Seminars in 4
`Oncology
`
`D7
`
` l M
`
`. D. Anderson Conference on Trastuzumab (Herceptin)
`
`Gabriel N. Hortobagyi, MD, Guest Editor
`
`VOL 26, NO 4, SUPPL 12
`
`AUGUST 1999
`
`
`
`Current Management of Metastatic Breast Cancer
`Edith A. Perez“
`
`Contents
`
`Recent Developments in Breast Cancer Therapy
`Gabriel N. Hortobagyi,* MiewChie Hung,* and Aman U. Buzdar*
`Recent Advances in Adjuvant Therapy of Breast Cancer
`Aman U. Buzdar* and Gabriel N. Hortobagyi*
`Biological Therapies for Breast Carcinoma: Concepts for Improvement in Survival
`Ernest C. Borden, Laura Esserman, Daniel J. Linde'r, Michael]. Campbell,
`and Amy M Fulton
`An Overview of Monoclonal Antibody Therapy of Cancer
`Louis M. Weiner
`
`1
`
`11
`
`21
`
`28
`
`41
`
`51
`
`BaSic Science of HERvZ/neu: A Review
`MiewChie Hung* and Yiu—Keung Lau
`Nonclinical Studies Addressing the Mechanism of Action of Trastuzumab (Herceptin)
`Mark X. Sliwkowski,* Julie A. Lofg'ren,* Gail D. Lewis,* Timothy E. Hotaling,*
`Brian M. Fendly,* and Judith A. Fox*
`OVervrew of the Trastuzumab (Herceptin) Anti—HERZ Monoclonal Antibody Clinical
`Program in HERZ—Overexpressing Metastatic Breast Cancer
`71
`Steven Shak,* for the Hercepn'n Multinational Investigator Study Group
`Genentech 2111
`Phase II Study of Weekly Intravenous Trastuzumab (Herceptin) in Patients With
`Hospira V. Genentech
`HERZ/neu'Overexpressing Metastatic Breast Cancer
`'
`lPR2017-00737
`José Baselga,* Debasish Tripathy, John Mendelsohn, Sharon Baughmann Christopher C. Benz,
`Lucy Dantis, Nancy T. Sklarin, Andrew D. Seidman, Clifford A. Hudls, Jackie Moore,
`Paul P. Rosen, Thomas Twaddell, 1. Craig Henderson, and Larry Norton
`78
`
`60
`
`ich, in the context of their presentation“), could be perceived as
`.
`' These faculty have indicated that they have a relationship wh
`honoraria or consulting fees, or direct research support from a
`a potential conflict of interest (eg, ownership of stock, significant
`commercial organization).
`% A.
`
`Genentech 2111
`Hospira v. Genentech
`IPR2017-00737
`
`1
`
`

`

`HealthrRelated Quality of Life in Women With Metastatic Breast Cancer Treated With
`Trastuzumab (Herceptin)
`David Osoba* and Michael Burchmore
`
`Combination Therapy With Trastuzumab (Herceptin) and Cisplatin for Chemoresistant
`Metastatic Breast Cancer: Evidence for Receptor'Enhanced Chemosensitivity
`Mark D. Pegram* and Dennis J. Slamon
`.
`
`Cardiotoxicity in Patients Receiving Trastuzumab (Herceptin): Primary Toxicity, Synergistic
`or Sequential Stress, or Surveillance Artifact?
`Michael-S. Ewer, Harry R. Gibbs, Joseph Swafford,* and Robert S. Benjamin
`
`Issues in the Design of Clinical Trials: Insights From the Trastuzumab (Herceptin)
`Experience
`Thomas R. Fleming"
`
`The Role of Immunohistochemistry and Fluorescence In Situ Hybridization for HER—Zlneu in
`Assessing the Prognosis of Breast Cancer
`Malcolm S. Mitchell and Michael F. Press
`
`-
`
`Should HERZ Status Be Routinely Measured for All Breast Cancer Patients?
`Peter M. Ravdin*
`
`CME Test
`
`Faculty Disclosure
`
`Unlabeled Uses of Commercial Products or Investigational Uses Not Yet Approved
`
`84
`
`89
`
`96
`
`102
`
`108
`
`117
`
`124
`
`134
`
`135
`
`2
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`

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`Page 2 of 8
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`Smog
`
`Overview of the Trastuzumab (Herceptin) Anti-HER2
`Monoclonal Antibody Clinical Program in HER2-Overexpressing
`Metastatic Breast Cancer
`
`Steven Shak. for the Herceptin Multinational Investlgator Study Group
`
`The recombinant humanized antl-HERI monoclonal
`antibody trastuzumab (Herceptln; Genentech. San
`Francisco, CA) was evaluated in human clinical trials
`for treatment of women with metamtic breast cancer
`who have tumors that overexpress HERl. The trastu-
`zumab clinical program consisted ofa series of phase I,
`phase II, and phase ill clinical trials. Clinical experience
`with this novel biologic has been obtained in more than
`I,DOO women with HERZ-overexpressing metastatic
`breast cancer. Twa pivotal trials were performed to
`evaluate trastuzumab efflcacy and safety: (I) trastu-
`zumab in combination with chemotherapy as first-line
`therapy and (2) trastuzumab as a single agent in sec-
`ond- and third-line chemotherapy. Preliminary results
`of the pivotal clinical trials that have been presented at
`national meetings are summarized below. The data
`suggest that trastu1umab will be an important new
`treatment option for women with HER2~overexpress-
`ing memtatic breast cancer.
`Semin Oncol 26 (Suppl
`l2):7l—77. Copyrlght © l999 by
`W.B. Saunders Company.
`
`ESPITE ADVANCES in early detection and
`surgical and adjuvant therapy of breasr cane
`cer, more than 43,000 women die of metastatic
`disease each year."2 Recently, a large number of
`acquired or inherited genetic defects have been
`discovered that likely play a role not only in the
`pathogenesis of malignancies, but also in their
`response to treatment. it is hoped. that a better
`underscanding of the molecular basis of cancer will
`lead to novel targeted approaches to cancer prcr
`vention and treatment.
`
`Growth factors and their receptors are known to
`play critical roles in development, cell growth, and
`differentiation. Overexpression of human epider‘
`mal growth factor receptor-2 (HERZ) prorein is
`observed in 25% to 30% of breast cancers.3'5 In
`most cases. overexpression of HER2 protein results
`from amplification of the HERZ gene. HERZ over—
`expression has been correlated with more aggres—
`sive disease and shortened Survival
`in patients
`with breast and other cancers.‘*‘7
`Several lines of evidence indicate a direct role
`for HERZ overexpression in the aggressive clinical
`course of HERZ—ovcrcxpressing human tumors.
`First, when the human HERZ gene is transfected
`into the mouse fibroblast cells (NIH—3'13) it causes
`cellular transformation; the resulting cells are me
`
`Sam/nor: in Oncology, Vol 26. No 4. Suppl
`
`l2 (August). I999: pp 7 I-77
`
`morigenic in the nude mouse.8 Second. studies
`using the rat neu gene to generate transgenic mice
`have revealed that animals expressing high levels
`of the mutated neu gene as well as the nonmutated
`neu gene develop breast cancer.9 These data are
`consistent with a direct role for HERZ in tumori-
`
`genicity and indicate a potential oncogene target
`for cancer therapy.
`Highly specific murine monoclonal antibodies
`that bind to the extracellular domain of HERZ
`
`were generated.10 The most potent growth’in—
`hibitory antibody, muMAb 4D5, was humanized
`to allow for chronic human administration.“
`
`Preclinical pharmacology studies indicate that
`antibodies to HERZ possess potent antitumor
`activity.”"3 Antibodies probably exert
`their
`therapeutic effect through several mechanisms.
`They may antagonize
`the function of
`the
`growth—signaling properties of the HERZ system
`and directly inhibit the growth of cancer cells.
`They also may enlist immune cells to attack and
`kill
`the tumor target and/or augment chemo—
`therapycinduced cytotoxicity.
`Based on these data, the recombinant humanv
`ized anti-HERZ monoclonal antibody trastuzumab
`(l-lerceptin; Genentech, San Francisco, CA) was
`evaluated in human clinical trials for efficacy and
`safety as a new treatment option for women with
`metastatic breast cancer who have tumors that
`
`overcxpress HERZ.
`
`OVERVIEW OF THE CLINICAL PROGRAM
`
`The trastuzumab clinical program consisted of a
`series of phase I, phase ll, and phase Ill clinical
`trials. Based on the large unmet medical need, the
`scientific rationale. and the preclinical studies, the
`focus of the clinical program was in patients with
`
`
`From the Department of BioOncolog-y, Medical Affairs, Gena»
`tech, lnc, South San Francisco, CA.
`Dr Shak is an employee of Gcncntcch, Inc.
`Address reprint requests to Steven Slmk, MD. Department of
`BioOnmlogy, Medical Affairs, Genentech,
`inc.
`1 DNA Way,
`Saudi San Francisco, CA 940804990.
`Copyright © 1999 by W3. Samulers Company
`0093v7754/99/2604—l 205$10.00/0
`
`7i
`
`3
`
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`’2
`
`STEVEN SHAK
`
`metastatic breast cancer who had tumors that
`Jverexprcssed HERZ. Except for a small number of
`patients with cancers other than breast cancer in
`phase l.
`the clinical
`trials were performed in
`women with metastatic breast cancer. In addition,
`all patients enrolled had rumors
`that overex-
`pressed HERE, as determined by immunocl‘tcmistry
`performed by a centralized core research labora—
`tory.
`
`PHASE I CLINICAL TRIALS
`
`trials
`clinical
`I
`phase
`open—label
`Three
`(l-IO407g. H0452g, and l-IO453g) were performed
`primarily to evaluate the safety of trastuzuinab in
`patients with refractory cancer (Table 1). The
`intravenous (IV) route of administration was se—
`lected to assure consistent systemic delivery of the
`recombinant protein. The schedule of weekly ad—
`ministration was based on the clearance of the
`antibody in preclinical Studies. Weekly infusions
`were maintained in the absence of disease progres—
`sion.
`The first phase I trial (H0407g) evaluated the
`safety and pl‘im'macokinetics of a single dose of
`trastuzumab. The selection of the low—dose and
`dose escalation plan was based on preclinical phar—
`macological studies. The two additional phase I
`studies,
`trastuzumab as a single agent (H0452g)
`and trasruzumab plus cisplatin (H0453g), evalu-
`ated the safety and phannacokinetics of multiple
`doses. The selecrion of cisplatin was based on
`available preclinical data that demonstrated excelv
`lent activity with that particular combination.l4
`Trastuzumab was well tolerated with repeated
`weekly lV administration of doses ranging from 10
`to 500 mg. Grade 3 and 4 adverse events were few
`
`and included those that would be expected in this
`patient population. Serious adverse events were
`reported in four patients; none of these events was
`considered to be related to trasruzumnb treatment.
`Trastuzumab coadministered with cisplatin was
`generally well tolerated. Adverse events that have
`been previously described to occur with cisplatin
`treatment alone at
`the doses used in this study
`were observed. Nausea and vomiting were ob
`served in almost all patients enrolled in the Study
`and 10 patients reported problems with hearing.
`Myelosuppression was observed in five of the 15
`patients. The frequency of these events was similar
`to previously described clinical experience with
`cisplatin alone.
`The serum half—life of trastuzumab increased
`with increasing dose; it ranged from approximately
`1 tiay in the low»dose group (10 mg) to 2 weeks in
`the highest dose group (500 mg). Concomitant
`administration ofcisplatin (50 or 100 mg/mz) with
`trastuzumab did not affect trastuzumab pharmaco—
`kinetics.
`No antibodies to trastuzumab were observed.
`
`PHASE II CLINICAL TRIALS
`
`Two open—label phase II clinical trials were per—
`formed to evaluate the anticancer activity and
`safety of trastuzumab as a single agent (H055 1g)
`and trastuzuinab plus cisplatin (HOSSZg) (Table
`2).‘5-”J One single—agent study is reviewed in detail
`elsewhere in this supplement.”
`As in the phase I studies.
`the population for
`these trials consisted of patients with refractory
`cancer. The doses and schedule were Selected
`based on the pharmacolcinetic parameters oh
`mined in the phase l
`trials.
`in these and subser
`
`Table I. 'Trastuzumah Phase I Trials
`
`IO-SOO mg
`
`First patient enrolled
`Last patient enrolled
`Enrollment status
`Enrollment
`
`Age range (yr)
`Design
`Treated
`Dose
`
`Abbreviation: IV. Intravenous.
`
`June I. I992
`july 27. I997.
`Complete
`
`l6
`
`29—67
`Open-label
`Trastuzumab alone
`Single-dose. IV. IO-500 mg
`
`November 9. I992
`March 4. I993
`Complete
`
`l7
`30—7I
`
`Open-label
`Trastuzumab alone
`
`Weekly. IV. III-500 mg
`
`October 6. I992
`October 26. W92
`Complete
`
`I5
`40-7l
`
`Open-label
`Trastmumab + clsplarin
`Weakly. IV.
`
`4
`
`

`

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`TRASTUZUMAB CLINICAL TRIALS
`
`73
`
`Table 2. Trastuzumab I’hase II Trial: '
`
`’
`
`
`
`Flrst patient enrolled
`Last patlent enrolled
`Enrollment status
`Enrollment
`
`Age range (yr)
`Deslgn
`Treated
`
`Dose
`
`I993
`March I5.
`June 14. I994
`Complete
`46
`30-65
`
`Open-label .
`Trastuzumab
`
`alone
`250 mg IV
`IOU
`(loading),
`mg IV weekly
`
`March 31, 1993
`May 25.
`i994
`Complete
`39
`29-75
`
`Open-label
`Trastuzurnab -I-
`
`clsplatln
`250 mg IV
`(Iaadlng). I00
`mg IV weekly
`
`the
`quent studies, a loading dose was used for
`initial infusion to achieve therapeutic levels more
`rapidly. The end point of objective tumor response
`was selected as the efficacy and point. The weekly
`infusions of trastuzumab were maintained in the
`
`absence of disease progression. Results of the phase
`II studies indicated that trasruzumab has activity
`in metastatic breast cancer and was generally well
`tolerated. Infusionvassociatecl adverse events, con—
`
`sisting primarily of fever and chills, were observed.
`
`PIVOTAL CLINICAL TRIALS
`
`The phase III program was designed with exten-
`sive input from the Food and Drug Administration
`and from investigators. The goals were to establish
`the benefits and risks of trastuzumab in metastatic
`breast cancer administered either in combination
`
`with chemotherapy or as a single agent.
`
`Trrts'tuzumab in Combination With Chemotherapy
`
`To determine the efficacy and safety of trastu—
`zumah in combination with chemotherapy in firStr
`line treatment
`for patients with HERZ—overex—
`pressing metasratic breast cancer, a randomized,
`placeboaconttolled phase III trial (H0648g) was
`designed and implemented (Table 3).18 The opv
`tion of using cisplatin in this phase III program was
`discarded because this agent was not commonly
`used as first—line treatment. The initial study der
`sign evaluated trasruzumab with anthracycline
`(doxorubicin
`or
`epirubicin)/cyclophosphaniide
`(AC) compared with AC alone. This anthracya
`Cline—based regimen was selected because it was
`considered the most effective chemotherapy regi'
`men for first-line treatment, and its use in combir
`
`nation with trastuzumab was supported by preclinv
`icnl studies.
`
`Enrollment to the original protocol was slow.
`First, many patients with HERZ—overexpressing
`primary breasr cancer were treated with anthracy—
`clines in the adjuvant setting and on relapse were
`ineligible for the trial. Second, experience showed
`that patients and their physicians were often un—
`willing to participate in a trial in which subjects
`could receive weekly placebo infusions for a seri-
`ous and lifErthreatening illness. The trial design
`was therefore amended to that of an ope-n’label,
`randomized, controlled trial. Patients who had
`been treated with anthracyclines in the adjuvant
`setting were eligible for the trial. Randomization of
`the patients without prior nnthracycline treatment
`was to trastuzumab plus AC or to AC alone. Ranv
`domization of patients with prior anthracycline
`treatment in the adjuvant setting was to trastuv
`zumab plus paclitaxel or to paelitaxel alone. Pac'
`litaxel was selected because of its activity in metv
`astatic breast cancer and preclinical studies that
`supported its use.'2
`Doxorubicin 80 mg/m2 or epirubicin 75 rug/mz
`was administered by IV bolus or infusion over a
`maximum period of 2 hours. Cyclophosphamide
`600 trig/mZ was administered in combination with
`one of the above anthracyclines by IV bolus or
`infusion over a maximum of 2 hours. Paclitaxel
`
`,
`
`Table}. Trastuzurnab Combination With
`, Chemotherapy CIinicnlITrIaI H0648g (Finis III)
`
`I995
`lune I2.
`Date first patient enroiled
`Date last patient enrolled March 7, I997
`Enrollment status
`Complete
`Enrollment
`
`469
`
`cyciophosphamide.
`
`Age range (yr)
`Design
`Control
`Treated
`
`Dose/schedule
`
`Patio“ population
`
`25-77
`Open-label. randomized
`Chemotherapy (AC or paclitnel)
`Tmstmurnab + chemotherapy
`(AC or paclimer)
`4 mglkg IV (loading dose), 1 mg!
`kg IV weekly until disease
`progrssion
`HERZ-ovcrcxpressing metastatic
`breast cancer First-line:
`
`No prior thematherapy for
`metastatic diseas:
`
`Abbreviation: AC. anthracytline Idoxorubicln or epirubiciny
`
`5
`
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`74
`
`STEVEN SHAK
`
`175 trig/mz was administered by lV infusion over 3
`hours after premedication with dexamethasone
`(20 mg orally 12 and 6 hours prior), diphenhydra-
`mine (50 mg iv subcutaneously 30 minutes prior).
`and cimetidine (300 mg IV 30 minutes prior).
`Chemotherapy was repeated every 3 weeks for six
`cycles. Additional cycles of chemotherapy could
`be administered at the discretion of the investiga—
`tor.
`
`Trastuzumab was administered intravenously as
`a loading dose of 4 rug/kg, followed by a weekly
`maintenance dose of 2 rug/kg. The first infusion
`was administered over 90 minutes and 24 hours
`
`before chemotherapy. if an infusion was well tol—
`erared. subsequent infusion periods were shortened
`to 30 minutes and given on the same day as
`chemorherapy. The 2 mg/kg weekly dose was con—
`tinued until disease progression without dosage
`modification.
`
`This multinational trial was performed at more
`than 150 clinical sites in 14 countries. Four hun-
`dred sixty-nine women were enrolled. The primary
`end points were time to disease progression and
`the further characterization of the safety profile of
`trastuzumab. The secondary end points of this trial
`were response rate.
`reSponse duration,
`time to
`treatment failure, and 1—year survival.
`To ensure objective and unbiased assessment of
`the primary and secondary tumor response end
`points, an independent response evaluation com—
`mirror: was created. Reading teams consisting of an
`oncologist and a radiologist evaluated cases during
`the course of the trial and remained blinded to
`
`treatment assignment. Patients who developed dis-
`ease progression as determined by the independent
`response evaluation committee had the option of
`entering a nonrandomized, openrlabei extension
`trial in which trastuzumab was administered alone
`or in combination with other breast cancer there
`
`apies.
`The preliminary results of this trial were re-
`ported at the 1998 meeting of the American So-
`ciety of Clinical Oncology.1s At a median fol—
`lowup of 10.5 months, investigator assessments of
`time to disease progression and response rates were
`increased with the addition of trastuzumab to che—
`
`motherapy. without an increase in overall severe
`adverse events (Table 4).
`A syndrome of cardiac dysfuncrion similar to
`that observed with anthracyclines was reported
`6more commonly with trastuzumab + AC (18%
`
`Table 4. Preliminary Results of Trastuxumab
`Combination With Chemotherapy
`Clinical Trial HOMBg
`
`Enrolled
`
`11'? (mo)
`
`RR (%)
`
`AE (7%)
`
`
`
`CT alone
`H + CT
`AC alone
`H + AC
`Padltaxel
`H + Paclltaxel
`
`Abbreviations: TTP. time to progression: RR. raponse rate.
`AE. severe adverse EVents: CT. chemotherapy; H, trastuzumab:
`AC. anthracycllne (doxorublcln or eplrubicln)lcyclophospha-
`mide.
`
`*P < .00l. log-rank tat.
`1P < .Ol. chi-squared test.
`
`grades 3/4) than with AC alone (3%). paclitaxel
`alone (0%), or trastuzumab + paclitaxcl (2%).
`These data indicate that the addition of trastu—
`
`zumab to chemotherapy significantly increases
`clinical benefit, as assessed by response rate and
`time to disease progression. Preliminary analysis of
`both risk and benefit favors the regimen of ttastu—
`zumab plus pacliraxel.
`‘
`
`Traszuzumab as a Single Agent
`
`To evaluate the safety and efficacy of trastu’
`zumab as a single agent, a second large trial
`(H0649g)
`(Table 5) was performed in patients
`with metastatic breast cancer with tumors that
`
`overexpressed l-IERZ and who had relapsed follow-
`ing one or two cytotoxic chemotherapy regimens
`for metastatic disease“),20
`
`Trastuzumab was adminisrered intravenously as
`a loading dose of 4 rug/kg. followed by a weekly
`maintenance dose of 2 rug/kg (the same dose and
`schedule used in the phase ill combination with
`chemotherapy clinical trial). The 2 rug/kg weekly
`dose was continued until disease progression with—
`out dosage modification. Patients who developed
`disease progression had the option of continuing
`treatment with trasruzumab alone at a higher close
`(4 rug/kg IV weekly) or in combination with other
`breast cancer therapies.
`This multinational
`trial was performed in 55
`clinical sites in eight countries. Two hundred
`twenty'two women were enrolled. The primary
`end points were response rates (complete [CR] and
`
`6
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`TRASTUZUMAB CLINICAL TRIAIS
`
`75
`
`Table 5. Trastuzumab Large Slngle-Agent Clinical
`Trial H0649g: Phase II
`
`
`
`Date first patient enrolled
`Date Inst patient enrolled
`Enrollment status
`Enrollment
`Age range (yr)
`Design
`Treated
`Dose/schedule
`
`Patient populatlon
`
`June ll. I995
`September 25. l996
`Complete
`
`222
`28-8l
`
`Open-label
`Trastuzurnab alone
`4 mg/kg IV (loading dose).
`2 mg/kg IV weekly until
`disease progression
`HERZ-overexpressing metastatic
`breast cancer; one or two
`prior chemotherapy regimens
`for metastatic dlsease
`
`partial responses [PR]) and the further character—
`ization of the safety profile of trastuzumab. The
`secondary and points of this trial were response
`duration. time to disease progression, and survival.
`To ensure objective and unbiased assessment of
`the tumor response end points, the independent
`response evaluation committee was also used to
`identify the CR5 and PRs.
`The preliminary results of this trial were re-
`ported at the 1998 meeting of the American So-
`ciety of Clinical Oncology.W The patients (3114
`rolled in this trial had received extensive prior
`treatment: one quarter had prior high-dose che‘
`motherapy with Stem cell or marrow rescue. almost
`all had prior anthracycline treatment, and two
`thirds had prior paclitaxel treatment.
`Preliminary efficacy and safety data were avail-
`able for all patients, with a median followup of 11
`months. Nine patients never
`received trastu—
`zumab. The investigator-determined best response
`in 213 trastuzumab’treated patients was CR in
`eight patients (4%), PR in 36 patients (17%),
`minor response in IS patients (7%). stable disease
`in 61 patients (30%), and progressive disease in 87
`patients
`(42%). The
`investigatorvdetermined
`overall response rate (CR + PR) in trastuzumab—
`treated patients was 21% (95% confidence inter
`val, 16% to 27%). The independent response eval—
`uation committee-determined overall
`response
`rate (CR + PR) in trastuzumab—treated patients
`was 15% (95‘s confidence interval, 10% to 20%),
`with eight confirmed CRs and 25 confirmed PR5.
`The Kaplan‘Meier estimate of the median dura-
`
`tion of the response in the responders was 8.4
`months. The Kaplan—Meier estimate of median
`survival in all patients was 13 months.
`Two patients discontinued treatment because of
`adverse events. Reduction in cardiac ejection frac—
`tion was observed in nine patients, of whom six
`were symptomatic; all had either prior anthracy—
`cline therapy or significant cardiac history at entry.
`One woman died of a ventricular arrhythmia.
`There was a very low incidence of adverse events
`commonly observed with chemotherapy, such as
`myelosuppression, stomatitis, or alopecia.
`These data indicate that trastuzumab has a fa—
`
`vorable toxicity profile, is active as a single agent
`in women with HERZ-overexpressing metastatic
`breast cancer, and induces durable objective tumor
`responses.
`
`ADDITIONAL BREAST CANCER
`CLINICAL TRIAL
`
`A phase II clinical trial (HO650g) was initiated
`in patients with HERZ—overcxpressing tumors who
`had not received and did not wish to rcéeivc
`
`cytotoxic chemotherapy for metastatic breaSt can’
`cer (Table 6). The primary end point was the
`overall response rate (CR and PR) and to further
`characterize the safety profile of trastuzumab as a
`single agent. In addition, to obtain additional ex-
`perience with alternative doses, patients were ran—
`domized to the dose and schedule of trastuzumab
`
`used in the pivotal trial (loading dose 4 mg/ltg,
`
`‘
`
`I Table 6. Tmstuzumab Phase II Clinical Trial H06§Og:
`Single-Ageanrastuzumab in First-Line Treatment,
`
`Date first patient enrolled
`Date last patlent enrolled
`Enrollment status
`Enrollment
`
`October I I, I995
`May I3. I998
`Complete
`
`I I3
`
`
`
`Age range (yr)
`Design
`Treated
`Dose/schedule
`
`Standard dose
`
`Higher dose
`
`Patient populatlon
`
`28-86
`' Open-label. randomlzed
`Tmstuzumab alone
`
`4 rug/kg IV (loading dose).
`2 mglkg IV weekly
`8 mg/kg IV (loading dose),
`4 mg/kg IV weekly
`HER2-overexpressing
`metastatic breas: cancer,
`
`no prior chemotherapy
`for metastatic disease
`
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`STEVEN SHAK
`
`weekly maintenance dose 2 mg/kg) or to a higher
`dose (loading dose 6 mg/lcg, weekly maintenance
`dose 4 rag/kg). One hundred thirteen women were
`enrolled in this trial, which was performed at 19
`sites in the United States and Canada.
`
`The preliminary results of this trial were re—
`ported at the 1998 San Antonio Breast Cancer
`meeting.“ The patients enrolled in this trial had
`received extensive prior adjuvant treatment: al-
`most 60% had prior anthracycline treatment and
`12% had prior adjuvant high-close chemotherapy
`with stem cell or marrow rescue.
`
`Preliminary efficacy and safety data were avail—
`able for 112 of the 113 enrolled patients, with a
`median follow-up of 11 months. The investigatorr
`determined best
`response in 112 trastuzumabv
`treated patients was CR in six patients (5%) and
`PR in 20 patients (18%). The investigator—deter;
`mined overall response rate (CR + PR) in trastu-
`zumab—treated patients was 23% (95% confidence
`interval, 15% to 31%). There was no difference in
`
`response rate between the two dose groups. The
`Kaplan’Meiet estimate of the median duration of
`the reSponses was 9 months.
`Trastuzumab was well tolerated. and no patients
`discontinued treatment because of adverse events.
`An increase in severe adverse events was not ob’
`
`served in patients treated with the higher dose.
`These data confirm the observation that trastu—
`
`zumab has a favorable toxicity profile, is active as
`a single agent in women with HERZ—overexpresse
`ing metastatic breast cancer, and induces durable
`objective tumor responses.
`
`SUMMARY AND CONCLUSION
`
`II, and III
`In summary, a series of phase 1,
`clinical trials was performed to evaluate the safety
`and efficacy of trastuzumab, both as a single agent
`and in combination with chemotherapy,
`in pa-
`tients with metastatic breast cancer who had tu—
`
`mors that overcxpress HERZ. Clinical experience
`with this novel biological agent has been obtained
`in more than 1,000 women with HERZ-overex-
`
`pressing metastatic breast cancer. The data suggest
`that trastuzumab will be an important treatment
`option. Additional clinical trials are clearly indi—
`cated to evaluate the role of trastuzumab in com—
`
`hination with other regimens. It will be particu'
`larly
`important
`to perform clinical
`trials
`in
`Spatients with early brcasr cancer,
`in which the
`
`more limited tumor burden would suggesr even
`greater opportunities for clinical benefit.
`The ability of this targeted biologic therapy to
`provide significant antitumor activity is “proof of
`principle" for the concept that understanding the
`basic molecular alterations in cancer cells can die
`
`rectly lead to new treatments and better patient
`outcomes.
`
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