CLINICAL THERAPEUTICSWVOL. 21, NO. 2, 1999
`
`New Drugs
`
`Trastuzumab, a Recombinant DNA—Derived Humanized
`Monoclonal Antibody, a Novel Agent for the 'Ii'eatment
`of Metastatic Breast Cancer
`
`Marvin M. Goldenberg, PhD
`Mount Sinai NYU Health, New York, New York
`
`
`
`steady state with mean trough and peak
`concentrations of 79 ug/mL and [23
`pg/mL, respectively. In a ZZZ-patient, single-
`ann Clinical study, treatment with a loading
`dose of trastuzumab 4 mg/kg administered
`IV followed by weekly IV doses of 2 mg/kg
`produced an overall response rate of 14%
`(2% complete remission and 12% partial
`remission). The beneficial effects were
`greatest in patients with the greatest degree
`(3+) of HER2 protein overexpression. In
`another clinical study, 469 women with
`metastatic breast carcinoma were random‘
`
`ABSTRACT
`
`Trastuzumab serum concentrations reach
`
`Amplification of the human epidermal
`growth factor receptor 2 protein (HERZ) in
`primary breast carcinomas has been shown
`to correlate with poor clinical prognosis for
`certain patients. Trastuzumab (Herceptin®,
`Genentech. Inc., South San Francisco, Ca]—
`ifornia) is a highly purified recombinant
`DNA—derived humanized monoclonal im-
`
`munoglobulin G1 kappa antibody that binds
`with high affinity and specificity to the ex-
`tracellular domain of the HERZ receptor. In
`vitro and in vivo preclinical studies have
`shown that administration of trastuzumab
`
`alone or in combination with paclitaxel or
`carboplatin significantly inhibits the growth
`of breast tumor—derived cell lines that over-
`
`express the HERZ gene product. At thera-
`peutic doses in breast cancer patients, the
`mean half-life of trastnzumab is 5.8 days.
`
`ized to a paclitaxel or anthracycline-plus-
`cyclophosphamide regimen with or without
`trastuzumab. The overall response rate was
`significantly greater in the trastnzumab-
`plus-chemotherapy group than in the
`chemotherapy~alone cohort. The magnitude
`of observed effects was greatest with pacli-
`
`0149-2918/99/51900
`
`309
`
`Hospira v. Genentech
`Hospira v. Genentech
`IPR2017-00805
`IPR2017—00805
`Genentech Exhibit 2001
`
`Genentech Exhibit 2001
`
`

`

`CLINICAL THERAPEUTICS®
`
`stant in white women between 1973 and
`1993 .45
`
`Growth factors and their receptors play
`pivotal roles in the regulation of cell growth
`and differentiation.6 Malignancy arises
`from a stepwise progression of genetic
`events that often includes unregulated ex
`pression of growth factor receptors or ele-
`ments of their signaling pathways .6-7 Over—
`expression, or amplification, of the human
`epidermal growth factor receptor (EGFR) 2
`protein (HER2), which is correlated with
`poor clinical outcome in patients with breast
`cancer, is believed to result from gene am-
`plification.ES This protein is located on the
`cell’s surface, where it interacts with growth
`factors. When the HERQ protein is overex-
`pressed, the cells divide. grow, and multi—
`ply at a faster rate than normal, contribut-
`ing to the development of cancer. When
`both node-negative and node—positive
`breast cancers were reviewed, a significant
`difference in 5~year survival was found
`between primary breast cancers that over-
`expressed HERZ compared with those that
`did not.” Studies in breast cancer patients
`have shown that 25% to 30% of breast can-
`
`cers overexpress the HERZ gene.10
`The HERZ gene (also known as new
`and c—erbB-Z) encodes a 185—kd trans-
`membrane/kinase receptor, designated
`p1 85HER2, that has partial homology with
`the other membeis of the EGFR family.l 1‘13
`Antibodies directed against HERZ can in-
`hibit the growth of tumor xenografts and
`transformcd cells that express high con-
`centrations of this receptor.”"5 The murine
`monoclonal antibody mumAB4D5,
`di—
`rected against human pl 85HER2, has been
`shown to specifically inhibit proliferation
`of human tumor cells overexpressing this
`receptor.‘6 Amplification or overexpres—
`sion of HER2 is associated with multiple
`human malignancies, especially breast can-
`
`taer plus trastuzumab. The most common
`adverse effects attributed to trastuzumab in
`
`clinical studies were fever and chills, pain,
`asthenia, nausea, vomiting,
`increased
`cough, diarrhea, headache, dyspnea, infec-
`tion, rhinitis. and insomnia. Trastuzumab in
`combination with chemotherapy can lead
`to cardiotoxicity, leukopenia, anemia, diar-
`rhea, abdominal pain, and infection. Tras-
`tuzumab has been approved by the US Food
`and Drug Administration as a single agent
`for the treatment of patients who have
`metastatic breast cancer involving overex-
`pression of the HER2 protein and who have
`received 1 or more chemotherapy regimens;
`in combination With paclitaxel, it has been
`approved for the treatment of such patients
`who have not received chemotherapy. Key
`words: trastuzumab, HERZ overexpression,
`metastatic breast cancer, rhuMabHERZ.
`
`INTRODUCTION
`
`Based on data in the Surveillance, Epi-
`demiology, and End Results database of
`the National Cancer Institute, the age
`adjusted incidence of invasive breast can-
`cer in white and black women for the years
`1990 and 1995 was 114.5 and 100.5 cases
`
`the
`per 100,000 persons, respectively;
`mortality rate was 26 and 31.5 cases per
`100,000 persons, respectively.1 It was es-
`timated that breast cancer (excluding
`breast carcinoma in situ) would be newly
`diagnosed in 178,700 women and be the
`reported cause of death in 43,500 women
`in 1998.2 In 1994, stage IV or metastatic
`breast cancer constituted 3.6% and 6.2%
`
`of all breast cancer types among white
`and black women, respectively} It has
`been estimated that over 80,000 women
`per year will develop metastatic or re—
`fractory breast cancer, with rates of
`metastatic disease having remained con-
`
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`

`M.M. GOLDENBERG
`
`cer,l7 and with more rapid cancer progres
`sion and shortened survival.In A similar
`but
`less frequent amplification of the
`HER2/c-erbB—2 gene has been described in
`gastric adenocarcinoma.18
`
`DESCRIPTION OF TRASTUZUMAB
`
`A recombinant humanized anti-HER2 an-
`
`tibody, trastuzumab (Herceptin®, Genen-
`tech, Inc, South San Francisco, Califor-
`nia) was constructed and developed to
`determine whether its use, either alone or
`in combination with chemotherapeutic
`agents, could reduce the progression of
`malignancy in women with advanced
`breast cancer. Assays were performed both
`in vitro and in animal models to find
`whether the recombinant human mono-
`
`clonal antibody inhibited the proliferation
`of tumor cells overexpressing HER2. The
`agent’s safety was also a critical concern
`of these studies.
`
`Trastuzumab is a highly purified recom-
`binant DNA—derived humanized mono-
`
`clonal immunoglobulin Gl kappa antibody
`that in a cell-based assay (kd = 5 nmol),
`binds selectively and with high affinity to
`the extracellular domain of the human
`
`EGFR2 protein, HER2.‘°v‘7 It is produced
`by mammalian cell culture using Chinese
`hamster ovary suspension culture in a nu-
`trient medium containing the antibiotic
`gentamicin. The antibiotic is not detectable
`in the final product. The approximate
`weight of the antibody is 148 kd.
`Trastuzumab binds with high affinity
`and specificity to the extracellular domain
`of the HER2 receptor that
`.is overex-
`pressed in some breast cancer cells. The
`antibody contains human framework re-
`gions, with the complementarity-deter-
`mining regions of a murine antibody
`(4D5) that binds to HER2.”
`
`PRECLINICAL STUDIES
`
`In 1 study,19 SKBR3 human breast tumor
`cells overexpressing the HER2/c—erbB-2
`gene or A431 human squamous carcinoma
`cells overexpressing the EGFR gene were
`grown in flasks. The cells were detached
`from the flasks by treatment with 25 mmol/L
`ethylenediarnine—tetraacetic acid/0. 15 mol/L
`sodium chloride, collected by low-speed
`centrifugation, and suspended at l x 106
`cells/mL in phosphate buffered saline/ 1%
`fetal bovine serum. Each cell line (1 mL)
`was incubated with 10 pg of either anti-
`HER2/c—erbB—2 monoclonal antibody (4D5)
`or a control antibody recognizing the
`hepatitis B surface antigen. The mono-
`clonal antibody 4D5 was bound to the sur-
`face cells of the human tumor cell line ex-
`
`pressing pl 85HER2, as measured by
`fluorescence-activated cell sorting. There
`was a 160-fold increase in cellular fluores—
`
`cence compared with a control monoclonal
`antibody when 4D5 was added to SKBR3
`breast adenocarcinoma cells. This cell line
`
`contains an amplified HER2/c-erbB-2 gene
`and expresses high concentrations of
`p185HER2.l9*20 In contrast, the squamous
`carcinoma cell line A431, which expresses
`about 2 x 106 EGFR per cell21 but only low
`concentrations of p185HER2, exhibited
`only a twofold increase in fluorescence
`with 4D5 compared with a control mono—
`clonal antibody.
`Most anti-HER2/c-erbB—2 monoclonal
`
`antibodies that recognize the extracellular
`domain inhibited the growth of SKBR3
`cells in this study.19 Maximum inhibition
`was obtained with monoclonal antibody
`4D5, which inhibited cellular prolifera-
`tion by 56%, The control antibodies had
`no significant effect on cell growth.
`In another study,16 the humanized mono-
`clonal antibody 4DS-8 was found to
`
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`

`CLINICAL THERAPEUTIng
`
`was observed that exceeded the effect of
`
`either agent alone (P < 0.005).
`In a study of tumor growth in athymic
`nude mice,24 treatment with rhuMabHER2
`0.1 to 30 mg/kg intrapcritoneally twice
`weekly plus paclitaxel 5 to 10 mg/kg IV
`on days 1 and 4 significantly enhanced
`inhibition of tumor growth (93%, P =
`0.006) compared with either agent ad-
`ministered alone.
`In addition,
`tumor
`growth inhibition at 5 weeks was signifi-
`cantly superior in the group treated with
`the monoclonal antibody plus paclitaxel
`compared with paclitaxel alone (P =
`0.016) but not rhuMabHER2 alone (P =
`0.4). Therapy combining the antibody
`with doxorubicin inhibited growth by 70%
`versus control—treated mice (P = 0.04) but
`was not statistically superior to doxoru-
`bicin alone (P = 0.16) or the antibody
`alone (P = 0.59).
`
`PHARMACOKINETICS
`
`The pharmacokinetic properties of tras-
`tuzumab have been studied in patients
`with metastatic breast cancer.” Short-
`duration IV infusions of 10 to 500 mg
`once weekly showed dose—response kinet—
`ics. That is, mean half—life increased and
`clearance decreased with increasing
`doses. The half—life averaged 1.7 and 12
`days at the 10— and SOD-mg doses, re-
`spectively. The volume of distribution was
`approximately equal to that of serum vol-
`ume (44 mL/kg). At the highest weekly
`dose (500 mg) studied, mean peak serum
`concentrations were 377 ug/mL.
`In studies of trastuzumab using a load—
`ing dose of 4 mg/kg followed by a weekly
`maintenance dose of 2 mg/kg, the mean
`half—life was 5.8 days (range,
`1
`to 32
`days).26 Between weeks 16 and 32, tras—
`tuzumab serum concentrations reached
`
`bind to p185HER2 with high affinity
`(250 times control) and to prevent the
`proliferation of the human mammary ade-
`nocarcinoma cell line SKBR3. The mono
`
`clonal antibody also promoted antibody-
`dependent cellular toxicity against SKBR3
`tumor cells in the presence of human ef-
`fector cells but was not effective in di-
`
`recting the killing of normal (WI-38) cells.
`which express p185HER2 at much lower
`concentrations. This finding predicted ef-
`fective treatment of human cancers that
`
`overexpress p185HER2 with human anti—
`body 4D5-8.
`The results of these 2 studies indicate
`
`that trastuzumab has a higher affinity for
`p185HER2 (kd = 0.1 nmol) than does the
`murine Mab 4D5 and has a cytostatic
`growth-inhibitory effect against breast
`cancer cells overexpressing HER2. An ad-
`ditional in vitro study22 suggests that the
`growth of those breast cancer cell lines
`having the highest basal concentration of
`p185HER2 is most inhibited by the anti-
`plSSHER2 antibody.
`In another in vitro study,23 a significant
`synergistic suppression of cell prolifera-
`tion was observed between 4D5 antibody
`and cisplatin in SKBR3 breast carcinoma
`cells overexpressing the HER2/neu gene
`(P < 0.001). Such synergistic activity was
`also noted when 4D5 was added to
`SKBR3 cells in combination with carbo-
`
`platin (P < 0.001). To confirm the relative
`receptor-dependent specificity of this phe-
`nomenon, Cl3pRV—CON cells that did not
`overexpress the HERZ/neu proto—oncogene
`were treated with identical antibody/drug
`combinations, and no apparent synergistic
`decrease in cell growth was observed. The
`synergistic effect of the combination of
`4D5 and cisplatin was confirmed in vivo
`in tumor-bearing mice, where significant
`and marked inhibition of tumor growth
`
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`

`M.M. GOLDENBERG
`
`steady-state with mean trough and peak
`concentrations of approximately 79 and
`123 ug/rnl., respectively.
`Detectable concentrations of the cir-
`
`culating extracellular domain of the
`HER2 receptor
`(shed antigen) were
`found in the serum of some patients with
`tumors overexpressing HER2. Determi-
`nation of shed antigen in baseline serum
`samples revealed that 64% of patients
`had detectable shed antigen at concen-
`trations ranging as high as 1.88 ug/mL.
`Patients with higher baseline concentra-
`tions of shed antigen were more likely to
`have lower serum trough concentrations
`of trastuzumab. However, with weekly
`dosing, most patients with elevated con—
`centrations of shed antigen achieved tar-
`get serum concentrations of trastuzumab
`by week 6.25
`
`CLINICAL EXPERIENCE
`
`A study was conducted in 46 patients with
`metastatic breast cancer that overex~
`
`pressed HER2.27 Patients received a load
`ing dose of 250 mg trastuzumab IV over
`a 90-minute period (day 0), followed by
`one 100«mg dose for 10 weeks beginning
`on day 7. At the conclusion of the treat~
`ment period, patients with stable disease
`or a minor, partial, or complete response
`were entered into a maintenance phase
`consisting of weekly trastuzumab admin
`istration until disease progression.
`All patients had measurable disease,
`had a Karnovsky performance status of
`260% (required occasional help carrying
`out normal activities), and retained hema»
`tologic, hepatic, renal, and pulmonary
`function. Chemotherapy or additive hor-
`mone therapy was not permitted within 3
`weeks before study entry (6 weeks for
`mitomycin or nitrosoureas). Tumor ex-
`
`pression of HER2 was determined by im—
`munohistochemical analysis},IO
`Tumor response was ascertained at the
`completion of the initial ll—week treatment
`period. Complete response was defined as
`the disappearance of all radiographically
`or visually apparent tumors; partial re—
`sponse as a 250% reduction in the sum of
`the products of the perpendicular diame—
`ters of all measurable lesions; minimal re-
`sponse as a 225% and 60% reduction in
`the diameters of all measurable lesions;
`stable disease as no change 225% in the
`size of any measurable lesion; and pro—
`gressive disease as a >25% increase in any
`measurable lesion or the appearance of any
`new lesion. To be considered responders,
`patients had to have achieved at least sta—
`bility of bone lesions. Time to tumor pro-
`gression was calculated from the begin-
`ning of therapy to progression.
`Forty-three patients were assessable for
`treatment response on day 77. Three pa
`tients were not assessable for response: 1
`had a bacteremic infection of an IV
`
`catheter that required prolonged antibiotic
`administration, precluding treatment with
`trastuzumab; 1 patient discontinued treat-
`ment for personal reasons; and 1 patient
`died of congestive heart failure associated
`with prior doxorubicin treatment. The
`overall
`response rate to trastuzumab
`(complete plus partial responses) was
`11.6% (95% confidence interval, 4.36 to
`25.9) in the 43 patients. Two patients had
`a minimal response, and 14 patients had
`stable disease at day 77. These patients
`entered a maintenance phase consisting of
`weekly antibody administration until pro-
`gression of disease. The median time to
`progression for patients with either mini-
`mal or stable disease was 5.1 months.
`
`An additional patient had 21 >50% re—
`duction in the size of the metastatic le-
`
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`

`sions on her mediastinum and chest wall
`
`after 2 weeks of treatment. Although the
`duration of the response was >4 weeks,
`by evaluation day 77 the lesion had begun
`to regrow from the size reached at its max—
`imal response to therapy. According to the
`protocol, this patient was considered not
`to have had a response to treatment but
`rather to have had progression of disease.
`Thus 37% of the patients achieved a min-
`imal response or stable disease with
`trastuzumab treatment.
`
`Therapy with trastuzumab was well tol-
`erated. Of 768 administrations of tras-
`
`tuzumab, only 11 events occurred that
`were considered related to use of the an—
`
`tibody. Fever and chills occurred on 5 oc-
`casions after the first administration of
`trastuzumab. The fever lasted <8 hours in
`
`all cases and did not recur on subsequent
`administrations of the antibody. Three pa-
`tients experienced chest pain in areas of
`tumor involvement shortly after infusion
`of the first dose of trastuzumab. The pain
`did not recur on successive administra-
`
`tions of the antibody. None of the patients
`whose cancer regression met the formal
`criteria for complete or partial response
`had pain at a tumor site after administra—
`tion of trastuzumab.
`
`The activity of trastuzumab was assessed
`in a phase II efficacy trial in 222 women.27
`This was a multicenter, open—label, single-
`agent, single-arm study in patients with
`metastatic breast cancer that overexpressed
`HERZ. Of the 222 patients, 66% had re
`ceived prior adjuvant chemotherapy, 68%
`had received 2 prior chemotherapy regi-
`mens for metastatic disease, and 25% had
`received prior myeloablatiVe treatment
`with hematopoietic rescue. Patients were
`treated with an IV loading dose of 4 mg/kg,
`followed by weekly doses of trastuzumab
`at 2 mg/kg IV. Nine patients did not re—
`
`314
`
`CLINICAL THERAPEUTICS‘“
`
`ceive trastuzumab. The overall response
`rate (complete plus partial responses), as
`determined by an independent response-
`evaluation committee, was 14%, with a 2%
`complete response rate and a 12% partial
`response rate. The overall response rate in
`trastuzumab—treated patients was 21%. Ma-
`jor responses were observed in lesions of
`the liver, mediastinum, lymph nodes, and
`chest wall. The median survival was 13
`
`months (Kaplan-Meier estimate). Two pa-
`tients discontinued treatment because of
`
`adverse effects. Reduction in cardiac ejec-
`tion fraction was observed in 9 patients, of
`whom 6 were symptomatic: all 9 had had
`either prior anthracycline therapy or a sig—
`nificant cardiac history at study entry. One
`patient died of ventricular arrhythmia.
`The degree of HER2 overexpression
`was a predictor of treatment effect in this
`study. Tumor specimens were subjected
`to a research-use-only immunohistochem-
`ical assay and scored from 0 to 3+. with
`3+ indicating the strongest positivity. Only
`patients with 2+ or 3+ tumors (about 33%
`of those screened) were eligible for study
`entry. Data from the efficacy trial27 sug—
`gested that beneficial treatment effects
`were largely limited to patients with the
`highest level (3+) of HERZ protein over—
`expression.
`The phase III study was a multinational,
`randomized, open-label, controlled study
`that assessed the safety and effectiveness
`of adding trastuzumab to first-line che—
`motherapy regimens.28 The primary end
`point of the study was time to disease pro-
`gression. A total of 469 women with
`metastatic breast carcinoma were ran-
`
`domized to treatment with either pacli-
`taxel or anthracycline plus cyclophos—
`phamide with or without trastuzumab.
`Eligible women were >18 years of age,
`had a Karnovsky performance status of
`
`
`
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`

`

`M.M. GOLDENBERG
`
`260%, and had received no previous cy-
`totoxic chemotherapy for metastatic dis-
`ease. Women who had received prior hor-
`mone therapy or radiotherapy in an
`adjuvant or metastatic setting Were eligi—
`ble, as were women who had received cy-
`totoxic chemotherapy in the adjuvant set—
`ting, Patients who had received prior
`adjuvant anthracycline therapy were as-
`signed to paclitaxel therapy, and patients
`who had not had prior adjuvant anthracy-
`cline therapy were assigned to the anthra-
`cycline treatment group. Trastuzumab was
`administered IV as a 4-mg/kg loading
`dose on day 0, followed by weekly IV in—
`fusions of 2 mg/kg until disease progres-
`sion. Each chemotherapeutic regimen was
`administered every 3 weeks for 6 cycles.
`Patients who were randomized to
`
`trastuzumab plus chemotherapy benefited
`measurably in terms of time to disease
`progression, overall response rate, median
`duration of response, and l-year survival
`compared with patients
`treated with
`chemotherapy alone. As determined by the
`independent response assessment commit-
`tee, the median time to disease progres-
`sion was 7.2 months in the trastuzumab-
`
`plus-chemotherapy cohort, compared with
`4.5 months in the chemotherapy-alone co—
`hort. The difference in overall time to dis-
`
`ease progression between treatment groups
`was statistically significant (P < 0.0001).
`The overall response rate was 45% in the
`trastuzumab-plus-chemotherapy group,
`compared with 29% in the chemotherapy-
`alone group (P < 0.001). The magnitude
`of effects was greatest in the paclitaxel
`subgroup.
`Both trastuzumab cohorts in the phase
`III trial28 had an increased incidence of
`cardiac dysfunction compared with either
`anthracycline plus cyclophosphamide
`alone or paclitaxel alone. The incidence
`
`and severity of cardiac dysfunction were
`particularly high in those patients who re—
`ceived trastuzumab in combination with
`
`anthracycline therapy. The reported inci-
`dence of any cardiac dysfunction (which
`could include dyspnea, increased cough,
`paroxysmal nocturnal dyspnea, peripheral
`edema, S3 gallop, and reduced ejection
`fraction) was 28% in patients treated with
`trastuzumab plus anthracycline and 7% in
`patients treated with anthracycline alone.
`Patients randomized to trastuzumab plus
`paclitaxel had a reported 11% incidence of
`cardiac dysfunction, compared with 1% with
`paclitaxel alone. Nineteen percent of patients
`in the n'astuzumab-plus-anthracycline cohort
`developed congestive heart failure of class
`III or IV severity.
`
`OVERALL SAFETY
`
`The most common adverse effects attrib-
`uted to trastuzumab in the clinical trials
`were fever and chills and other constitu—
`
`tional symptoms, most often infusion re-
`lated. Other adverse effects reported in-
`cluded pain, asthenia, nausea, vomiting,
`increased cough, diarrhea, headache, dysp-
`nea,
`infection, rhinitis, and insomnia.
`Mild-to-moderate diarrhea was experi-
`enced by 25% of patients.
`In the randomized, controlled clinical
`trials, the incidence of the following ad—
`verse events was higher in patients re-
`ceiving trastuzumab in combination with
`chemotherapy than in patients receiving
`chemotherapy alone: cardiotoxicity, leu-
`kopenia, anemia, diarrhea, abdominal
`pain, and infection. The majority of cy—
`topenic events were mild or moderate and
`reversible, and none resulted in discontin—
`uation of trastuzumab therapy.
`During the first infusion of trastuzumab,
`a symptom complex most commonly con—
`
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`

`CLINICAL THERAPEUTICS“
`
`and Drug Administration has approved
`trastuzumab for marketing as a single
`agent or in combination with paclitaxel in
`patients whose tumors overexpress HER2.
`The use of trastuzumab in combination
`
`with chemotherapeutic agents is not without
`substantial risk (ie, the possibility of devel<
`oping clinically significant congestive heart
`failure, cardiac dysfunction, and ventricular
`dysfunction). Therefore, candidates for tras-
`tuzumab therapy should undergo a thorough
`baseline cardiac assessment (cg, electrocar-
`diogram, echocardiogram, and multigated
`angiograrn). Patients receiving trastuzumab
`should be monitored frequently for deterio—
`rating cardiac function. The probability of
`cardiac dysfunction appears to be greatest in
`patients receiving trastuzumab concurrently
`with anthracycline and cyclophosphamide
`therapy. Discontinuation of trastuzumab
`therapy should be considered in patients
`with signs and symptoms of clinically sig-
`nificant congestive heart failure, as well as
`those with a significant decrease in left ven—
`tricular function.
`
`Amplification of the HER2 gene is a
`predictor of both relapse and survival in
`patients With node—positive breast cancer
`and is superior to all other prognosticators
`with the exception of lymph-node posi-
`tivity.8 The fact that the HER2 gene is a].
`tered in 25% to 30% of these cases and
`
`that alteration is associated with poor pa-
`tient outcome indicates that HER2 may
`play a role in the pathogenesis of a sig-
`nificant number of human tumors. How-
`
`ever, this does not preclude the possibil—
`ity that other genes or genetic elements
`may be of importance in these diseases.
`The HER2 gene should be a focus of at-
`tention in the diagnosis and treatment of
`human breast cancer.
`
`Although trastuzumab has been ap-
`proved, additional studies are needed to
`
`sisting of chills and/or fever was observed
`in about 40% of patients. The symptoms
`were usually of mild—to-moderate severity
`and were treated with acetaminophen,
`diphenhydramine, or meperidine. Overall,
`discontinuation of trastuzumab treatment
`
`was infrequent. Other signs and symptoms
`after the first infusion included nausea,
`vomiting, pain, rigors, headache, dizzi—
`ness, dyspnea, hypotension, rash, and as-
`thenia. Symptoms occurred infrequently
`with subsequent trastuzumab infusions.
`
`PRESCRIBING INFORMATION
`
`Treatment may be carried out in an out-
`patient setting by administering a 4—mg/kg
`trastuzumab loading dose by IV infusion
`over 90 minutes and subsequent weekly
`IV doses of 2 mg/kg administered over 30
`minutes.
`
`As a single agent, trastuzumab is indi-
`cated for the treatment of patients with
`metastatic breast cancer Whose tumors
`
`overexprcss the HER2 protein and who
`have received 1 or more chemotherapy
`regimens for their metastatic disease.
`Trastuzumab is indicated in combination
`
`with paclitaxel for the treatment of pa—
`tients with metastatic breast cancer whose
`
`tumors overexpress the HER2 protein and
`who have not received chemotherapy for
`their metastatic disease.
`
`DISCUSSION AND CONCLUSIONS
`
`Trastuzumab is the first biologic agent or
`recombinant humanized monoclonal anti—
`
`body designed to selectively target the ex—
`tracellular HER2 receptor. The results of
`preclinical and clinical studies indicate
`that an anti-EGFR-directed strategy is
`useful
`in the treatment of advanced
`metastatic breast cancer. The US Food
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`M .M. GOLDENBERG
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`determine its efficacy in combination with
`chemotherapy compared with chemother—
`apy alone in patients with 2+ HER2 over-
`expression (weakly positive). Additional
`studies are also needed to predict and di—
`minish the risk of trastuzumab-induced
`
`cardiotoxicity.
`
`Address correspondence to: Marvin M.
`Goldenberg, PhD, Mount Sinai NYU
`Health, 1 Gustave Levy Place, New York,
`NY 10029.
`
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