The New England
`
`Journal of Medicine
`Copyright © 2001 by the Massachusetts Medical Society
`VOLUME 344
`NUMBER 11
`
`MARCH 15, 2001
`
`
`
`
`
`
`
`USE OF CHEMOTHERAPY PLUS A MONOCLONAL ANTIBODY AGAINST HER2
`FOR METASTATIC BREAST CANCER THAT OVEREXPRESSES HER2
`
`DENNIS J. SLAMON, M.D., PH.D., BRIAN LEYLAND-JONES, M.D., STEVEN SHAK, M.D., HANK FUCHS, M.D.,
`VIRGINIA PATON, PHARM.D., ALEX BAJAMONDE, PH.D., THOMAS FLEMING, PH.D., WOLFGANG EIERMANN, M.D.,
`JANET WOLTER, M.D., MARK PEGRAM, M.D., JOSE BASELGA, MD, AND LARRY NORTON, M.D.*
`
`ABSTRACT
`
`Background The HER2 gene, which encodes the
`growth factor receptor HER2, is amplified and HER2
`is overexpressed in 25 to 30 percent of breast cancers,
`increasing the aggressiveness of the tumor.
`Methods We evaluated the efficacy and safety of
`trastuzumab, a recombinant monoclonal antibody
`against HER2, in women with metastatic breast can-
`cer that overexpressed HER2. We randomly assigned
`234 patients to receive standard chemotherapy alone
`and 235 patients to receive standard chemotherapy
`plus trastuzumab. Patients who had not previously re-
`ceived adjuvant (postoperative) therapy with an an-
`thracycline were treated with doxorubicin (or epirubi-
`cin in the case of 36 women) and cyclophosphamide
`with (143 women) or without trastuzumab (138 wom-
`en). Patients who had previously received adjuvant
`anthracycline were treated with paclitaxel alone (96
`women) or paclitaxel with trastuzumab (92 women).
`Results The addition of trastuzumab to chemother-
`apy was associated with a longer time to disease pro-
`gression (median, 7.4 vs. 4.6 months; P<0.001), a high-
`er rate of objective response (50 percent vs. 32 percent,
`P<0.001), a longer duration of response (median, 9.1
`vs. 6.1 months; P<0.001), a lower rate of death at1 year
`(22 percent vs. 33 percent, P=0.008), longer survival
`(median survival, 25.1 vs. 20.3 months; P=0.046), and
`a 20 percent reduction in the risk of death. The most
`important adverse event was cardiac dysfunction,
`which occurred in 27 percent of the group given an
`anthracycline, cyclophosphamide, and trastuzumab;
`8 percent of the group given an anthracycline and
`cyclophosphamide alone; 13 percent of the group
`given paclitaxel and trastuzumab; and 1 percent of
`the group given paclitaxel alone. Although the car-
`diotoxicity was potentially severe and, in some cases,
`life-threatening, the symptoms generally improved
`with standard medical management.
`Conclusions Trastuzumab increases the clinical
`benefit of first-line chemotherapy in metastatic breast
`cancer that overexpresses HER2. (N Engl J Med 2001;
`344:783-92.)
`Copyright © 2001 Massachusetts Medical Society.
`
`
`
`ESPITE advances in the diagnosis and
`treatment of breast cancer, more than
`44,000 women in the United States will
`die this year of metastatic disease},2 Al—
`though objective responses to some chemotherapy
`regimens are common, few patients with metastatic
`disease are cured,3)4 and treatments frequently cause
`substantial adverse effects.
`
`A growth factor receptor genef“7 human epidermal
`growth factor receptor (HER2), is amplified in 25 to
`30 percent of breast cancers and in these cases the en—
`coded protein is present in abnormally high levels in
`the malignant cells.8)9 Women with breast cancers that
`overexpress HER2 have an aggressive form of the dis—
`ease with significantly shortened disease—free survival
`and overall survival}?12 Laboratory studies indicate that
`amplification of HER2 has a direct role in the patho—
`genesis of these cancers,”17 thereby providing inves—
`tigators with an opportunity to target a therapeutic
`agent directly against the alteration.
`Several murine monoclonal antibodies against the
`extracellular domain of the HER2 protein were found
`to inhibit the proliferation of human cancer cells that
`overexpressed HER2, both in vitro and in vivo.13*20
`To minimize immunogenicity, the antigen—binding re—
`gion of one of the more effective antibodies was
`
`From the Division of Hematology and Oncology, UCLA School of
`Medicine, Los Angeles (D.].S., M.P.);
`the Department of Oncology,
`McGill University, Montreal (B.L:].): Medical Affairs, Genentech, South
`San Francisco, Calif. (S.S., V.P., A.B.); IntraBiotics, Mountain View, Calif.
`(HF); the Department of Biostatistics, University of Washington, Seattle
`(TE); the Department of Obstetrics and Gynecology, Frauenklinik vom
`Roten Kreuz, Munich, Germany (W.E.); the Department of Oncology,
`RushiPresbyterianiSt. Luke’s Medical Center, Chicago (].W.); the Depart,
`ment of Oncology, Hospital General Universitari Vall d’Hebron, Barceloa
`na, Spain (1.13.); and the Department of Medical Oncology, Memorial
`SloanaKettering Cancer Center, New York (L.N.). Address reprint requests
`to Dr. Slamon at UCLA School of Medicine, Division of Hematology/
`Oncology, 117244 Factor Bldg, 10833 Le Conte, Los Angeles, CA 900957
`1678, or at dslamon@mednet.ucla.edu.
`*Additional study investigators are listed in the Appendix.
`
`N Engl IMed, Vol. 344, No. 11 - March 15, 2001
`
`The New England Journal of Medicine
`Downloaded from nejm.org on April 20, 2017. For personal use only. No other uses without permission.
`Copyright © 2001 Massachusetts Medical Society. All rights reserved.
`
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`IPR2017-01122
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`

`
`The New England Journal of Medicine
`
`fused to the framework region of human IgG21 and
`tested against breast—cancer cells that overexpressed
`HER2 in vitro and in vivo.21,22 This antibody, called
`trastuzumab, inhibited tumor growth when used
`alone4 but had synergistic effects20a22’24 when used in
`combination with cisplatin and carboplatin,2°)23 do—
`cetaxel,24 and ionizing radiation25 and additive effects
`when used with doxorubicin, cyclophosphamide,
`methotrexate, and paclitaxel.”26
`Phase 1 clinical trials showed that the antibody is
`safe and confined to the tumor (unpublished data).
`Subsequent phase 2 trials demonstrated that many
`women with HERZ—positive metastatic disease who
`had relapsed after chemotherapy had a response to
`trastuzumabZZZS; as suggested by the preclinical data,
`the efficacy of trastuzumab when given with chemo—
`therapy was superior to its effectiveness when used
`alone.28>29 We report the results of a phase 3 trial in
`which women with cancers that overexpressed HER2
`who had not previously received chemotherapy for
`metastatic disease were randomly assigned to receive
`either chemotherapy alone or chemotherapy plus tras—
`tuzumab. The primary end points of the study were
`the time to disease progression and the incidence of
`adverse effects. Secondary end points were the rates
`and the duration of responses, the time to treatment
`failure, and overall survival.
`
`METHODS
`
`Patients
`
`Women with progressive metastatic breast cancer that overex—
`pressed HERZ who had not previously received chemotherapy for
`metastatic disease were eligible for the study. Written informed con—
`sent was obtained from all patients. The level of expression of HERZ
`was determined by immunohistochemical analysis in a central lab-
`oratory. Only patients who had weak—to—moderate staining of the
`entire tumor—cell membrane for HERZ (referred to as a score of 2+)
`or more than moderate staining (referred to as a score of 3+) in
`more than 10 percent oftumor cells on immunohistochemical analy—
`sis were eligible for the study.
`Patients were excluded if they had bilateral breast cancer, un—
`treated brain metastases, osteoblastic bone metastases, pleural effu—
`sion or ascites as the only evidence of disease, a second type of pri—
`mary cancer, or a Karnofsky score ofless than 60. Patients were also
`excluded if they were pregnant or had received any type of inves—
`tigational agent within 30 days before the study began.
`
`Treatments
`
`Patients were randomly assigned to receive either chemotherapy
`alone or chemotherapy plus trastuzumab. Chemotherapy consisted
`of an anthracycline (doxorubicin at a dose of 60 mg per square
`meter of body—surface area or epirubicin at a dose of 75 mg per
`square meter) plus cyclophosphamide (at a dose of 600 mg per
`square meter) for patients who had never before received an anthra—
`cycline, or paclitaxel (at a dose of 175 mg per square meter) for
`patients who had received adjuvant (postoperative) anthracycline.
`Doxorubicin or epirubicin plus cyclophosphamide or paclitaxel was
`administered once every three weeks for six cycles, and additional
`cycles were administered at the investigator’s discretion. Trastuzu—
`mab was administered intravenously in a loading dose of4 mg per
`kilogram of body weight, followed by a dose of 2 mg per kilo—
`gram once a week, until there was evidence of disease progression.
`On the detection of disease progression, patients were given the
`
`
`
`option of entering a nonrandomized, open—label study in which
`trastuzumab was administered at the same doses alone or in com—
`bination with other therapies. Sixty—six percent of such patients
`elected to do so.
`
`Efficacy
`
`Patients were evaluated for a response at weeks 8 and 20 and
`then at 12—week intervals. The determinations were made by the
`members of an independent response—evaluation committee, who
`were unaware of the patients’ treatment assignments. A complete
`response was defined as the disappearance of all tumor on the ba—
`sis of radiographic evidence, visual inspection, or both. A partial
`response was defined as a decrease of more than 50 percent in the
`dimensions of all measurable lesions. Disease progression was de—
`fined as an increase of more than 25 percent in the dimensions
`of any measurable lesion. The primary study end point was the time
`to disease progression. Prespecified secondary end points were the
`rate of objective response, the duration of a response, the time to
`treatment failure (a composite ofdisease progression, death, discon—
`tinuation of treatment, and the use of other types of antitumor
`therapy), and survival as of October 1999.
`
`Adverse Events
`
`Clinical assessments were performed at base line, at specified
`times, and at the time the patient was removed from the study.
`Adverse events were classified as mild, moderate, or severe. An in—
`dependent cardiac evaluation committee whose members were un—
`aware of patients’ treatment assignments assessed the incidence,
`severity, treatment, and outcome of cardiac dysfunction. Abnor—
`malities in laboratory values were classified by the grading system
`of the World Health Organization and cardiac dysfunction by the
`criteria of the New York Heart Association.
`
`Statistical Analysis
`
`We estimated that 450 patients would be needed in order for the
`study to detect at a power of 90 percent a 50 percent increase in
`the median time to disease progression, given a median time to pro—
`gression of eight months in the subgroups receiving chemotherapy
`alone and a significance level of 0.05 with the use of a two—tailed
`log—rank test. All end points were analyzed according to the inten—
`tion—to—treat principle. The primary analysis of all efficacy variables
`was performed on data pooled from both chemotherapy regimens.
`Additional analyses were performed within each chemotherapy
`group. The time to the various end points was analyzed with the use
`of Kaplan—Meier methods, and a two—sided log—rank test was used
`to compare the groups. The rate ofobjective response was analyzed
`with the use of normal approximation methods; a two—sided chi—
`square test was used to compare the groups.
`
`Characteristics of the Patients
`
`RESULTS
`
`We enrolled 469 patients between June 1995 and
`March 1997 (Table 1); 5 patients were never treated:
`2 declined treatment, 1 died before treatment was
`begun, 1 had disease progression at enrollment, and
`1 was enrolled inadvertently. The median time in the
`study was 40 weeks (range, 1 to 127) in the group
`given chemotherapy plus trastuzumab, as compared
`with 25 weeks (range, 1 to 131) in the group given
`chemotherapy alone, reflecting the longer time to dis—
`ease progression in the group that received combina—
`tion treatment. The median number of doses of tras—
`
`tuzumab was 36 (range, 1 to 98).
`The base—line characteristics of the patients were
`similar among the treatment groups. Stratification
`
`784 - N Engl IMed, Vol. 344, No. 11 - March 15, 2001 - www.nejm.org
`
`The New England Journal of Medicine
`Downloaded from nejm.org on April 20, 2017. For personal use only. No other uses without permission.
`Copyright © 2001 Massachusetts Medical Society. All rights reserved.
`
`

`

`ANTI-HERZ MONOCLONAL ANTIBODY PLUS CHEMOTHERAPY FOR METASTATIC BREAST CANCER
`
`
`
`TABLE 1. BASE—LINE CHARACTERISTICS OF THE PATIENTS.
`
`CHARACTERISTIC
`
`Age 7 yr
`Mean :SD
`Range
`Karnofsky score 7 no./no. analyzed (%)
`907100
`60780
`Median no. of positive lymph nodes
`at diagnosis
`Prior therapy 7 no./no. analyzed (%)
`Adjuvant chemotherapy
`Hormonal therapy (as adjuvant, for
`metastasis, or both)
`Radiotherapy (as adjuvant, for metasi
`tasis, or both)
`Median diseaseifree interval 7 mo
`Degree of overexpression of HERZ
`7 no./no. analyzed
`2,,
`3,,
`
`No. of metastatic sites at enrollment
`7 no./no. analyzed (%)
`
`AN ANTHRAcvcuNE,
`CYCLOPHOSPHAMIDE,
`AND TRASTUZUMAB
`(N = 143) *
`
`AN ANTHRAcYcuNE AND
`CYCLOPHOSPHAMIDE
`ALONE
`(N=138lf
`
`PAcLITAXEL
`AND
`TRASTUZUMAB
`lN=92l
`
`PAan'AXEL
`ALONE
`(N=96l
`
`54:10.3
`27776
`
`54:10.1
`25775
`
`51:11.5
`25777
`
`51:11.0
`26773
`
`91/138 (66)
`47/138 (34)
`1.0
`
`89/135 (66)
`46/135 (34)
`0.5
`
`68/90 (76)
`22/90 (24)
`5.0
`
`61/94 (65)
`33/94 (35)
`6.0
`
`81/142 (57)
`88/142 (62)
`
`69/143 (48)
`24.5
`
`50/136 (37)
`76/134 (57)
`
`76/136 (56)
`22.8
`
`88/91 (97)
`49/89 (55)
`
`95/95 (100)
`53/95 (56)
`
`60/89 (67)
`22.4
`
`72/95 (76)
`18.9
`
`35/143 (24)
`108/143 (76)
`
`42/138 (30)
`96/138 (70)
`
`24/92 (26)
`68/92 (74)
`
`19/96 (20)
`77/96 (80)
`
`27/95 (28)
`31/91 (34)
`49/136 (36)
`48/143 (34)
`35/95 (37)
`32/91 (35)
`48/136 (35)
`38/143 (27)
`
`
`28/91 (31)39/136 (29)57/143 (40) 33/95 (35)
`
`
`*Twenty of these patients received epirubicin rather than doxorubicin.
`TSixteen of these patients received epirubicin rather than doxorubicin.
`1A score of 2+ indicated that more than 10 percent of tumor cells had weakitoimoderate staining of the entire mem7
`brane for HERZ on immunohistochemical analysis, and a score of 3+ that more than 10 percent of tumor cells had more
`than moderate staining for HER2 on immunohistochemical analysis.
`
`on the basis of a history of adjuvant anthracycline
`treatment resulted in differences between the sub—
`
`groups given an anthracycline and cyclophosphamide
`and the subgroups given paclitaxel. Patients who re—
`ceived paclitaxel had more involved lymph nodes at
`diagnosis and were more likely to have received ad—
`juvant high—dose chemotherapy with stem—cell or mar—
`row support than patients who received an anthracy—
`cline and cyclophosphamide. Of the 235 patients who
`received trastuzumab, 216 (92 percent) received at
`least 80 percent of the planned infusions and fewer
`than 5 percent required a delay in treatment or a re—
`duction in doses of the chemotherapy. The final analy—
`sis of the primary end points was performed nine
`months after the enrollment of the last patient. Sur—
`vival was analyzed 31 months after enrollment end—
`ed. The median duration of follow—up was 30 months
`(range, 30 to 51).
`
`Efficacy
`
`The median time to disease progression in the
`group assigned to chemotherapy plus trastuzumab
`was 7.4 months, whereas in the group given chemo—
`therapy alone it was 4.6 months (P<0.001) (Table 2
`
`and Fig. 1). This difference was evident in both the
`subgroup that received an anthracycline, cyclophos—
`phamide, and trastuzumab (median time to progres—
`sion, 7.8 months, as compared with 6.1 months in the
`subgroup given only an anthracycline and cyclophos—
`phamide; P<0.001) and the subgroup that received
`paclitaxel and trastuzumab (median time to progres—
`sion, 6.9 months, as compared with 3.0 months in
`the group given paclitaxel alone; P<0.001) (Fig. 1).
`AS compared with chemotherapy alone, treatment
`with chemotherapy plus trastuzumab was associated
`with a significantly higher rate of overall response (50
`percent vs. 32 percent, P<0.001), a longer duration
`of response (median, 9.1 vs. 6.1 months; P<0.001),
`and a longer time to treatment failure (median, 6.9
`vs. 4.5 months; P<0.001) (Tables 2 and 3). Statistical—
`ly significant dilTerences in the overall rates of response,
`the duration of response, and time to treatment fail—
`ure were also found in the subgroup treated with an
`anthracycline, cyclophosphamide, and trastuzumab
`and the subgroup treated with paclitaxel and trastu—
`zumab, as compared with the subgroups treated with
`an anthracycline and cyclophosphamide alone or pac—
`litaxel alone, respectively (Tables 2 and 3).
`
`
`
`N Engl IMed, Vol. 344, No. 11 - March 15, 2001 - www.nejm.org - 785
`
`The New England Journal of Medicine
`Downloaded from nejm.org on April 20, 2017. For personal use only. No other uses without permission.
`Copyright © 2001 Massachusetts Medical Society. All rights reserved.
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`

`

`The New England Journal of Medicine
`
`
`
`TABLE 2. RESULTS OF AN INTENTION—TO—TREAT ANALYSIS OF THE END POINTS.*
`
`END POINT
`
`CHEMOTHERAPY
`PLUS
`TRASTUZUMAB
`(N=235)
`
`EITHER TYPE OF
`CHEMOTHERAPY
`ALONE
`(N=234l
`
`AN ANTHRAcchINE,
`CYCLOPHOSPHAMIDE,
`AND TRASTUZUMAB
`(N=143)
`
`AN ANTHRAcchINE
`AND
`CycLOPHOSPHAMIDE
`ALONE
`(N=138)
`
`PAcLITAXEL AND
`TRASTUZUMAB
`(N=92)
`
`PAcLITAXEL
`ALONE
`(N=96)
`
`Median time to disease progression
`7 mo
`P value
`Relative risk of progression
`(95% CI)
`Median time to treatment failure
`7 mo
`P value
`Relative risk of treatment failure
`(95% CI)
`Median survival 7 mo
`0.17
`0.16
`0.046
`P value
`
`
`
`0.80 (06471.00) 0.82 (06171.09)Relative risk of death (95% CI) 0.30 (0,564.11)
`
`6.1
`
`5 .6
`
`6.9
`
`3.0
`
`< 0.001
`0.38 (02770.53)
`5 .8
`2.9
`
`< 0.001
`0.46 (03370.63)
`22.1
`18.4
`
`7.4
`
`4.6
`
`<0.001
`0.51 (0.417063)
`6.9
`4.5
`
`<0.001
`0.58 (0.477070)
`25.1
`20.3
`
`7.8
`
`<0.001
`0.62 (0.477081)
`7.2
`
`<0.001
`0.67 (05270.86)
`26.8
`
`21.4
`
`*The time to treatment failure was defined as the time from randomization to disease progression, discontinuation of treatment for any
`reason, use of other types of antitumor therapy, or death. The final analysis of the primary end point (time to disease progression) was per,
`formed nine months after enrollment of the last patient. The most recent survival data were obtained 31 months after the enrollment of the
`last patient, with a median followiup of 35 months (range, 30 to 51). As of the dataicutoff date of December 31, 1997, a total of 388 (83
`percent) of the 469 patients had discontinued the study, including 173 (74 percent) of the 235 patients assigned to receive chemotherapy
`plus trastuzumab and 215 (92 percent) of the 234 patients assigned to receive chemotherapy alone. The responseievaluation committee as,
`sessed the tumor response in 446 patients: 99 percent of the 452 patients who had an assessment after the baseline evaluation and 95 percent
`of the 469 patients who enrolled in the study. In the group given paclitaxel and trastuzumab, the increase in the interval between random,
`ization and disease progression was greater among patients who had a Karnofsky score of 90 or more at base line. The most common sites
`of disease progression among patients who received chemotherapy plus trastuzumab and among those who received chemotherapy alone were
`the liver (32 percent and 46 percent), the lungs (20 percent and 21 percent), bone (18 percent and 15 percent), and the central nervous
`system (18 percent and 9 percent). CI denotes confidence interval.
`
`The addition of trastuzumab was also associated
`
`with a significantly lower rate of death at one year (22
`percent, as compared with 33 percent in the group
`given chemotherapy alone; P=0.008). The median
`survival was 25.1 months in the group given chemo—
`therapy plus trastuzumab and 20.3 months in the
`group that received chemotherapy alone (P=0.046)
`(Table 2 and Fig. 2). This calculation included pa—
`tients in the group given chemotherapy alone who
`received open—label trastuzumab after the occurrence
`of disease progression. The risk of death was reduced
`by 18 to 20 percent in the subgroups given trastu—
`zumab (Table 2). The efficacy of trastuzumab was con—
`sistently observed in both subgroups; however, pa—
`tients with a score of 3+ for the overexpression of
`HER2 benefited to a greater degree from such treat—
`ment than those with a score of 2+.
`
`Deaths
`
`As of October 1999, 314 patients had died (149 in
`the group given chemotherapy plus trastuzumab and
`165 in the group given chemotherapy alone); 95 per—
`cent of these deaths were attributed to progressive
`
`disease. Two deaths, both in patients who had received
`an anthracycline, cyclophosphamide, and trastuzumab,
`were possibly related to trastuzumab therapy: one pa—
`tient died of sepsis after 2 doses of trastuzumab, and
`the second died of hepatitis B—related hepatorenal
`syndrome after 11 doses of trastuzumab.
`Adverse Events
`
`Approximately 25 percent of patients had chills,
`fever, or both during the initial infusion of trastuzu—
`mab. Slowing the infusion rate ameliorated these
`symptoms. No episodes of frank anaphylaxis occurred,
`but one patient had moderate hypotension, and three
`had mild bronchospasm, all of which resolved with—
`out treatment.
`
`Infection occurred in 47 percent of patients who
`were given chemotherapy plus trastuzumab and in
`29 percent of those treated with chemotherapy alone
`(Table 4). These infections consisted of mild—to—mod—
`erate infections of the upper respiratory tract in 72
`percent of cases, catheter—related infections in 9 per—
`cent, a Viral syndrome in 3 percent, and other types
`of infections in 16 percent. Of the 14 catheter—related
`
`
`
`Figure 1 (facing page). Kaplan—Meier Estimates of Progression—free Survival, According to Whether Patients Were Randomly As—
`signed to Receive Chemotherapy plus Trastuzumab or Chemotherapy Alone (Panel A), and Whether Chemotherapy Consisted of
`Either a Combination of an Anthracycline and Cyclophosphamide (Panel B) or Paclitaxel (Panel C).
`
`786 - N Engl IMed, Vol. 344, No. 11 - March 15, 2001 - www.nejm.org
`
`The New England Journal of Medicine
`Downloaded from nejm.org on April 20, 2017. For personal use only. No other uses without permission.
`Copyright © 2001 Massachusetts Medical Society. All rights reserved.
`
`

`

`ANTI-HERZ MONOCLONAL ANTIBODY PLUS CHEMOTHERAPY FOR METASTATIC BREAST CANCER
`
`Chemotherapy plus trastuzumab
`
`
`
`
`0
`
`5
`
`10
`
`15
`
`20
`
`25
`
`100
`:\5
`: 90
`(U
`.2
`80
`g
`70
`m 60
`a)
`q.
`2
`50
`&
`40
`O
`
`30
`20
`
`10
`0
`
`a)
`
`ao
`
`\—
`D—
`
`A
`
`Months after Enrollment
`
`235
`
`234
`
`152
`
`103
`
`63
`
`25
`
`15
`
`6
`
`
`
`
`Anthracycline and cyclo—
`phosphamide alone
`
`0
`
`5
`
`10
`
`15
`
`20
`
`25
`
`.
`_
`Anthracycllne, cyclophosphamlde,
`and trastuzumab
`
`P<0.001
`
`100
`:\5
`: 90
`(U
`.2
`80
`
`70
`
`60
`50
`40
`
`m
`a,
`q.
`2
`é
`.9
`30
`a
`20
`a)
`0\—
`a 10
`D—
`0
`
`> 5
`
`No. AT RISK
`
`Chemotherapy
`plus trastuzumab
`Chemotherapy alone
`
`B
`
`No. AT RISK
`
`Anthracycline, cyclophos—
`phamide, and trastuzumab
`Anthracycline and cyclo—
`phosphamide alone
`
`143
`
`138
`
`Months after Enrollment
`
`98
`
`77
`
`40
`
`20
`
`12
`
`6
`
`E3
`
`70
`m 60
`$
`50
`q‘:
`&
`40
`O
`
`30
`20
`9
`g 10
`D—
`0
`
`C
`
`100 .
`:\5
`: 90
`(U
`.2
`80
`
`
`
`
`Paclitaxel and trastuzumab
`
`0
`
`5
`
`10
`
`15
`
`20
`
`25
`
`No. AT RISK
`Paclitaxel and
`trastuzumab
`Paclitaxel alone
`
`Months after Enrollment
`
`92
`
`96
`
`54
`
`26
`
`23
`
`5
`
`N Engl IMcd, Vol. 344, No. 11 - March 15, 2001 - www.ncjm.org - 787
`
`The New England Journal of Medicine
`Downloaded from nejm.org on April 20, 2017. For personal use only. No other uses without permission.
`Copyright © 2001 Massachusetts Medical Society. All rights reserved.
`
`

`

`
`The New England Journal of Medicine
`
`
`
`TABLE 3. RATES AND DURATIONS or RESPONSES.*
`
`VARIABLE
`
`CHEMOTHERAPY PLUS
`TRASTUZUMAB
`(N = 235)
`
`CHEMOTHERAPY
`ALONE
`(N = 234)
`
`AN ANTHRAcchINE,
`0chOPHOSPHAMIDE,
`AND TRASTUZUMAB
`(N=143)
`
`Complete response 7 no. (%)
`Partial response 7 no. (%)
`Complete and partial responses
`7 no. (% [95% CI])
`P value
`
`8 (3)
`18 (8)
`66 (28)
`100 (43)
`74 (32 [26738])
`118 (50 [44757])
`<0.001
`
`11(8)
`69 (48)
`80 (56 [48764])
`0.02
`
`AN ANTHRAcchINE
`AND
`CycLOPHOSPHAMIDE
`ALONE
`(N=138)
`
`6 (4)
`52 (38)
`58 (42 [34750])
`
`PAan'AXEL AND
`TRASTUZUMAB
`(N=92)
`
`PAcLITAXEL
`ALONE
`(N=96)
`
`2 (2)
`7 (8)
`14 (15)
`31 (34)
`16 (17 [9724])
`38 (41 [31751])
`<0.001
`
`6.1
`9.1
`Median duration of response
`7 mo
`
`<0.001 0.005P value <0.01
`
`9.1
`
`6.7
`
`10.5
`
`4.5
`
`
`
`
`
`*The analysis included all 469 patients. A complete response was defined as the disappearance of all tumors on the basis of radiographic evidence, Visual
`inspection, or both. A partial response was defined as a decrease in the dimensions of all measurable lesions of more than 50 percent. The duration of
`response was defined as the time from the first response to disease progression or death. The responseievaluation committee assessed the tumor response
`in 446 patients: 99 percent of the 452 patients who had an assessment after the baseline evaluation and 95 percent of the 469 patients who enrolled in
`the study. In the group given paclitaxel and trastuzumab, the response rate was higher among patients who had a Karnofsky score of 90 to 100 at base
`line. CI denotes confidence interval.
`
`infections among patients who received trastuzumab,
`3 were severe, 13 required treatment, and 4 required
`surgical removal of the catheter. The incidence of sep—
`sis was low and evenly distributed among the four sub—
`groups. The addition of trastuzumab to the chemo—
`therapy regimen increased the frequency of leukopenia
`and anemia (Table 4). These cases of cytopenia were
`mild to moderate in severity and did not necessitate
`the discontinuation of trastuzumab or withdrawal
`
`from the study.
`Twenty—five patients (19 in the subgroup given an
`anthracycline, cyclophosphamide, and trastuzumab
`and 6 in the subgroup given paclitaxel and trastuzu—
`mab) stopped taking trastuzumab because of adverse
`events. Eighteen patients (15 in the subgroup given
`an anthracycline, cyclophosphamide, and trastuzumab
`and 3 in the subgroup given paclitaxel and trastuzu—
`mab) had clinical signs of cardiac dysfunction. Two
`additional adverse events were attributed to trastuzu—
`
`mab therapy: an embolic stroke as a possible compli—
`cation of cardiac dysfunction and chest pain after 49
`doses of trastuzumab and siX cycles of an anthracycline
`and cyclophosphamide. The events in the remaining
`five patients were not considered to be related to tras—
`tuzumab.
`
`Cardiotoxicity
`
`The adverse cardiac events prompted a retrospective
`analysis of all cases of cardiac dysfunction by an in—
`
`dependent cardiac review and evaluation committee.
`This review identified 63 patients with symptomatic or
`asymptomatic cardiac dysfunction: 39 of 143 patients
`had received an anthracycline, cyclophosphamide, and
`trastuzumab (accounting for 27 percent of this sub—
`group); 11 of 135 had received an anthracycline and
`cyclophosphamide alone (incidence, 8 percent); 12
`of 91 had received paclitaxel and trastuzumab (inci—
`dence, 13 percent); and 1 of 95 had received pacli—
`taxel alone (incidence, 1 percent). Among these pa—
`tients, the incidence of cardiac dysfunction of New
`York Heart Association class III or IV was highest
`among patients who had received an anthracycline,
`cyclophosphamide, and trastuzumab (16 percent, as
`compared with 3 percent among patients who had
`received an anthracycline and cyclophosphamide alone,
`2 percent among those who had received paclitaxel
`and trastuzumab, and 1 percent among those who had
`received paclitaxel alone).
`Of the 63 patients with cardiac dysfunction, 44
`received standard medical treatment. The condition
`
`improved in 33 of these 44 patients, did not change
`in 5, and worsened in 4. One patient in the group
`given an anthracycline, cyclophosphamide, and tras—
`tuzumab died of cardiac dysfunction, as did one in the
`group given an anthracycline and cyclophosphamide
`alone. Among the five patients with persistent class
`III or IV cardiac dysfunction, three were in the group
`given an anthracycline, cyclophosphamide, and tras—
`
`
`
`Figure 2 (facing page). Kaplan—Meier Estimates of Overall Survival, According to Whether Patients Were Randomly Assigned to
`Receive Chemotherapy plus Trastuzumab or Chemotherapy Alone (Panel A) and Whether Chemotherapy Consisted of Either 3 Com—
`bination of an Anthracycline and Cyclophosphamide (Panel B) or Paclitaxel (Panel C).
`
`788 - N Engl IMed, Vol. 344, No. 11 - March 15, 2001 - www.nejm.org
`
`The New England Journal of Medicine
`Downloaded from nejm.org on April 20, 2017. For personal use only. No other uses without permission.
`Copyright © 2001 Massachusetts Medical Society. All rights reserved.
`
`

`

`ANTI-HERZ MONOCLONAL ANTIBODY PLUS CHEMOTHERAPY FOR METASTATIC BREAST CANCER
`
`Chemotherapy plus trastuzumab
`
`Chemotherapy alone
`
`
`
`
`
`
`Survival(%) 8
`
`0
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`No. AT RISK
`
`Chemotherapy
`plus trastuzumab
`Chemotherapy alone
`
`B
`
`No. AT RISK
`
`Months after Enrollment
`
`235
`
`234
`
`214
`
`205
`
`192
`
`160
`
`165
`
`136
`
`134
`
`116
`
`114
`
`97
`
`96
`
`76
`
`47
`
`37
`
`11
`
`13
`
`100
`90
`80
`
`A 70
`o\°
`: 60
`(U
`>
`50
`'S
`‘5
`‘0
`
`4o
`30
`20
`10
`0
`
`
`
`
`_
`Anthracycllne and cycle
`phosphamide alone
`
`Anthracycline, cyclophosphamide,
`and trastuzumab
`
`0
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`Months after Enrollment
`
`9
`
`Anthracycline, cyclophos—
`phamide, and trastuzumab
`Anthracycline and cyclo—
`phosphamide alone
`
`143
`
`138
`
`134
`
`124
`
`123
`
`102
`
`107
`
`85
`
`89
`
`72
`
`75
`
`60
`
`62
`
`48
`
`32
`
`23
`
`11
`
`C
`
`1 00
`90
`
`70
`;\3
`: 60
`m
`3
`50
`:5
`E
`40
`(D
`30
`20
`10
`0
`
`80
`
`
`Paclitaxel and trastuzumab
`
`Paclitaxel alone
`
`n:
`
`.
`"
`
`0
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`No. AT RISK
`Paclitaxel and
`trastuzumab
`Paclitaxel alone
`
`Months after Enrollment
`
`92
`
`96
`
`80
`
`81
`
`69
`
`58
`
`58
`
`51
`
`45
`
`44
`
`39
`
`37
`
`34
`
`28
`
`15
`
`14
`
`2
`
`2
`
`N Engl IMcd, Vol. 344, No. 11 - March 15, 2001 - www.ncjm.org - 789
`
`The New England Journal of Medicine
`Downloaded from nejm.org on April 20, 2017. For personal use only. No other uses without permission.
`Copyright © 2001 Massachusetts Medical Society. All rights reserved.
`
`

`

`
`The New England Journal of Medicine
`
`
`
`TABLE 4. ADVERSE EVENTS THAT OCCURRED IN MORE THAN 10 PERCENT OF PATIENTS AS A GROUP.*
`
`TYPE OR LocATION
`OF ADVERSE EVENT
`
`CHEMOTHERAPY
`PLUS TRASTUZUMAB
`(N=234)
`
`CHEMOTHERAPY
`ALONE
`(N=230)
`
`AN ANTHRACYCLINE,
`CYCLOPHOSPHAMIDE,
`AND TRASTUZUMAB
`(N=143)
`
`AN ANTHRAcYcLINE AND
`CycLOPHOSPHAMIDE
`ALONE
`(N=135)
`
`PAcLITAXEL AND
`TRASTUZUMAB
`(N=91)
`
`PAcLITAXEL
`ALONE
`(N=95)
`
`percentage with event (percentage with severe event)
`
`Any type
`Abdominal pain
`Asthenia
`Back pain
`Chest pain
`Chills
`Fever
`Headache
`Infection
`Pain
`Heart failure
`Digestive tract
`Anorexia
`Constipation
`Diarrhea
`Nausea
`Stomatitis
`Vomiting
`Hematologic and lyme
`phatic systems
`Anemia
`Leukopenia
`Musculoskeletal system
`Arthralgia
`Myalgia
`Nervous system
`Paresthesia
`Respiratory tract
`Increased coughing
`Dyspnea not related
`to heart failure
`Pharyngitis
`Skin
`56 (26)
`56 (26)
`59 (42)
`58 (25)
`58 (35)
`57 (26)
`Alopecia
`
`Rash 18(1) 31 (<1) 17 (<1) 27(0) 17 (<1) 38(1)
`
`
`
`
`
`
`27 (3)
`57 (7)
`31 (4)
`24(3)
`38 (<1)
`53 (8)
`41 (4)
`47 (2)
`58 (6)
`22 (10)
`
`28 (<1)
`32 (1)
`45(1)
`66 (5)
`22 (<1)
`47 (5)
`
`27(2)
`41 (11)
`
`20 (4)
`23(3)
`
`29 (<1)
`
`43 (<1)
`36 (3)
`
`27(0)
`
`20 (3)
`56 (7)
`22(4)
`24(4)
`8 (<1)
`29 (4)
`30 (4)
`29 (2)
`50 (7)
`5 (2)
`
`22(2)
`28 (3)
`27(3)
`66 (7)
`21 (0)
`40 (7)
`
`19 (2)
`26 (9)
`
`14 (2)
`22(3)
`
`23 (< 1)
`
`26 (<1)
`25 (3)
`
`16 (< 1)
`
`23 (2)
`54 (7)
`27(2)
`20(3)
`35 (<1)
`56 (11)
`44 (3)
`47 (2)
`57 (4)
`27 (16)
`
`31 (0)
`36 (2)
`45(1)
`76 (6)
`30(1)
`53 (3)
`
`35 (3)
`52 (15)
`
`8 (<1)
`13 (<1)
`
`17(0)
`
`43 (<1)
`42 (4)
`
`30 (0)
`
`18 (2)
`55 (7)
`16(2)
`21 (2)
`11(2)
`33 (7)
`31 (5)
`30 (2)
`42 (8)
`8 (3)
`
`26(2)
`28 (3)
`25(3)
`79 (10)
`31 (3)
`49 (8)
`
`25 (2)
`33 (11)
`
`10 (<1)
`13 (<1)
`
`11 (0)
`
`28 (0)
`24 (4)
`
`18 (0)
`
`34 (3)
`62 (8)
`36(8)
`30(3)
`42(1)
`47 (2)
`36 (7)
`46 (1)
`60 (10)
`l3 (2)
`
`24(1)
`25 (0)
`45(1)
`50 (3)
`10(0)
`37 (9)
`
`14(1)
`24(6)
`
`37 (9)
`38(7)
`
`47(2)
`
`42 (0)
`28 (I)
`
`22 (0)
`
`22 (4)
`57 (8)
`30(5)
`27(5)
`4(0)
`23 (1)
`28 (2)
`27 (2)
`61 (6)
`l (l)
`
`16 (2)
`27 (2)
`30(3)
`48 (3)
`7(0)
`28 (5)
`
`10(1)
`17(5)
`
`21 (4)
`36(6)
`
`39(1)
`
`22 (l)
`26 (l)
`
`14 (2)
`
`*The analysis of adverse events excluded five patients who were never treated.
`
`tuzumab. Increasing age was the only base—line char—
`acteristic that was a significant risk factor for cardiac
`dysfunction in patients who were receiving the com—
`bination of an anthracycline, cyclophosphamide, and
`trastuzumab. The cumulative dose of anthracycline
`was not identified as a risk factor, but this finding
`should be interpreted with caution, since the majority
`of patients received all siX cycles of an anthracycline
`and cyclophosphamide as specified in the protocol.
`Adding trastuzumab to the chemotherapy regimen did
`not increase the risk of other adverse events related
`
`to chemotherapy, and in no patient were antibodies
`against trastuzumab detected.
`
`DISCUSSION
`
`We found that trastuzumab—based combination
`
`therapy was effective in that it reduced the relative
`risk of death by 20 percent at a median follow—up of
`30 months. Few studies of metastatic breast cancer
`
`have demonstrated a survival advantage of this mag—
`nit