this knowledge has come the possibil-
`_
`_
`_
`_
`1ty of effectlve anti-cancer treatments a1med at novel targets
`with few of the toxicities associated with conventional cyto-
`toxic therapies. This review focuses on the development and BaCKground
`use of trastuzumab (Herceptin), a humanised monoclonal
`HER-2 is a member of the erbB epidermal growth factor
`antibody specific for HER-2, a growth factor receptor found
`receptor tyrosine kinase family. In the early 1980s the erbB
`to be overexpressed in 20—30% of human breast cancers
`receptor tyrosine kinases became implicated in cancer when
`(Slamon et al. 1987, 1989). The clinical data that have led
`it was found that the avian erythroblastosis tumour Virus
`encoded an oncogene that was highly homologous to the
`human epidermal growth factor receptor (HER-1, also known
`as ErbBl and EGFR). Subsequently a gene called new was
`
`to the recent licensing of trastuzumab as a treatment for
`metastatic breast cancer will be presented together with a
`discussion of the controversial areas that surround its use
`
`Endocrine-Related Cancer (2002) 9 75—85
`1351—0088/02/009—075 © 2002 Society for Endocrinology Printed in Great Britain
`
`rg
`Online version via http://ngendpcrinolog
`enentech
`elltrion v.
`IPR2017—01122
`
`Genentech Exhibit 2016
`
`

`

`Harries and Smith: Trastuzumab
`
`identified from a chemically induced rat neuroblastoma that
`was able to transform fibroblast cell lines in culture and was
`
`shown to be related to but distinct from the HER—1 gene
`(Shih et al. 1981, Schechter et al. 1984). At about the same
`
`time two other groups independently isolated human erbB-
`related proto-oncogenes and named them HER-2 (Coussens
`et al. 1985) and c-erbB2 (Semba et al. 1985). These genes
`were then shown to be the same as new. King and colleagues
`also identified an EGFR-related gene that was overamplified
`in a human mammary carcinoma cell line; this gene was also
`found to be identical to the HER-2/neu/erbB2 gene (King et
`al. 1985).
`HER-1 and HER-2 differ in a number of ways: the HER-2
`gene is located on chromosome 17 whereas the HER-1 gene
`has been mapped to chromosome 7, and the HER-2 mRNA and
`protein are of different sizes from the HER-1 gene products.
`The erbB receptor tyrosine kinase family has two other mem-
`bers, HER-3 and HER-4 (erbB3 and erbB4), with the four
`receptors sharing an overall membrane spanning structure
`composed of extracellular and transmembrane components
`together with an intracellular region containing a kinase
`domain flanked by tyrosine autophosphorylation sites. There
`are a number of functional differences between the domains of
`
`the different family members. For example, HER-2 appears to
`have no direct ligand and HER-3 has no intrinsic kinase
`activity and therefore a number of complex interactions
`between the different family members involving dimerisation
`are required for signalling. The HER-2 receptor can signal by
`forming heterodimers with other members of the HER family
`that are bound to a ligand, or two HER-2 molecules can com-
`bine to form a homodimer which has intrinsic kinase activity.
`Overexpression of HER-2 favours the production of both acti-
`vated homo- and hetero-dimers. erbB receptor kinase acti-
`vation recruits a number of adaptor proteins to the cytoplasmic
`domains which in turn trigger a number of downstream signal-
`ling cascades. The end results of HER-2 activation are effects
`on cell growth, division, differentiation, migration and
`adhesion (reviewed in Yarden & Sliwkowski 2001).
`Slamon and colleagues initially reported that the HER-2
`receptor was overexpressed in 20—30% of human breast can-
`cers (Slamon et al. 1987). In the vast majority of cases over-
`expression is caused by amplification of the HER-2 gene
`(Pauletti et al. 1996). HER-2 gene amplification results in
`increased levels of mRNA as detected by Northern blot and
`of the HER-2 receptor as detected by imrnunohistochemistry
`(IHC) or Western blot analysis. Over amplification of the
`gene is most strikingly seen using fluorescence in situ hybrid-
`isation (FISH), when multiple copies of the HER-2 gene can
`be seen in the nuclei of affected cells. This technique has
`become a useful method of detecting HER-2 gene amplifica-
`tion in clinical samples.
`HER-2 gene amplification is seen early in the develop-
`ment of invasive breast carcinoma and can also be seen in
`
`ductal carcinoma in situ (Barnes et al. 1992). Overexpression
`
`of HER-2 in breast cancer cells correlates with a number
`
`of well recognised adverse histological prognostic features
`including tumour size, high grade, a high percentage of
`S-phase cells, aneuploidy and lack of steroid receptors
`(Slamon et al. 1987, Ross & Fletcher 1999). Overexpression
`of HER-2 correlates with poor breast cancer prognosis. In
`1987, Slamon and colleagues examined tumour samples from
`86 node-positive patients and found that overamplification of
`the HER-2 gene was a strong independent adverse prognostic
`factor (Slamon et al. 1987). In 1989, Slamon and co-workers
`
`collected a total of 668 human breast cancer specimens, 526
`of which had sufficient clinical information to examine a link
`
`between HER-2 expression and outcome. Of 345 node-
`positive patients, 27% had HER-2 gene amplification. This
`was found to be a significant predictor of disease-free and
`overall survival in multivariate analysis (P = 0.006 and 0.045
`respectively) and was superior to all other prognostic factors
`except nodal status. In this initial study there was no associa-
`tion found between gene amplification and disease outcome
`in the 181 node-negative patients (Slamon et al. 1989). In a
`subsequent retrospective series of 1506 patients from the
`Ludwig International Breast Cancer Study Group, HER-2
`overexpression was again found to be prognostically signifi-
`cant in node-positive but not in node-negative patients with
`breast cancer (Gusterson et al. 1992). However, more recent
`
`studies have demonstrated that HER-2 gene amplification is
`an independent prognostic factor even in node-negative
`patients (Seshadri et al. 1993, Press et al. 1997 and reviewed
`in Ross & Fletcher 1998).
`
`Current evidence suggests that there may be an associa-
`tion between the overexpression of HER-2 and response to
`therapy. For example, in endocrine therapy a recent neoadju-
`vant trial has suggested a significantly higher response rate
`to letrozole than to tamoxifen in a small subset of patients
`with both HER-l- and/or HER-2-positive and oestrogen
`receptor (ER)-positive cancers (15/17 88% compared with
`4/19 21%, odds ratio 28, P = 0.004) (Ellis et al. 2001). Like-
`
`that
`in chemotherapy circumstantial data suggest
`wise,
`anthracyclines may be more effective than cyclophospham—
`ide, methotrexate and 5-fluorouracil (CMF) schedules for
`
`patients with HER-2-overexpressing breast cancer. This com-
`plex area has recently been reviewed by Piccart et al. (2000).
`Although the evidence is intriguing, there are currently
`insufficient data to suggest that HER-2 status be used to
`select therapy for patients other than their suitability for
`HER-2-directed therapies. In 2000, the American Society of
`Clinical Oncology (ASCO) committee on the update of re-
`commendations for the use of tumour markers in breast and
`
`colorectal cancer stated that ‘levels of c-erbB2 expression
`should not be used to exclude patients from anthracycline
`treatment’ and ‘the use of c-erbB2 data to decide whether to
`
`prescribe endocrine therapy either in the adjuvant or meta-
`static setting is not recommended’ (Bast et al. 2001).
`
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`
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`

`Development of trastuzumab
`
`The discovery of HER-2 overexpression in a significant min-
`ority of human breast cancers and its adverse prognostic sig-
`nificance prompted investigators to develop agents using
`HER-2 as a target for treatments. Several groups including
`workers at Genentech Inc. raised murine monoclonal anti-
`bodies to the extracellular domain of HER-2 and showed that
`
`some of these antibodies were capable of inhibiting the
`growth of cell lines that overexpressed the receptor (Hudziak
`et al. 1989, Fendly et al. 1990). This effect was also seen in
`HER-2-overexpressing human breast
`cancer xenografts
`where the effects of the antibody were found to be synergistic
`to anti-neoplastic agents such as cisplatin (Pietras et al.
`1994).
`
`The Genentech researchers developed a panel of murine
`monoclonal antibodies capable of inhibiting HER-2+ cell
`lines; the most potent of these was muMAb 4D5. This anti-
`body was found markedly to inhibit proliferation of cell lines
`that overexpressed HER-2 but had little or no effect on cells
`without elevated levels of HER-2 (Sarup et al. 1991). 4D5
`was found to be a potent inhibitor of growth of human breast
`cancer xenografts (Baselga & Mendelsohn 1994) and was
`therefore selected for further clinical development.
`In order to reduce the potential for generating a human
`anti-mouse immune response the 4D5 murine monoclonal
`antibody was humanised. Carter and colleagues subcloned
`the hypervariable region of the antibody into plasmids en-
`coding a human K light chain and the IgG1 constant region
`to generate a vector encoding a chimeric antibody which was
`then further humanised by site-directed mutagenesis (Carter
`et al. 1992). The vector was transduced into Chinese hamster
`
`ovary (CHO) cells that then secrete the antibody into the
`culture medium from which it is purified. The chimeric anti-
`body called trastuzumab is 95% human and 5% murine and
`retains the high affinity for the HER-2 epitope of the parental
`antibody.
`
`Preclinical pharmacology
`
`Trastuzumab has a binding affinity for HER-2 that is three
`times greater than that of its parent murine antibody 4D5.
`Like 4D5,
`it has been shown to have a marked anti-
`proliferative effect on HER-2-overexpressing cell lines and
`very little effect on cells not expressing HER-2 (Carter et al.
`1992). This anti-proliferative effect has also been demonstra-
`ted in viva in breast cancer xenograft experiments by Baselga
`and colleagues in which established BT-474 tumour xeno-
`grafts were inhibited from growing by trastuzumab. In doses
`of less than 1 mg/kg growth was inhibited in a dose-
`dependent fashion and no growth at all was seen at higher
`doses
`(Baselga et al.
`1998).
`In the same study,
`the
`researchers explored the addition of trastuzumab to either
`paclitaxel or doxorubicin. Chemotherapy alone was shown
`
`Endocrine-Related Cancer (2002) 9 75—85
`
`to have only modest anti-tumour activity, whereas combined
`treatment with trastuzumab resulted in a marked enhance-
`
`ment of the effect of chemotherapy with the greatest growth
`inhibition being seen with paclitaxel and trastuzumab
`(Baselga et al. 1998).
`Pegram and colleagues examined the effect of trastu-
`zumab on a number of other chemotherapeutic agents in a
`HER-2 transfected MCF7 xenograft model. Synergistic inter-
`actions were seen with cisplatin, docetaxel, thiotepa, cyclo-
`phosphamide, vinorelbine and etoposide. Additive effects
`were seen with doxorubicin, paclitaxel, vinblastine and
`methotrexate and the combination of trastuzumab with
`
`S-fluorouracil (5-FU) was found to be antagonistic (Pegram
`et al. 1999, Konecny et al. 2001 and reviewed in Pegram et
`al. 2000). The synergy seen in these in viva models has led
`to the exploration in clinical trials of trastuzumab in combi-
`nation with chemotherapy.
`Trastuzumab was shown to be safe when administered
`
`chronically to a range of animals
`(reviewed in Roche 2001).
`
`including primates
`
`Mechanism of action
`
`The mechanism by which trastuzumab inhibits the growth
`of HER-2-expressing breast cancer cells and interacts with
`cytotoxic drugs is uncertain. It has been shown that trastu-
`zumab downregulates the HER-2 receptor by accelerating
`endocytic degradation (De Santes et al. 1992). The reduction
`in available HER-2 receptor results in fewer homo- and hetero-
`dimers capable of signalling. Either as a result of reduced
`numbers of receptors or by a direct inhibitory effect, trastu-
`zumab antagonises growth and cell division signals associ-
`ated with HER-2 signalling (reviewed in Sliwkowski et al.
`1999). In addition to cell cycle effects, trastuzumab may also
`antagonise the induction of angiogenic factors such as vascu-
`lar endothelial growth factor by HER-2 (Petit et al. 1997).
`The ability of cells to repair DNA damage after radiation or
`chemotherapy damage may also be impeded by trastuzumab
`(Pietras et al. 1999). In addition to direct effects on HER-2
`
`signalling, trastuzumab may induce a host tumour response
`via antibody-dependent cell cytotoxicity (ADCC) mechan-
`isms and complement activation (Hotaling et al. 1996).
`
`Early clinical trials
`
`The first single agent phase I studies of trastuzumab began
`in 1992. In the first study, 16 patients with HER-2-positive
`metastatic breast cancer were treated with fixed doses of 10—
`
`500mg as a single dose. Subsequently, two phase I studies
`evaluated a weekly schedule of trastuzumab either alone or
`in combination with cisplatin. In neither study was dose-
`limiting toxicity reached with trastuzumab doses of 10—
`500 mg, and 100 mg was taken forward as the recommended
`phase H dose. Pharmacokinetic data showed a half-life of 8.3
`
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`
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`

`

`Harries and Smith: Trastuzumab
`
`thus suggesting a weekly schedule (summarised in
`days,
`Roche 2001).
`
`Baselga and colleagues reported on 46 patients with
`metastatic breast cancer who had received extensive prior
`chemotherapy treated with a 250 mg loading dose of trastu-
`zumab followed by weekly doses of 100 mg until disease
`progression. Five out of 43 assessable patients had clinical
`responses (12%) and 16 additional patients also had minor
`responses or stable disease with a median time to progression
`of 5.1 months (Baselga et al. 1996). A separate study evalua-
`ted the same dose of trastuzumab in combination with cispla-
`tin in a similar group of heavily pretreated patients. Of 37
`patients evaluable for response, 9 patients had a partial
`response (24%). No excessive toxicity was seen above that
`expected for cisplatin alone (Pegram et al. 1998).
`
`Pivotal trials
`
`In parallel with these early trials a large multinational phase
`II study was initiated to confirm the efficacy and safety of
`trastuzumab. Two hundred and twenty-two women were
`enrolled into the study between April 1995 and September
`1996. All women had previously received one or two chemo-
`therapy regimens for metastatic breast cancer and had
`tumours that overexpressed HER-2 as determined by IHC in
`a central reference laboratory by weak to strong membrane
`staining in >10% of cells (IHC 2 + or 3 + ). Patients received
`trastuzumab 4mg/kg as a loading dose and then 2 mg/kg
`weekly thereafter until disease progression. The primary
`endpoint was response rate and secondary endpoints were
`duration of response, time to disease progression, time to
`treatment failure, and survival. In an intent to treat analysis
`the overall response rate was found to be 15% (95%, confi-
`dence interval (CI) 11—21%) as determined by an indepen-
`dent response evaluation comrnittee. The median duration of
`response was 9.1 months
`(95%, CI 6.5—10.5 months).
`Amongst all treated patients median survival was 13 months,
`median time to progression was 3.1 months and median time
`to treatment failure was 11 months. In the subgroup of
`patients whose tumours had IHC staining that was 3 + , the
`response rate was 18% and median survival 16.4 months,
`suggesting that this group of patients derived greatest benefit
`from trastuzumab. A retrospective analysis of gene expres-
`sion by FISH showed that the response rate was 19% in
`patients with gene amplification (FISH+) and was 0% in
`the FISH-negative group. The median number of infusions
`received was 12 (range 1—96) and treatment was generally
`found to be well tolerated, with the most common adverse
`
`event being mild to moderate infusion reactions that usually
`only occurred with the first treatment and were managed suc-
`cessfully with paracetamol and/or antihistamines. The inci-
`dence of cardiac dysfunction, defined as congestive heart
`failure, cardiomyopathy and/or a decrease in ejection fraction
`of >10% was examined by retrospective analysis and was
`
`identified in 4.7% of patients. This trial confirmed that trastu-
`zumab was active and generally well tolerated as a single
`agent in heavily pretreated patients (Cobleigh et al. 1999).
`The synergy seen in the preclinical studies between tras-
`tuzumab and cytotoxic agents encouraged investigators to
`evaluate combination therapy in the clinic. A large multi-
`national phase III study was performed to compare chemo-
`therapy in combination with trastuzumab to chemotherapy
`alone as first-line therapy in patients with metastatic breast
`cancer whose tumours were found to overexpress HER-2
`(again as determined to be IHC 2 + or 3 + in a central refer-
`ence laboratory). Four hundred and sixty-nine patients were
`randomised to receive chemotherapy alone or chemotherapy
`plus trastuzumab. Patients who had received an anthracycline
`in an adjuvant setting received paclitaxel 175 mg/m2 three-
`weekly and for other patients chemotherapy was an anthra-
`cycline (the majority receiving doxorubicin 60 mg/m2) and
`cyclophoshamide 600 mg/m2 three-weekly. Chemotherapy
`was given every three weeks for 6 cycles and then further
`chemotherapy was allowed to be given at the discretion of
`the investigator. Trastuzumab was given as a loading dose
`of 4 mg/kg and then 2 mg/kg weekly thereafter until disease
`progression. Patients had measurable disease and were of
`good performance status. The primary study endpoint was
`time to progression, with secondary endpoints of objective
`response rate, duration of response, time to treatment failure
`and 1-year survival. At a median of 30 months of follow-up
`the time to progression for patients receiving both trastu-
`zumab and chemotherapy was 7.4 months compared with 4.6
`months for patients who received chemotherapy alone. The
`overall
`response rate and response duration were also
`improved in patients receiving the combination treatment.
`The addition of trastuzumab to paclitaxel
`increased the
`response rate from 17% to 41% and median response dura-
`tion from 4.5 to 10.5 months. The addition of trastuzumab to
`
`the anthracycline regimens increased response rates from 42
`to 56% and median duration of response from 6.7 to 9.1
`months compared with chemotherapy alone.
`Taking both groups of patients together, overall survival
`was significantly improved with the addition of trastuzumab
`to chemotherapy from 20.3 to 25.1 months (P = 0.046). Sev-
`enty-two percent of patients who had been randomised to
`receive chemotherapy alone subsequently received trastu-
`zumab and therefore the magnitude of the survival advantage
`may be underrepresented due to this crossover effect. As with
`the multicentre phase II trial, the benefit for the addition of
`trastuzumab was particularly marked for patients whose
`tumours were 3 + on IHC staining. In addition, the benefit
`of trastuzumab was only seen in patients whose tumours had
`amplification of the HER-2 gene as determined by FISH. In
`patients without gene amplification, response rates were not
`significantly improved in the trastuzumab-containing regi-
`mens. In contrast, for patients with HER-2 amplification the
`response rate to chemotherapy alone was 31% and this
`
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`

`

`increased to 54% in the trastuzumab-containing regimens. In
`this group median survival was increased from 20 to 26.2
`months (P = 0.007) (Mass et al. 2001a, Slamon et al. 2001).
`
`were mild to moderate infusion reactions that were easily
`manageable and usually only associated with the first treat-
`ment.
`
`Endocrine-Related Cancer (2002) 9 75—85
`
`Trastuzumab as first-line monotherapy
`
`Subsequent to the two pivotal studies discussed above, Vogel
`and colleagues (2002) have reported the results of an impor-
`tant phase II study of single agent trastuzumab as first-line
`treatment for 114 patients with metastatic breast cancer. In
`this study HER-2-overexpressing patients were randomised
`to receive either stande dose (4 mg/kg loading then 2 mg/
`kg weekly) or a higher dose regimen (8 mg/kg loading dose
`and 4mg/kg weekly thereafter) until disease progression.
`The overall response rate was 24% for the stande trastu-
`zumab dose arm, 28% for those receiving the higher dose
`(non-significantly different) and was 26% for all patients in
`the study. A further 13 patients had stable disease that per-
`sisted for greater than 6 months. As in the previous studies,
`higher response rates were seen in IHC 3+ patients and
`FISH+ patients (35% and 41% respectively).
`In FISH-
`negative patients, the response rate was only 7%. Median
`survival for all patients was 24.4 months but follow-up is
`short and at the time of censor 49 patients were alive or lost
`to follow-up. In this group of patients single agent trastu-
`zumab was extremely well
`tolerated with only 2 (2%)
`patients discontinuing therapy due to adverse events, both of
`whom had a history of cardiac disease and were withdrawn
`due to cardiac dysfunction. Furthermore, there was an overall
`improvement
`in global quality of life and fatigue scores
`(Vogel et al. 2002).
`
`Measuring HER-2 expression
`
`These clinical studies have shown a strong correlation
`between the efficacy of trastuzumab and the strength of IHC
`staining, with patients with IHC 3+ tumours responding
`better than those with 2+ tumours. Trastuzumab efficacy
`was also highly correlated with gene amplification with
`almost no benefit seen in tumours that had normal copy num-
`bers of the gene. FISH has been shown to select almost all
`IHC 3 + HER-2-expressing tumours. In addition, in these
`studies and others about 24% of patients whose tumours
`stained 2+ by IHC were found to be FISH+ (Mass et al.
`2001b). It is therefore becoming the practice of many clin-
`icians to select patients for trastuzumab on the basis of IHC
`3 + reactivity and if staining is 2+ then treatment is only
`given if gene amplification is present on FISH analysis.
`Unfortunately FISH is not so far available in all centres.
`
`Clinical safety of trastuzumab
`
`The large studies of trastuzumab have shown it to be gener-
`ally a well tolerated treatment. The commonest side effects
`
`Unexpectedly, cardiac dysfunction that had not been
`seen or predicted from the preclinical studies occurred in a
`number of patients. In the single agent phase II study for
`pretreated patients, the incidence of symptomatic heart fail-
`ure was 6—8.8% and all but one of these patients had received
`prior anthracyclines (Cobleigh et al. 1999). In the first-line
`phase II study of single agent
`trastuzumab only 2% of
`patients had to stop treatment due to cardiac dysfunction
`(Vogel et al. 2002). In the trastuzumab—chemotherapy com-
`bination study there was a marked increase in the incidence
`of heart failure for patients receiving trastuzumab plus an
`anthracycline, with an incidence of cardiac dysfunction (all
`grades) of 26—28% compared with 6—9.6% for patients who
`had received the anthracycline regimen alone. The incidence
`of marked symptomatic dysfunction (New York Heart Asso-
`ciation (NYHA) grade III—IV) was 16% and 3% respectively.
`Only 1—4% of patients treated with paclitaxel alone devel-
`oped cardiac dysfunction (1% at NYHA grade III/IV) com-
`pared with 8.8—1 1% (2% at NYHA grade III/IV) in patients
`treated with the trastuzumab and paclitaxel combination. In
`the small numbers of patients who had not received prior or
`concurrent anthracycline the incidence of cardiac dysfunction
`was 4%, all of whom were found to have had risk factors for
`
`cardiac disease. Most of the patients with symptomatic heart
`failure continued to receive trastuzumab and 75% improved
`with stande medical management. Only in the anthracyc-
`line/trastuzumab-treated patients were a small minority of
`patients (6%) left with NYHA grade III/IV toxicity at the
`end of treatment. Deaths related to cardiac dysfunction were
`very rare with no significant difference in incidence between
`the subgroups (Slamon et al. 2001, Tripathy et al. 2001). It
`should be noted that these data were collected retrospectively
`but prospective monitoring of cardiac function is an integral
`part of all current trastuzumab studies.
`Thus experience with trastuzumab to date suggests that
`cardiac toxicity is particularly related to the concurrent use
`of anthracyclines. In addition, the incidence of cardiac dys-
`function seems greatest in patients with pre-existing risk fac-
`tors for heart failure.
`
`The mechanism of cardiotoxicity is unclear. It appears
`unlikely that
`trastuzumab-associated heart damage occurs
`directly as a result of HER-2 expression on heart muscle. In
`60 patients with evidence of cardiac dysfunction, including
`25 patients with previous anthracycline exposure, Fuchs and
`colleagues found only faint membrane staining in less than
`10% of cardiac biopsies and no evidence of gene amplifica-
`tion by FISH (Fuchs et al. 2001). It also seems unlikely that
`trastuzumab alters the pharmacokinetic properties of anthra-
`cyclines and one study has failed to demonstrate any differ-
`ence in the pharmacokinetics of doxorubicin when it was
`administered before or after trastuzumab (Gianni et al. 2001).
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`
`79
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`

`Harries and Smith: Trastuzumab
`
`One possible hypothesis, partly born out by preclinical data,
`is that trastuzumab impairs growth factor-mediated repair of
`anthracycline-induced cardiac damage (reviewed in Chien
`2000).
`
`Therefore, it is current policy not to recommend concur-
`rent treatment with trastuzumab and doxorubicin. In patients
`with previous exposure to anthracyclines or with a predis-
`position to heart disease careful monitoring of cardiac func-
`tion either with echocardiography or multigated radionucleo-
`tide angiography (MUGA) should be performed to pick up
`early evidence of cardiac dysfunction that may necessitate
`withdrawal of trastuzumab. If symptomatic cardiac dysfunc-
`tion develops whilst on trastuzumab then stande medical
`therapy should be initiated and is generally effective.
`Post-marketing safety analysis has indicated that there is
`also a rare incidence of severe pulmonary events associated
`with trastuzumab that may or may not follow severe infusion
`reactions. The clinical picture can include dyspnoea, pulmon-
`ary infiltrates, pleural effusions, non-cardiogenic pulmonary
`oedema, and adult respiratory distress syndrome. Patients
`with symptomatic intrinsic lung disease or with extensive
`tumour involvement of the lungs resulting in dyspnoea at rest
`may be at greater risk of such events (Roche 2001).
`
`Summary of the pivotal trials and
`licensing of trastuzumab
`
`The two large pivotal trials discussed above demonstrated
`that trastuzumab was active as a single agent in patients with
`metastatic breast cancer who had previously received chemo-
`therapy and when used in combination with paclitaxel or
`anthracycline—cyclophosphamide regimens was associated
`with improved survival
`in first-line therapy of metastatic
`breast cancer compared with chemotherapy alone. The ben-
`efit of trastuzumab was greatest for patients whose tumours
`expressed HER-2 at the 3 + level by IHC and was generally
`only seen in patients who had evidence of gene amplification
`as detected by FISH. Although trastuzumab was generally
`well tolerated, cardiac dysfunction was seen in some patients
`who received an anthracycline—cyclophosphamide regimen
`together with trastuzumab.
`As a result of these trials trastuzumab is now licensed in
`
`many countries for use as first-line therapy in combination
`with paclitaxel
`for patients whose tumours overexpress
`HER-2 and as a single agent in paclitaxel pretreated patients.
`It is our view that overexpression of HER-2 in this context
`should be defined as IHC 3 + or IHC 2 + and FISH + .
`
`at progression, or in combination with chemotherapy, or as
`single agent therapy after failure of first-line chemotherapy.
`As discussed above the pivotal phase III trial demonstrated
`a survival advantage for the trastuzumab and chemotherapy
`combination compared with chemotherapy alone despite a
`large number of the patients on the chemotherapy alone arms
`receiving trastuzumab on disease progression. These data and
`the synergy seen in preclinical xenografts would suggest that
`combination therapy should be superior to sequential therapy
`with chemotherapy followed by trastuzumab.
`On the other hand, for patients whose tumours were
`FISH+ the phase II study of first-line single agent trastu-
`zumab reported by Vogel and colleagues reported an overall
`survival on a par with the combination of chemotherapy and
`trastuzumab seen in the large phase HI studies (23 months
`compared with 26.8 months). This suggests that there may
`be no survival disadvantage for sequential therapy compared
`with combination treatment for this group (Slamon et al.
`2001, Vogel et al. 2002). Furthermore, some patients relaps-
`ing after adjuvant chemotherapy might prefer the improved
`quality of life associated with trastuzumab alone compared
`with trastuzumab in combination with more chemotherapy.
`Trials addressing this issue are ongoing: for example, a Euro-
`pean study is comparing first-line trastuzumab followed at
`disease progression by combination trastuzumab and pacli-
`taxel compared with a first line combination of trastuzumab
`and paclitaxel.
`
`Duration of therapy for metastatic
`disease
`
`The trials discussed above have all continued the use of tras-
`
`tuzumab until disease progression based on the preclinical
`tumour xenograft models that demonstrated tumour regrowth
`could occur after trastuzumab withdrawal
`(Pietras et al.
`1998). Nevertheless, clinical trials to determine the optimum
`duration of therapy are necessary on both clinical and cost
`grounds.
`For patients being treated with chemotherapy and trastu-
`zumab conventional practice in cancer therapy would suggest
`tha