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`SEPTEMBER 1999
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`Genentech Exhibit 2058
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`osBrrersiteotanseriewcailctceme=
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`Hospirav. Genentech ;
`(cid:43)(cid:82)(cid:86)(cid:83)(cid:76)(cid:85)(cid:68)(cid:3)(cid:89)(cid:17)(cid:3)(cid:42)(cid:72)(cid:81)(cid:72)(cid:81)(cid:87)(cid:72)(cid:70)(cid:75)(cid:3)
`(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:26)(cid:16)(cid:19)(cid:19)(cid:27)(cid:19)(cid:24)(cid:3)
`IPR2017-00805
`(cid:42)(cid:72)(cid:81)(cid:72)(cid:81)(cid:87)(cid:72)(cid:70)(cid:75)(cid:3)(cid:40)(cid:91)(cid:75)(cid:76)(cid:69)(cid:76)(cid:87)(cid:3)(cid:21)(cid:19)(cid:24)(cid:27)
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`1
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`JOURNAL OF CLINICAL ONCOLOGY
`The Official Journal of the American Society of Clinical Oncology
`
`
`
`
`Journal of Clinical Oncology (ISSN 0732-183X) is published monthly by Lippincott Williams & Wilkins, 351
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`
`
`2
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`

`

`This material may be protected by Copyright law (Title 17 U.S. Code)
`
`3
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`

`

`2640
`
`COBLEIGH ET AL
`
`the safety and efficacy of rhuMAb HER2plus chemotherapy
`versus chemotherapy alone in first-line treatment.!? A sec-
`ondtrial, reported here, investigated the safety and efficacy
`of rhuMAb HER2in patients with metastatic breast cancer
`that had progressed after one or two chemotherapy regimens
`for metastatic disease. The primary objectives of this trial
`were to determine the overall objective response rate to
`rhuMAb HER2treatment as a single agent and to further
`characterize the safety profile of rhuMAb HER2.
`
`PATIENTS AND METHODS
`
`Patients
`
`Eligible patients were women with HER2-overexpressing metastatic
`breast cancer. All patients had progressive disease after one or two
`cytotoxic chemotherapy regimens for metastatic disease and bidimen-
`sionally measurable disease. Patients were excluded if they had
`untreated brain metastases, bone metastases as the only disease site,
`concomitant malignancy not curatively treated, or a Karnofsky perfor-
`mancestatus of less than 60%. Patients were also excluded if they were
`pregnant, nursing, or if they had used investigational or unlicensed
`agents within 30 days. Informed consent was obtained and documented
`in writing before study entry. This study was performed after approval
`by local humaninvestigations committees.
`Expression of HER2 was determined by immunohistochemical
`analysis of tumor tissue, collected either at
`the time of primary
`diagnosis or at recurrence, and used the 4D5 and CBI! murine
`monoclonal anti-HER2 antibodies. Expression was scored by a core
`research pathology laboratory as 0, 1+, 2+, or 3+ using standardized
`criteria. All enrolled patients had 2+ or 3+ overexpression using either
`antibody (weak to strong complete membranestaining observed in >
`10% of the tumorcells).
`
`Antibody Administration
`
`rhuMAb HER2(trastuzumab [Herceptin]) was produced by Genen-
`tech, Inc (South San Francisco, CA) and was administered intrave-
`nously in the outpatient setting at a dose selected to maintain a minimal
`serum trough concentration of 10 g/mL to 20 pg/mL.Patients received
`a loading dose of 4 mg/kg, followed by weekly administration of 2
`mg/kg. The infusion wasinitially administered over 90 minutes. If the
`infusion waswell tolerated, subsequentinfusion periods were shortened
`to 30 minutes.
`
`The 2-mg/kg weekly maintenance dose was continued without
`dosage modification. If a patient developed disease progression, the
`investigator could continue the 2-mg/kg dosage, increase the dose to 4
`mg/kg weekly, or discontinue treatment. Additional antitumor therapy
`wasalso permitted upon disease progression.
`
`TumorResponse
`
`The primary end point of objective tumor response wasassessedat
`specified time points; before treatment, at weeks 8, 16, and 24, and
`every 12 weeks thereafter. Responses were determined by an indepen-
`dent response evaluation committee (REC). Reading teams were
`composed of an oncologist and a radiologist, who were blinded to
`treatment. Responses (complete or partial responses) were confirmed 4
`weeksafter the initial response determination. Complete response was
`defined as the disappearance of radiographically, palpable, and/or
`visually apparent tumor. Partial response was defined as a = 50%
`decrease in the sum of the products of the perpendicular diametersofall
`
`measurable lesions. Disease progression was defined as a = 25%
`increase in any measurable lesionor the appearanceofa newlesion.
`The prespecified secondary end points were duration of response,
`time to disease progression,
`time to treatment failure, and survival.
`Duration of response was defined as the time from first response to
`disease progression. Time to disease progression was defined as the
`time from enrollment
`to disease progression or death (whichever
`occurredfirst) and was censored at the last date of contact for patients
`whosediseasedid not progress. Time to treatmentfailure wasdefined as
`the time from enrollment
`to disease progression, death,
`treatment
`discontinuation, orinitiation of a new antitumortherapy. Survival was
`defined as the time from enrollment to death and was censored at the
`
`date of last contact for patients who werealive.
`
`i
`
`Other Assessments
`
`A complete physical examination, a clinical assessment, a vital sign
`analysis, chest x-rays, and laboratory tests were performedat predeter-
`mined intervals and at study termination. Adverse events were classified
`as mild, moderate, or severe. A mild adverse event was defined as
`annoying but not affecting baseline status or hindering the patient’s
`normalfunctioning level. A moderate adverse event was uncomfortable
`and impaired normalfunction but was not hazardousto health. A severe
`adverse event caused severe discomfort, severely limited or prevented
`normal function, and was a definite hazard to health. The National
`Cancer Institute Common Toxicity Criteria were not used to classify
`clinical adverse events. Laboratory abnormalities were classified by the
`World Health Organization grading system.
`A blinded independent cardiac review and evaluation committee was
`established retrospectively to assess cardiac dysfunction in all rhuaMAb
`HER?clinical trials.2° Clinical data from all patients enrolled in this
`study were thoroughly reviewed by the committee to identify all
`potential cases of cardiac dysfunction. The severity of cardiac dysfunc-
`tion wasclassified using the New York Heart Associationcriteria.
`The Quality of Life Questionnaire—C30, a questionnaire developed
`by the European Organization for Research and Treatment of Cancer,”!
`wasusedto assess quality oflife initially at weeks 1, 12, 24, 36, and 48,
`then every 12 weeks, and finally at study termination.
`Blood samples were collected at predetermined intervals for the
`pharmacokinetic analysis of serum rhuMAb HER2 concentrations,
`determination of serum concentrations of the extracellular domain of
`
`the HER2 protein/(shed antigen), and measurements of antibody to
`rhuMAb HER2. Serum rhuMAb HER2 concentrations were determined
`
`by an enzyme-linked immunosorbent assay (ELISA) with a lowerlimit
`of sensitivity of 156 ng/mL at a minimumdilution of 1/100.!7!8 Serum
`baseline shed antigen concentrations were determined by an ELISA
`with a lowerlimit of detection of 3.4 ng/mL. Antibodies to the Fab and
`Fc regions of rhuMAb HER2 were measured by ELISAs.
`
`Statistical Methods
`
`Thefinal analysis of efficacy and safety was performed 15 months
`after enrollmentof the last patient. The median follow-upforall patients
`was 12.8 months. Demographic and baseline characteristics were
`summarized by descriptive statistics.
`Response rate was evaluated inall enrolled patients (intent-to-treat
`analysis) and intreated patients (ie, all patients who received at least
`one rhuMAb HER2dose). Response duration was evaluated in patients
`withpartial or complete responses. Time to disease progression,time to
`treatmentfailure, and survival were evaluated by intent-to-treat analysis
`of all patients. Time to event end points were estimated by Kaplan-
`Meier survival methodology. The effect of baseline characteristics on
`response rates was evaluated by the y* test and logistic regression
`
`4
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`

`

`ANTI-HER2 MONOCLONAL ANTIBODY AS A SINGLE AGENT
`
`2641
`
`model. The risk factors for time to progression were determined by the
`Coxproportional hazards regression model.
`The analysis of safety was performedonall patients who receivedat
`least one dose of rhuMAb HER2. Adverse events and laboratory
`abnormalities were summarized by descriptive statistics.
`Infusion-
`associated adverse events were evaluated by comparing the rates of
`events after the loading dose with the rates of the same events after
`subsequentinfusions.
`Quality-of-life data were evaluated in patients with baseline and at
`least one follow-up assessment. The primary analysis was a repeated-
`measures analysis of variance on the global quality-of-life score and
`four functioning scales (ie, fatigue, physical, emotional, and social
`functions).
`The pharmacokinetic profile of rhuMAb HER2 was determined in 50
`randomly selected patients. Pharmacokinetic parameters were estimated
`by nonlinear regression using Professional WinNonlin (v.1.5; Scientific
`Consulting, Inc, Cary, NC), a software program for pharmacokinetic
`analysis. Baseline shed antigen data were summarized; an analysis of
`variance on logarithmic transformationat base 10 of the absolute value
`of the baseline shed antigen was performed to evaluate the interaction
`with patient baseline characteristics.
`
`RESULTS
`
`A total of 222 patients were enrolled by investigators from
`54 centers in the United States, Canada, Belgium, France,
`Germany, the United Kingdom, and Australia between April
`1995 and September1996. A total of 213 patients received at
`least one dose of rhuMAb HER2. Nine patients were not
`treated for the following reasons: brain metastases (n = 3),
`laboratory abnormality (n = 2), adverse event (n = 1), re-
`fusal to participate (n = 1), clinical instability (n = 1), and
`death (n = 1). As of the cutoff date of December 31, 1997,
`179 patients (81%) had discontinued the study, 14 patients
`(6%) remained on the study without disease progression,
`and 29 patients (13%) were continuing treatment after
`disease progression.
`Patient baseline characteristics are listed in Table 1. Less
`
`than half had estrogen receptor—positive tumors. Twenty-
`seven percent had = 10 positive lymph nodesat the time of
`primary diagnosis. Thirty-seven percent had a disease-free
`interval of less than 12 months. Most patients (78%) had
`metastatic disease at multiple sites, and 72% had liver or
`lung involvement. All patients had received extensive previ-
`ous treatment. Sixty-eight percent had prior adjuvant chemo-
`therapy, and all had received prior chemotherapy for meta-
`static disease; 32% had one prior and 68% had two prior
`chemotherapy regimens for metastatic disease. Most had
`received both prior anthracycline and taxane therapy; 26%
`had undergone high-dose chemotherapy with bone marrow
`or stem-cell rescue before enrollment.
`
`TumorResponse
`
`The independent REC determined eight complete (4%)
`and 26 partial (11%) responses, for an objective response
`rate of 15% in the intent-to-treat population of 222 patients
`
`Table 1. Patient Characteristics
`No.of
`Patients/No.
`
`Characteristic
`Analyzed
`
`%
`
`Age, years
`Mean + SD
`
`Range
`Karnofsky score
`90% to 100%
`80%
`= 70%
`Receptorstatus
`Estrogen receptor positive
`Progesteronereceptorpositive
`HER2 overexpression
`2+
`
`3+
`No.of lymph nodesat primary diagnosis
`None
`1-2
`210
`Disease-free interval, months
`<12
`12-24
`> 24
`No. of metastatic sites
`1
`2
`= 3
`Metastatic site
`Skin orsoft tissue
`Liver or lung
`Prior therapy
`Adjuvant chemotherapy
`Chemotherapy metastatic disease, no.
`_
`of regimens
`
`50: 11.6
`
`28-81
`
`152/211
`36/211
`23/211
`
`85/190
`77/188
`
`50/222
`172/222
`
`42/176
`87/176
`47/176
`
`80/214
`48/214
`86/214
`
`47/214
`91/214
`76/214
`
`14/214
`155/214
`
`146/214
`
`72
`17
`11
`
`45
`Al
`
`22
`78
`
`24
`49
`27
`
`37
`22
`40
`
`22
`42
`36
`
`6
`72
`
`68
`
`100
`214/214
`32
`69/214
`]
`68
`145/214
`a2
`94
`201/214
`Prior anthracyclines
`67
`143/214
`Prior taxanes
`7
`151/214
`Radiotherapy
`57
`122/214
`Hormonal therapy
`
`Bone marrow orstem-cell transplantation 26 53/205
`
`
`(Table 2). The investigators identified nine complete re-
`sponses (4%) and 37 partial
`responses (17%),
`for an
`objective response rate of 22% in the treated population of
`213 patients. In addition,
`there were 12 minor responses
`(6%), 62 patients (29%) with stable disease, and 93 patients
`(44%) with progressive disease. Twenty-two percent of
`patients were free of disease progression at 6 months.
`The median duration of response to rhuMAb HER2, in the
`patients identified as complete or partial responses by the
`REC, was 9.1 months (range, 1.6 to > 26 months) (Fig 1).
`Eight (24%) of 34 patients with a response were free of
`disease progression at the cutoff date. Among all treated
`patients, the median time to disease progression was 3.1
`
`5
`
`

`

`2642
`
`COBLEIGH ET AL
`
`
`Table 2. Tumor Response
`Complete Responders
`Partial Responders
`Objective
`No.of
`No.of
`Response
`
`Patients
`%
`Patients
`%
`Rate (%)
`95% Cl
`
`8
`8
`
`4
`4
`
`26
`26
`
`12
`12
`
`15
`16
`
`11-21
`11-22
`
`Population
`REC assessment
`All enrolled, intent-to-treat
`All treated
`Investigators’ assessment
`16-27
`21
`17
`37
`4
`9
`222
`All enrolled, intent-to-treat
`16-28
`22
`17
`37
`4
`9
`213
`All treated
`
`No.of
`Patients
`
`222
`213
`
`the median time to
`months (range, 0 to > 28 months);
`treatment failure was 2.4 months (range, 0 to > 28 months).
`The median time to treatment failure among the 34
`patients with a response was 11 months (range, 2 to > 28
`months). In contrast, for the prior regimen of cytotoxic
`chemotherapyin these patients, the median timeto treatment
`failure was 5.4 months (range, 0 to 27.4 months). The
`
`100
`
`A +
`
`median duration of survival in all patients was 13 months
`(range, 0.5 to > 30 months) (Fig 1).
`In general, the efficacy of rhuMAb HER2 was observed
`consistently across patient subgroups, with a few excep-
`tions. Patients whose tumors overexpressed HER2at the 3+
`level tended to have higher responserates than those with a
`2+ level of overexpression (18% v 6%; P = .06). Patients
`whosetimeto first relapse was more than 6 monthstended to
`have higher response rates than those who relapsed earlier
`(20% v 9%; P= .03). Of note,
`tumor responses were
`observed in 12 (11%) of 109 patients with liver metastases,
`and in 14 (26%) of 53 patients with prior transplants. In a
`multivariate logistic regression analysis, none ofthe patient
`baseline characteristics were independently predictive of
`tumorresponse.
`Significant correlations were detected between time to
`disease progression andpatient baseline characteristics. In a
`univariate analysis, the median time to disease progression
`was longer among patients whose tumors overexpressed
`HER2at the 3+ level (3.3 v 1.9 months; P = .0034), who
`had relapsed more than 6 months after treatment (3.4 v 2.1
`months; P = .0045), who had a Karnofsky score of 100% or
`90% versus less than 90% (3.2 or 3.5 v 2.0 months;
`P = .0068), or who had oneor two versus = three metastatic
`sites (3.5 or 3.2 v 2.3 months; P = .001). In a multivariate
`proportional hazards model, three factors (number of meta-
`static sites at study entry, level of HER2 overexpression, and
`monthsto first relapse) significantly (P < .05) affected time
`to disease progression.
`A numberof patients were treated after disease progres-
`sion with 4 mg/kg rhuMAb HER2asa single agent. Of the
`34 patients treated with 4 mg/kg as a single agent, three
`patients, each of whom had aninitial partial response or
`minor response to the 2-mg/kg dose, had a subsequent
`partial response to 4 mg/kg.
`
`os
`median = 13.0 months %ofAll
`
`EnrolledPatients
`
`®-
`
`80
`
`a=
`es
`© 2% 60
`ce
`oD
`
`median = 9.1 months
`
`0
`
`25
`20
`15
`10
`5
`Monthsfrom Initial Response
`
`20
`
`a 6
`
`Ww
`
`0
`
`25
`20
`15
`10
`5
`Months From Enrollment
`
`30
`
`Quality-of-Life Assessment
`
`(A) Kaplan-Meierplots of the duration of responsein patients with
`Fig 1.
`tumorresponse(complete or partial response) and (B) survivalin all enrolled
`patients.
`
`One hundred fifty-four patients completed the EORTC
`Quality of Life Questionnaire—C30 at baseline and at week
`12. Before disease progression,
`treatment with rhuoMAb
`
`6
`
`

`

`ANTI-HER2 MONOCLONAL ANTIBODY AS A SINGLE AGENT
`
`2643
`
`HER2 was associated with maintenance of health-related
`
`quality of life, as measured by the physical function, role
`function, social function, global quality-of-life, and fatigue
`scales. However, after disease progression, overall health-
`related quality of life declined. The subset of 34 patients
`with a response had clinically meaningful improvementsin
`the evaluated parameters. A detailed analysis of quality of
`life will be published separately.
`
`Pharmacokinetics and Shed Antigen
`
`The mean volumeof distribution (38.0 mL/kg) approxi-
`mated the serum volume. The meansteady-state concentra-
`tion was 59.7 ug/mL. The meaneliminationhalf-life was 6.2
`days. Among the 195 patients with pharmacokinetic data,
`the mean peak and trough serum concentrations of rhuMAb
`HER2afterthefirst dose were 100.3 ug/mLand 25.0 g/mL,
`respectively. The trough serum concentrations tended to
`increase through week 20 and, thereafter, tended to plateau
`(Fig 2). To minimize the potential confounding effect of the
`declining numberof assessable patients over time, trough
`concentrations were evaluated in a subset of 37 patients who
`had data through week 36. Similarfindings were observed in
`this subset, except that the trough concentrations tended to
`plateau after week 12 (data not shown). Mean trough
`concentrations at weeks 7 and 8 were higher in complete
`(70.3 ug/mL) and partial (58.4 pg/mL) responders than in
`nonresponders (44.3 pg/mL; P < .001).
`
`Serum concentrations of baseline shed antigen were
`below the detectable level
`in 73 (38%) of 191 patients,
`between 3.4 ng/mL and 100 ng/mL in 78 patients (41%),
`between 100 ng/mL and 500 ng/mL in 28 patients (15%),
`and above 500 ng/mL in 12 patients (6%). Patients whose
`tumors overexpressed HER2 at
`the 3+ level had higher
`median shed antigen concentrations (16.2 ng/mL)
`than
`patients whose tumors overexpressed HER2at the 2+ level
`(3.4 ng/mL; P < .0001). No significant correlations were
`demonstrable between shed antigen concentrations and
`responsestatus.
`
`Safety
`Patients who received at least one dose of rhuMAb HER2
`
`were evaluated for safety. Chemotherapy was added to
`thuMAb HER2in 36 patients after disease progression. This
`safety analysis included adverse events occurring before
`disease progression unless otherwise noted. The median
`numberof infusions was 12 (range,
`| to 96). A total of 210
`patients (99%) experienced at least one adverse event; 88
`patients (41%) had severe adverse events. When events were
`limited to those that
`the investigator considered to be
`possibly or probablyrelated to treatment (hereafter, treatment-
`related events), 179 patients (84%) experienced at least one
`adverse event; only 29 patients (14%) had severe events.
`Severe treatment-related adverse events that occurred in
`
`—e— Mean Trough Serum Conc. (ug/ml)
`
`2 miele eit
`
`Fig 2. Mean trough (+SD) serum
`concentrations of rhuMAb HER2for
`all patients for whom data were
`available (n = numberof patients).
`
`(ug/ml) 200
`MeanTroughSerumConc.
`
`
`150
`
`100
`
`50
`
`Week
`
`7
`
`

`

`2644
`
`COBLEIGH ET AL
`
`in eightpatients (4%) after a subsequentinfusion, and in five
`(2%) after multiple infusions. Only two patients (1%) had
`temperatures that exceeded 39°C. Therefore, 176 patients
`(84%) did not have postinfusion temperatures that exceeded
`38°C.
`
`the initial infusion, particularly fever, chills, pain, asthenia,
`nausea, vomiting, and headache (Table 3). These adverse
`events were mild to moderate in intensity and were rarely
`severe. Often, the infusion was temporarily interrupted. The
`symptomswere usually successfully treated with acetamino-
`phen, diphenhydramine, and/or meperidine and usually did
`not recur with subsequent infusions. For example, 40% of
`patients experienced fever and/or chills during or shortly
`after the first infusion, but less than 3% of these patients
`experienced recurrent fever or chills. Temperature exceeded
`38°C in 20 (10%) of 209 patients after the loading dose only,
`
`Table 3. Adverse Events in > 10% of 213 Patients Treated With at Least One
`Dose of rhuMAb HER2,Including Those Not Related to Treatment
`Any Adverse Event
`Severe Adverse Event
`No.of
`No.of
`Adverse Event
`Patients
`%
`Patients
`
`
`%
`
`more than one patient were pain (n = 9), chills (n = 5),
`dyspnea (n = 2), and abdominal pain (n = 2).
`Six patients (3%) discontinued the study because of
`adverse events, four before disease progression and two
`after disease progression. One patient developed an anaphy-
`Reports of serious cardiac events in this trial and in the
`lactoid reaction during the first dose. One patient withdrew
`large comparative trial of rhuMAb HER2 in combination
`from treatment after developing tuberculosis, and one pa-
`tient withdrew from treatment because of atherosclerotic
`with chemotherapy,!? promptedaretrospective analysis of
`heart disease. The other three patients discontinued the study
`all cardiac events. Cardiac dysfunction was manifested as
`because of adverse events experienced before initiation of
`congestive heart failure, cardiomyopathy, and/or a decrease
`rhuMAb HER?treatment.
`in ejection fraction (> 10%). Ten patients (4.7%) were
`The most commonadverse events seemedto be related to
`identified, including three whose cardiac events occurred
`after the cutoff date. Nine of these patients had received
`anthracycline therapy and had at least one risk factor for
`anthracycline-induced cardiomyopathy, such as a cumula-
`tive doxorubicin dose of more than 400 mg/m? (n = 6),
`radiotherapy to the left chest (n = 3), age over 70 years
`(n = 3), or history of hypertension (n = 1). One patient had
`never received anthracycline therapy, and had significant
`cardiac disease at study entry. The majority of these cardiac
`events wereclinically significant. The most severe outcome
`occurred in a 39-year-old woman who had received a
`cumulative doxorubicin dose of approximately 450 mg/m?
`and had a cardiac ejection fraction of 60% at study entry.
`After 18 infusions of rhuMAb HER2, she had two episodes
`of severe cardiac dysfunction, each of which improved after
`aggressive therapy. She died 2 daysafterher last infusion of
`rhuMAb HER2because of presumed ventricular arrhythmia.
`This was the only death that was considered to be possibly
`related to rhuMAb HER2 treatment. Cardiac status was
`
`103
`OF
`81
`77
`76
`60
`58
`56
`55
`49
`47
`44
`42
`Al
`34
`33
`27
`
`48
`46
`38
`36
`36
`28
`27
`26
`26
`23
`22
`21
`20
`19
`16
`15
`13
`
`Pain
`Asthenia
`Fever
`Nausea
`Chills
`Vomiting
`Cough increased
`Headache
`Diarrhea
`Dyspnea
`Abdominal pain
`Chest pain
`Back pain
`Infection
`Insomnia
`Rhinitis
`Anorexia
`
`Anxiety
`Constipation
`Pharyngitis
`Dizziness
`Rash
`Flu syndrome
`Pruritus
`
`17
`6
`2
`2
`5
`ll
`1
`4
`3
`10
`4
`3
`]
`]
`
`8
`3
`]
`]
`2
`0.5
`0.5
`2
`]
`5
`2
`]
`0.5
`0.5
`
`0
`0
`0
`
`0
`
`0
`0
`0
`
`]
`
`0.5
`
`stable in six of eight patients with cardiac dysfunction who
`continued to receive rhuMAb HER2. Two patients with
`decreased ejection fraction remained asymptomatic.
`Laboratory results were rarely abnormal during treatment
`before disease progression. No cases of World Health
`Organization grade 4 hematologic abnormalities were pres-
`ent. Nine (4%) of 211 patients experienced grade 3 hemato-
`logic abnormalities, which were manifested by leukopenia
`(n = 3), neutropenia (n = 2), thrombocytopenia (n = 3), or
`decreased hemoglobin (n = 1). Twenty (9%) of 212 patients
`experiencedatleast one grade 3 hepatic laboratory abnormal-
`ity, which was manifested by elevated alkaline phosphatase
`(n= 11), AST (n=9), ALT (n=5), or total bilirubin
`(n = 1). Seven patients (3%), all with disease involving the
`hepatobiliary system, experienced at
`least one grade 4
`hepatic laboratory abnormality, which was manifested by
`elevated alkaline phosphatase (n = 6), AST (n = 4),ortotal
`bilirubin (n = 1). Grade 3 or 4 elevations in liver function
`tests were associated with disease progression in 16 patients.
`
`13
`2
`13
`27
`13
`27
`12
`26
`12
`26
`0.5
`1
`11
`23
`
`
`
`23 0.5 11 ]
`
`8
`
`

`

`ANTI-HER2 MONOCLONAL ANTIBODY AS A SINGLE AGENT
`
`2645
`
`Only one (0.5%) of 211 patients had detectable levels of
`antibodies against rhuMAb HER2. Treatment was stopped
`after nine infusions because of disease progression, when
`antibody measurements revealed antibody formation against
`the Fab region of rhuMAb HER2. Peak serum concentra-
`tions of rhuMAb HER2 fell from more than 40 pg/mL
`between days 0 and 36 to 11.4 ug/mL on day 50. Noclinical
`signs or symptomsofallergy were observed. Adverse events
`were reviewed in the 36 patients who were treated after
`disease progression with rhuMAb HER2 combined with
`cytotoxic chemotherapy. Diverse chemotherapy regimens
`were used, and no unexpected toxicity findings were ob-
`served,
`
`DISCUSSION
`
`The results of this trial indicate that rhuMAb HER2is
`
`active as a single agent and produces durable objective
`responses in women with HER2-overexpressing metastatic
`breast cancer that has progressed after chemotherapy for
`metastatic disease. The 15% objective response rate is
`noteworthy in view of the study design and patient popula-
`tion. Objective response wasdefinedbystrict criteria and by
`independent RECreview.The investigators’ responserate of
`21% washigher than the REC assessment.
`The study population had a very poor prognosis. All
`patients had tumors that overexpressed HER2. Mostpatients
`had visceral disease because of the requirementfor bidimen-
`sionally measurable disease; patients whose only assessable
`disease site was bone, a population with generally indolent
`disease, were ineligible. Patients were heavily pretreated.
`The great majority had received multiple chemotherapy
`regimens, and approximately one fourth had undergone
`bone marrow or stem-cell transplantation.
`The investigator-reported objective responserate in these
`patients approached the 20% to 27% response rate reported
`for standard second-line chemotherapy in patients who have
`failed anthracycline-containing regimens.** The response
`rate to single agent vinorelbine in anthracycline-resistant
`patients is 16%,?> and that to paclitaxel given by 24-hour
`infusion is approximately 23%.”4 Higherresponse rates have
`been reported for some second-line agents, such as doce-
`taxel, which yielded a 41% response rate in three phase II
`trials.2> However, the complete response rate (2%), median
`duration of response (6 months), and median duration of
`survival (10 months) in the docetaxel trials were not superior
`to the findings in this study. Furthermore,
`the response
`duration in patients receiving rhuMAb HER2in this study
`(9.1 months) compared very favorably with the duration
`associated with previous chemotherapy in responders (5.2
`months). Finally, the secondary end points in the current
`
`study may improve with additional follow-up because, at the
`cutoff date, approximately one quarter of responders had not
`experienced treatment failure and 82% of patients with a
`response remainedalive.
`An important difference between rhuMAb HER2 and
`most standard chemotherapy agents is tolerability. Typical
`chemotherapy-induced complications, such as alopecia, mu-
`cositis, and hematologic toxicity, occurred in no more than
`4% of patients. The most common adverse events were
`fever, chills, and other acute and self-limited symptoms.
`These infusion-associated symptoms occurred in approxi-
`mately 40% of patients during or shortly after the loading
`dose was administered and were usually treatable with
`acetaminophen and diphenhydramine or,
`less commonly,
`meperidine. Symptoms rarely recurred with subsequent
`infusions. Only one patient was discontinued from the study
`because of infusion-associated symptoms. Only two