The New England
`Journal of Medicine
`
`Copyr ight © 2001 by the Massachusetts Medical Societ y
`
`VOLUME 344
`
`M A R C H 15, 2001
`
`NUMBER 11
`
`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, M.D., 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 at 1 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.
`
`D
`
`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.1,2 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 gene,5-7 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.8-12 Laboratory studies indicate that
`amplification of HER2 has a direct role in the patho-
`genesis of these cancers,13-17 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.18-20
`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.J.S., M.P.); the Department of Oncology,
`McGill University, Montreal (B.L.-J.): Medical Affairs, Genentech, South
`San Francisco, Calif. (S.S., V.P., A.B.); IntraBiotics, Mountain View, Calif.
`(H.F.); the Department of Biostatistics, University of Washington, Seattle
`(T.F.); the Department of Obstetrics and Gynecology, Frauenklinik vom
`Roten Kreuz, Munich, Germany (W.E.); the Department of Oncology,
`Rush–Presbyterian–St. Luke’s Medical Center, Chicago (J.W.); the Depart-
`ment of Oncology, Hospital General Universitari Vall d’Hebron, Barcelo-
`na, Spain (J.B.); and the Department of Medical Oncology, Memorial
`Sloan-Kettering Cancer Center, New York (L.N.). Address reprint requests
`to Dr. Slamon at UCLA School of Medicine, Division of Hematology/
`Oncology, 11-244 Factor Bldg., 10833 Le Conte, Los Angeles, CA 90095-
`1678, or at dslamon@mednet.ucla.edu.
`*Additional study investigators are listed in the Appendix.
`
`N Engl J Med, Vol. 344, No. 11 · March 15, 2001 · www.nejm.org · 783
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`(cid:55)(cid:75)(cid:72)(cid:3)(cid:49)(cid:72)(cid:90)(cid:3)(cid:40)(cid:81)(cid:74)(cid:79)(cid:68)(cid:81)(cid:71)(cid:3)(cid:45)(cid:82)(cid:88)(cid:85)(cid:81)(cid:68)(cid:79)(cid:3)(cid:82)(cid:73)(cid:3)(cid:48)(cid:72)(cid:71)(cid:76)(cid:70)(cid:76)(cid:81)(cid:72)(cid:3)
`(cid:39)(cid:82)(cid:90)(cid:81)(cid:79)(cid:82)(cid:68)(cid:71)(cid:72)(cid:71)(cid:3)(cid:73)(cid:85)(cid:82)(cid:80)(cid:3)(cid:81)(cid:72)(cid:77)(cid:80)(cid:17)(cid:82)(cid:85)(cid:74)(cid:3)(cid:82)(cid:81)(cid:3)(cid:49)(cid:82)(cid:89)(cid:72)(cid:80)(cid:69)(cid:72)(cid:85)(cid:3)(cid:20)(cid:21)(cid:15)(cid:3)(cid:21)(cid:19)(cid:20)(cid:26)(cid:17)(cid:3)(cid:41)(cid:82)(cid:85)(cid:3)(cid:83)(cid:72)(cid:85)(cid:86)(cid:82)(cid:81)(cid:68)(cid:79)(cid:3)(cid:88)(cid:86)(cid:72)(cid:3)(cid:82)(cid:81)(cid:79)(cid:92)(cid:17)(cid:3)(cid:49)(cid:82)(cid:3)(cid:82)(cid:87)(cid:75)(cid:72)(cid:85)(cid:3)(cid:88)(cid:86)(cid:72)(cid:86)(cid:3)(cid:90)(cid:76)(cid:87)(cid:75)(cid:82)(cid:88)(cid:87)(cid:3)(cid:83)(cid:72)(cid:85)(cid:80)(cid:76)(cid:86)(cid:86)(cid:76)(cid:82)(cid:81)(cid:17)(cid:3)
`(cid:3)(cid:38)(cid:82)(cid:83)(cid:92)(cid:85)(cid:76)(cid:74)(cid:75)(cid:87)(cid:3)(cid:139)(cid:3)(cid:21)(cid:19)(cid:19)(cid:20)(cid:3)(cid:48)(cid:68)(cid:86)(cid:86)(cid:68)(cid:70)(cid:75)(cid:88)(cid:86)(cid:72)(cid:87)(cid:87)(cid:86)(cid:3)(cid:48)(cid:72)(cid:71)(cid:76)(cid:70)(cid:68)(cid:79)(cid:3)(cid:54)(cid:82)(cid:70)(cid:76)(cid:72)(cid:87)(cid:92)(cid:17)(cid:3)(cid:36)(cid:79)(cid:79)(cid:3)(cid:85)(cid:76)(cid:74)(cid:75)(cid:87)(cid:86)(cid:3)(cid:85)(cid:72)(cid:86)(cid:72)(cid:85)(cid:89)(cid:72)(cid:71)(cid:17)(cid:3)
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`(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)
`(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:28)
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`The New England Journal of Medicine
`
`fused to the framework region of human IgG
` and
`21
`tested against breast-cancer cells that overexpressed
`HER2 in vitro and in vivo.
` This antibody, called
`21,22
`trastuzumab, inhibited tumor growth when used
`alone
` but had synergistic effects
`when used in
`4
`20,22-24
`combination with cisplatin and carboplatin,
` do-
`20,23
`cetaxel,
` and ionizing radiation
` and additive effects
`24
`25
`when used with doxorubicin, cyclophosphamide,
`methotrexate, and paclitaxel.
`22-26
`Phase 1 clinical trials showed that the antibody is
`safe and confined to the tumor (unpublished data).
`Subsequent phase 2 trials demonstrated that many
`
`HER2-positive metastatic disease who
`women with
`had relapsed after chemotherapy had a response to
`; as suggested by the preclinical data,
`trastuzumab
`27,28
`the efficacy of trastuzumab when given with chemo-
`therapy was superior to its effectiveness when used
`alone.
` We report the results of a phase 3 trial in
`28,29
`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 HER2 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 HER2
`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 HER2 (referred to as a score of 2+)
`or more than moderate staining (referred to as a score of 3+) in
`more than 10 percent of tumor 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 of less 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 of 4 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 of disease 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 of objective response was analyzed
`with the use of normal approximation methods; a two-sided chi-
`square test was used to compare the groups.
`
`RESULTS
`
`Characteristics of the Patients
`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 J Med, Vol. 344, No. 11
`
`·
`
`March 15, 2001
`
`·
`
`www.nejm.org
`
`(cid:55)(cid:75)(cid:72)(cid:3)(cid:49)(cid:72)(cid:90)(cid:3)(cid:40)(cid:81)(cid:74)(cid:79)(cid:68)(cid:81)(cid:71)(cid:3)(cid:45)(cid:82)(cid:88)(cid:85)(cid:81)(cid:68)(cid:79)(cid:3)(cid:82)(cid:73)(cid:3)(cid:48)(cid:72)(cid:71)(cid:76)(cid:70)(cid:76)(cid:81)(cid:72)(cid:3)
`(cid:39)(cid:82)(cid:90)(cid:81)(cid:79)(cid:82)(cid:68)(cid:71)(cid:72)(cid:71)(cid:3)(cid:73)(cid:85)(cid:82)(cid:80)(cid:3)(cid:81)(cid:72)(cid:77)(cid:80)(cid:17)(cid:82)(cid:85)(cid:74)(cid:3)(cid:82)(cid:81)(cid:3)(cid:49)(cid:82)(cid:89)(cid:72)(cid:80)(cid:69)(cid:72)(cid:85)(cid:3)(cid:20)(cid:21)(cid:15)(cid:3)(cid:21)(cid:19)(cid:20)(cid:26)(cid:17)(cid:3)(cid:41)(cid:82)(cid:85)(cid:3)(cid:83)(cid:72)(cid:85)(cid:86)(cid:82)(cid:81)(cid:68)(cid:79)(cid:3)(cid:88)(cid:86)(cid:72)(cid:3)(cid:82)(cid:81)(cid:79)(cid:92)(cid:17)(cid:3)(cid:49)(cid:82)(cid:3)(cid:82)(cid:87)(cid:75)(cid:72)(cid:85)(cid:3)(cid:88)(cid:86)(cid:72)(cid:86)(cid:3)(cid:90)(cid:76)(cid:87)(cid:75)(cid:82)(cid:88)(cid:87)(cid:3)(cid:83)(cid:72)(cid:85)(cid:80)(cid:76)(cid:86)(cid:86)(cid:76)(cid:82)(cid:81)(cid:17)(cid:3)
`(cid:3)(cid:38)(cid:82)(cid:83)(cid:92)(cid:85)(cid:76)(cid:74)(cid:75)(cid:87)(cid:3)(cid:139)(cid:3)(cid:21)(cid:19)(cid:19)(cid:20)(cid:3)(cid:48)(cid:68)(cid:86)(cid:86)(cid:68)(cid:70)(cid:75)(cid:88)(cid:86)(cid:72)(cid:87)(cid:87)(cid:86)(cid:3)(cid:48)(cid:72)(cid:71)(cid:76)(cid:70)(cid:68)(cid:79)(cid:3)(cid:54)(cid:82)(cid:70)(cid:76)(cid:72)(cid:87)(cid:92)(cid:17)(cid:3)(cid:36)(cid:79)(cid:79)(cid:3)(cid:85)(cid:76)(cid:74)(cid:75)(cid:87)(cid:86)(cid:3)(cid:85)(cid:72)(cid:86)(cid:72)(cid:85)(cid:89)(cid:72)(cid:71)(cid:17)(cid:3)
`
`

`

`ANTI-HER2 MONOCLONAL ANTIBODY PLUS CHEMOTHERAPY FOR METASTATIC BREAST CANCER
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`T
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`ABLE
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` 1.
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` B
`
`ASE
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`-L
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`INE
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` C
`
`HARACTERISTICS
`
`
`
`OF
`
`
`
`THE
`
` P
`
`ATIENTS
`
`.
`
`C
`HARACTERISTIC
`
`Age — yr
`Mean ±SD
`Range
`Karnofsky score — no./no. analyzed (%)
`90–100
`60–80
`Median no. of positive lymph nodes
`at diagnosis
`Prior therapy — no./no. analyzed (%)
`Adjuvant chemotherapy
`Hormonal therapy (as adjuvant, for
`metastasis, or both)
`Radiotherapy (as adjuvant, for metas-
`tasis, or both)
`Median disease-free interval — mo
`Degree of overexpression of HER2
`— no./no. analyzed (%)‡
`2+
`3+
`No. of metastatic sites at enrollment
`— no./no. analyzed (%)
`«1
`2
`»3
`
`,
` A
`A
`NTHRACYCLINE
`N
`C
`,
`YCLOPHOSPHAMIDE
` T
`
`AND
`RASTUZUMAB
`(N=143)*
`
`
` A
`A
`AND
`NTHRACYCLINE
`N
`C
`
`YCLOPHOSPHAMIDE
`A
`LONE
`(N=138)†
`
`
`
`P
`ACLITAXEL
`AND
`T
`RASTUZUMAB
`(N=92)
`
`
`
`P
`ACLITAXEL
`A
`LONE
`(N=96)
`
`54±10.3
`27–76
`
`91/138 (66)
`47/138 (34)
`1.0
`
`54±10.1
`25–75
`
`89/135 (66)
`46/135 (34)
`0.5
`
`51±11.5
`25–77
`
`51±11.0
`26–73
`
`68/90 (76)
`22/90 (24)
`5.0
`
`61/94 (65)
`33/94 (35)
`6.0
`
`81/142 (57)
`88/142 (62)
`
`50/136 (37)
`76/134 (57)
`
`88/91 (97)
`49/89 (55)
`
`95/95 (100)
`53/95 (56)
`
`69/143 (48)
`
`76/136 (56)
`
`60/89 (67)
`
`72/95 (76)
`
`24.5
`
`22.8
`
`22.4
`
`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)
`
`48/143 (34)
`38/143 (27)
`57/143 (40)
`
`49/136 (36)
`48/136 (35)
`39/136 (29)
`
`31/91 (34)
`32/91 (35)
`28/91 (31)
`
`27/95 (28)
`35/95 (37)
`33/95 (35)
`
`*Twenty of these patients received epirubicin rather than doxorubicin.
`†Sixteen of these patients received epirubicin rather than doxorubicin.
`‡A score of 2+ indicated that more than 10 percent of tumor cells had weak-to-moderate staining of the entire mem-
`brane for HER2 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 differences 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 J Med, Vol. 344, No. 11
`
`·
`
`March 15, 2001
`
`·
`
`www.nejm.org
`
`·
`
`785
`
`(cid:55)(cid:75)(cid:72)(cid:3)(cid:49)(cid:72)(cid:90)(cid:3)(cid:40)(cid:81)(cid:74)(cid:79)(cid:68)(cid:81)(cid:71)(cid:3)(cid:45)(cid:82)(cid:88)(cid:85)(cid:81)(cid:68)(cid:79)(cid:3)(cid:82)(cid:73)(cid:3)(cid:48)(cid:72)(cid:71)(cid:76)(cid:70)(cid:76)(cid:81)(cid:72)(cid:3)
`(cid:39)(cid:82)(cid:90)(cid:81)(cid:79)(cid:82)(cid:68)(cid:71)(cid:72)(cid:71)(cid:3)(cid:73)(cid:85)(cid:82)(cid:80)(cid:3)(cid:81)(cid:72)(cid:77)(cid:80)(cid:17)(cid:82)(cid:85)(cid:74)(cid:3)(cid:82)(cid:81)(cid:3)(cid:49)(cid:82)(cid:89)(cid:72)(cid:80)(cid:69)(cid:72)(cid:85)(cid:3)(cid:20)(cid:21)(cid:15)(cid:3)(cid:21)(cid:19)(cid:20)(cid:26)(cid:17)(cid:3)(cid:41)(cid:82)(cid:85)(cid:3)(cid:83)(cid:72)(cid:85)(cid:86)(cid:82)(cid:81)(cid:68)(cid:79)(cid:3)(cid:88)(cid:86)(cid:72)(cid:3)(cid:82)(cid:81)(cid:79)(cid:92)(cid:17)(cid:3)(cid:49)(cid:82)(cid:3)(cid:82)(cid:87)(cid:75)(cid:72)(cid:85)(cid:3)(cid:88)(cid:86)(cid:72)(cid:86)(cid:3)(cid:90)(cid:76)(cid:87)(cid:75)(cid:82)(cid:88)(cid:87)(cid:3)(cid:83)(cid:72)(cid:85)(cid:80)(cid:76)(cid:86)(cid:86)(cid:76)(cid:82)(cid:81)(cid:17)(cid:3)
`(cid:3)(cid:38)(cid:82)(cid:83)(cid:92)(cid:85)(cid:76)(cid:74)(cid:75)(cid:87)(cid:3)(cid:139)(cid:3)(cid:21)(cid:19)(cid:19)(cid:20)(cid:3)(cid:48)(cid:68)(cid:86)(cid:86)(cid:68)(cid:70)(cid:75)(cid:88)(cid:86)(cid:72)(cid:87)(cid:87)(cid:86)(cid:3)(cid:48)(cid:72)(cid:71)(cid:76)(cid:70)(cid:68)(cid:79)(cid:3)(cid:54)(cid:82)(cid:70)(cid:76)(cid:72)(cid:87)(cid:92)(cid:17)(cid:3)(cid:36)(cid:79)(cid:79)(cid:3)(cid:85)(cid:76)(cid:74)(cid:75)(cid:87)(cid:86)(cid:3)(cid:85)(cid:72)(cid:86)(cid:72)(cid:85)(cid:89)(cid:72)(cid:71)(cid:17)(cid:3)
`
`

`

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`
`
`The New England Journal of Medicine
`
`T
`
`ABLE
`
` 2.
`
` R
`
`ESULTS
`
`
`
`OF
`
`
`
`AN
`
` I
`
`NTENTION
`
`-
`
`TO
`
`-T
`
`REAT
`
` A
`
`NALYSIS
`
`
`
`OF
`
`
`
`THE
`
` E
`
`ND
`
` P
`
`OINTS.*
`
`END POINT
`
`Median time to disease progression
`— mo
`P value
`Relative risk of progression
`(95% CI)
`Median time to treatment failure
`— mo
`P value
`Relative risk of treatment failure
`(95% CI)
`Median survival — mo
`P value
`Relative risk of death (95% CI)
`
`CHEMOTHERAPY
`PLUS
`TRASTUZUMAB
`(N=235)
`
`EITHER TYPE OF
`CHEMOTHERAPY
`ALONE
`(N=234)
`
`AN ANTHRACYCLINE,
`CYCLOPHOSPHAMIDE,
`AND TRASTUZUMAB
`(N=143)
`
`AN ANTHRACYCLINE
`AND
`CYCLOPHOSPHAMIDE
`ALONE
`(N=138)
`
`PACLITAXEL AND
`TRASTUZUMAB
`(N=92)
`
`PACLITAXEL
`ALONE
`(N=96)
`
`7.4
`
`4.6
`
`7.8
`
`<0.001
`0.51 (0.41–0.63)
`
`<0.001
`0.62 (0.47–0.81)
`
`6.9
`
`4.5
`
`7.2
`
`6.1
`
`5.6
`
`<0.001
`0.58 (0.47–0.70)
`
`25.1
`
`20.3
`
`0.046
`0.80 (0.64–1.00)
`
`<0.001
`0.67 (0.52–0.86)
`
`26.8
`
`0.16
`0.82 (0.61–1.09)
`
`21.4
`
`6.9
`
`3.0
`
`<0.001
`0.38 (0.27–0.53)
`
`5.8
`
`2.9
`
`<0.001
`0.46 (0.33–0.63)
`
`22.1
`
`18.4
`
`0.17
`0.80 (0.56–1.11)
`
`*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 follow-up of 35 months (range, 30 to 51). As of the data-cutoff 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 response-evaluation committee as-
`sessed the tumor response in 446 patients: 99 percent of the 452 patients who had an assessment after the base-line 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 J Med, Vol. 344, No. 11
`
`·
`
`March 15, 2001
`
`·
`
`www.nejm.org
`
`(cid:55)(cid:75)(cid:72)(cid:3)(cid:49)(cid:72)(cid:90)(cid:3)(cid:40)(cid:81)(cid:74)(cid:79)(cid:68)(cid:81)(cid:71)(cid:3)(cid:45)(cid:82)(cid:88)(cid:85)(cid:81)(cid:68)(cid:79)(cid:3)(cid:82)(cid:73)(cid:3)(cid:48)(cid:72)(cid:71)(cid:76)(cid:70)(cid:76)(cid:81)(cid:72)(cid:3)
`(cid:39)(cid:82)(cid:90)(cid:81)(cid:79)(cid:82)(cid:68)(cid:71)(cid:72)(cid:71)(cid:3)(cid:73)(cid:85)(cid:82)(cid:80)(cid:3)(cid:81)(cid:72)(cid:77)(cid:80)(cid:17)(cid:82)(cid:85)(cid:74)(cid:3)(cid:82)(cid:81)(cid:3)(cid:49)(cid:82)(cid:89)(cid:72)(cid:80)(cid:69)(cid:72)(cid:85)(cid:3)(cid:20)(cid:21)(cid:15)(cid:3)(cid:21)(cid:19)(cid:20)(cid:26)(cid:17)(cid:3)(cid:41)(cid:82)(cid:85)(cid:3)(cid:83)(cid:72)(cid:85)(cid:86)(cid:82)(cid:81)(cid:68)(cid:79)(cid:3)(cid:88)(cid:86)(cid:72)(cid:3)(cid:82)(cid:81)(cid:79)(cid:92)(cid:17)(cid:3)(cid:49)(cid:82)(cid:3)(cid:82)(cid:87)(cid:75)(cid:72)(cid:85)(cid:3)(cid:88)(cid:86)(cid:72)(cid:86)(cid:3)(cid:90)(cid:76)(cid:87)(cid:75)(cid:82)(cid:88)(cid:87)(cid:3)(cid:83)(cid:72)(cid:85)(cid:80)(cid:76)(cid:86)(cid:86)(cid:76)(cid:82)(cid:81)(cid:17)(cid:3)
`(cid:3)(cid:38)(cid:82)(cid:83)(cid:92)(cid:85)(cid:76)(cid:74)(cid:75)(cid:87)(cid:3)(cid:139)(cid:3)(cid:21)(cid:19)(cid:19)(cid:20)(cid:3)(cid:48)(cid:68)(cid:86)(cid:86)(cid:68)(cid:70)(cid:75)(cid:88)(cid:86)(cid:72)(cid:87)(cid:87)(cid:86)(cid:3)(cid:48)(cid:72)(cid:71)(cid:76)(cid:70)(cid:68)(cid:79)(cid:3)(cid:54)(cid:82)(cid:70)(cid:76)(cid:72)(cid:87)(cid:92)(cid:17)(cid:3)(cid:36)(cid:79)(cid:79)(cid:3)(cid:85)(cid:76)(cid:74)(cid:75)(cid:87)(cid:86)(cid:3)(cid:85)(cid:72)(cid:86)(cid:72)(cid:85)(cid:89)(cid:72)(cid:71)(cid:17)(cid:3)
`
`

`

`ANTI-HER2 MONOCLONAL ANTIBODY PLUS CHEMOTHERAPY FOR METASTATIC BREAST CANCER
`
`Chemotherapy plus trastuzumab
`
`P<0.001
`
`Chemotherapy alone(cid:2)
`(cid:2)
`
`0
`
`5
`
`10
`15
`Months after Enrollment
`
`20
`
`25
`
`100
`90
`80
`70
`60
`50
`40
`30
`20
`10
`0
`
`Progression-free Survival (%)
`
`A
`
`15(cid:2)
`
`(cid:2) 6
`
`235(cid:2)
`(cid:2)
`234
`
`152(cid:2)
`(cid:2)
`103
`
`63(cid:2)
`(cid:2)
`25
`
`NO. AT RISK
`Chemotherapy(cid:2)
`plus trastuzumab(cid:2)
`Chemotherapy alone(cid:2)
`(cid:2)
`
`Anthracycline, cyclophosphamide,(cid:2)
`and trastuzumab(cid:2)
`
`(cid:2)
`
`P<0.001
`
`Anthracycline and cyclo-(cid:2)
`phosphamide alone(cid:2)
`
`(cid:2)
`
`10
`15
`Months after Enrollment
`
`20
`
`25
`
`12(cid:2)
`
`(cid:2) 6
`
`40(cid:2)
`(cid:2)
`20
`
`5
`
`98(cid:2)
`(cid:2)
`77
`
`100
`90
`80
`70
`60
`50
`40
`30
`20
`10
`0
`
`Progression-free Survival (%)
`
`0
`
`B
`
`NO. AT RISK
`Anthracycline, cyclophos-Ł
`phamide, and trastuzumab(cid:2)
`Anthracycline and cyclo-(cid:2)
`phosphamide alone(cid:2)
`
`(cid:2)
`
`143(cid:2)
`(cid:2)
`138
`
`Paclitaxel and trastuzumab(cid:2)
`(cid:2)
`
`P<0.001
`
`10
`15
`Months after Enrollment
`
`20
`
`25
`
`23(cid:2)
`
`(cid:2) 5
`
`Paclitaxel alone(cid:2)
`(cid:2)
`
`0
`
`92(cid:2)
`(cid:2)
`96
`
`5
`
`54(cid:2)
`(cid:2)
`26
`
`100
`90
`80
`70
`60
`50
`40
`30
`20
`10
`0
`
`Progression-free Survival (%)
`
`C
`
`NO. AT RISK
`Paclitaxel and(cid:2)
`trastuzumab(cid:2)
`Paclitaxel alone(cid:2)
`(cid:2)
`
`N Engl J Med, Vol. 344, No. 11 · March 15, 2001 · www.nejm.org · 787
`
`(cid:55)(cid:75)(cid:72)(cid:3)(cid:49)(cid:72)(cid:90)(cid:3)(cid:40)(cid:81)(cid:74)(cid:79)(cid:68)(cid:81)(cid:71)(cid:3)(cid:45)(cid:82)(cid:88)(cid:85)(cid:81)(cid:68)(cid:79)(cid:3)(cid:82)(cid:73)(cid:3)(cid:48)(cid:72)(cid:71)(cid:76)(cid:70)(cid:76)(cid:81)(cid:72)(cid:3)
`(cid:39)(cid:82)(cid:90)(cid:81)(cid:79)(cid:82)(cid:68)(cid:71)(cid:72)(cid:71)(cid:3)(cid:73)(cid:85)(cid:82)(cid:80)(cid:3)(cid:81)(cid:72)(cid:77)(cid:80)(cid:17)(cid:82)(cid:85)(cid:74)(cid:3)(cid:82)(cid:81)(cid:3)(cid:49)(cid:82)(cid:89)(cid:72)(cid:80)(cid:69)(cid:72)(cid:85)(cid:3)(cid:20)(cid:21)(cid:15)(cid:3)(cid:21)(cid:19)(cid:20)(cid:26)(cid:17)(cid:3)(cid:41)(cid:82)(cid:85)(cid:3)(cid:83)(cid:72)(cid:85)(cid:86)(cid:82)(cid:81)(cid:68)(cid:79)(cid:3)(cid:88)(cid:86)(cid:72)(cid:3)(cid:82)(cid:81)(cid:79)(cid:92)(cid:17)(cid:3)(cid:49)(cid:82)(cid:3)(cid:82)(cid:87)(cid:75)(cid:72)(cid:85)(cid:3)(cid:88)(cid:86)(cid:72)(cid:86)(cid:3)(cid:90)(cid:76)(cid:87)(cid:75)(cid:82)(cid:88)(cid:87)(cid:3)(cid:83)(cid:72)(cid:85)(cid:80)(cid:76)(cid:86)(cid:86)(cid:76)(cid:82)(cid:81)(cid:17)(cid:3)
`(cid:3)(cid:38)(cid:82)(cid:83)(cid:92)(cid:85)(cid:76)(cid:74)(cid:75)(cid:87)(cid:3)(cid:139)(cid:3)(cid:21)(cid:19)(cid:19)(cid:20)(cid:3)(cid:48)(cid:68)(cid:86)(cid:86)(cid:68)(cid:70)(cid:75)(cid:88)(cid:86)(cid:72)(cid:87)(cid:87)(cid:86)(cid:3)(cid:48)(cid:72)(cid:71)(cid:76)(cid:70)(cid:68)(cid:79)(cid:3)(cid:54)(cid:82)(cid:70)(cid:76)(cid:72)(cid:87)(cid:92)(cid:17)(cid:3)(cid:36)(cid:79)(cid:79)(cid:3)(cid:85)(cid:76)(cid:74)(cid:75)(cid:87)(cid:86)(cid:3)(cid:85)(cid:72)(cid:86)(cid:72)(cid:85)(cid:89)(cid:72)(cid:71)(cid:17)(cid:3)
`
`

`

`The New England Journal of Medicine
`
`TABLE 3. RATES AND DURATIONS OF RESPONSES.*
`
`VARIABLE
`
`Complete response — no. (%)
`Partial response — no. (%)
`Complete and partial responses
`— no. (% [95% CI])
`P value
`Median duration of response
`— mo
`P value
`
`CHEMOTHERAPY PLUS
`TRASTUZUMAB
`(N=235)
`
` CHEMOTHERAPY
`ALONE
`(N=234)
`
`AN ANTHRACYCLINE,
`CYCLOPHOSPHAMIDE,
`AND TRASTUZUMAB
`(N=143)
`
`AN ANTHRACYCLINE
`AND
`CYCLOPHOSPHAMIDE
`ALONE
`(N=138)
`
`PACLITAXEL AND
`TRASTUZUMAB
`(N=92)
`
`PACLITAXEL
`ALONE
`(N=96)
`
`18 (8)
`100 (43)
`118 (50 [44–57])
`
`8 (3)
`66 (28)
`74 (32 [26–38])
`
`11 (8)
`69 (48)
`80 (56 [48–64])
`
`6 (4)
`52 (38)
`58 (42 [34–50])
`
`7 (8)
`31 (34)
`38 (41 [31–51])
`
`2 (2)
`14 (15)
`16 (17 [9–24])
`
`9.1
`
`<0.001
`
`<0.001
`
`6.1
`
`9.1
`
`0.02
`
`0.005
`
`6.7
`
`10.5
`
`4.5
`
`<0.001
`
`<0.01
`
`*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,