Combinations of two, three, or more
`Chemotherapeutic agents are occasion-
`ally employed based onpreclinical data
`suggesting improved antitumor activity
`(ic, additive or synergistic effects),
`many ofthese combinations are derived
`empirically, however. Although com-
`bination regimens may sometimes yield
`higher response proportions than sin-
`gie-agenttherapy, this can occur at the
`cost of greater toxicity, perhaps result-
`ing in an overall lower therapeutic in-
`dex.[4] This issue was specifically
`addressed by two studies presented at
`High-Dose Chemotherapy.
`the 34th annual meeting of the Amen-
`With Stem-Cell Support
`can Society of Clinical Oncology
`Regarding dose escalation, the po-
`(ASCO)in 1998.
`teatial role of high-dose chemotherapy
`with stern-cell rescue still awaits defi-
`The first suady, conducted by the
`Finnish Breast Cancer Group, random-
`nition. Although some authors have re-
`ported S-ycar disease-free survival
`ized 303 breast cancerpatients with dis-
`lant metastases to one of two regimens:
`proportions of approximatcly 20% ia
`(1) single-agent chemotherapy with epi-
`selected patients treated with such regi-
`means,[9,10] to date there has been no
`rubicin (20 mg/m? weekly until disease
`progression or a cumulative dose of
`Teast canceris Lhe most frequent
`demonstration of clear supenonty of
`ly diagnosed cancer in Ameri-
`high-dose consolidation over other strat-
`1,000 mg/m"), followed by mitomycin
`can women, and the second most
`(8 mg/m? every 4 weeks) as second-line
`egies in the management of stage 1V
`breast cancer.
`Recent trials comparing single-agent vs combination therapy in meta-
`cammoa cause ofcancer death.{1] Over
`therapy; or (2) the CEF polychemother-
`static breast cancer suggest that it may be time to reconsider the beliefthat
`the past several decades, there has been
`Most studies of high-dose chemo-
`apy regimen, consisting of cyclophos-
`combination chemotherapy is the goldstandardoftreatment. Based on the
`phamide (500 mg/m), epirubicin (60
`a faitly steady increasein the incidence
`therapy have been uncontrolled phase |
`ofthe disease. Epidemiologic dasa from
`and II trials, often accompanied by the
`mg/m"), and fluorouracil (500 mg/m?)
`limited randomized trial data available to date, high-dose chemotherapy
`every 3 weeks, followed by mitomycin
`ihe United States analyzed between
`irresistible, but problematic and unfor-
`with stem-cell rescue should not be viewed as “state-of-the art” treatment
`1988 and 1990indicate that the lifetime
`tunate, comparisons with historicat con-
`(8 mg/m’) and vinblastine (6 mg/m’)
`for metastatic disease and should be used only in the context of clinical
`trols. Moreover, the inherent bias of
`tisk of developing breast cancer is
`every 4 weeks. Although responses to
`trials, Recent trials have explored the optimal dosing and scheduling of
`Patient selection for these trials has also
`CEFtended to last modestly longer than
`12.2%, or, stated in another way, one in
`the taxanes, as well as the possible role of these agents in combination
`vesponses to epirubicin alone (median
`cight women will developthe disease at
`been an issue. The first reported ran-
`regimens. Capecitabine (Xeloda), a new oralfluoropyrimidine, appears to
`domized trial of standard chemothera-
`duration, 12 vs 10.5 months; P = .07),
`Somcpoint during her life.{2}
`be comparable in efficacy to CMF (cyclophosphamide, methotrexate, and
`
`IsMoreBetter?
`Although approximately 80% of
`no significam difference in time to pro-
`py vs high-dose chemotherapy with
`Sluorouracil), and preclinical data suggest possible synergy between this
`gression (P =.28) or overall survival (P
`breast cancer palicnis present with dis-
`either autologous bone marrow or pe-
`cease limited to the breast and/or axil-
`= .65) was found betweenthe two arms.
`agent and the taxanes. Other promising agents under study include lipo-
`ripheral blood stem-cell support, con-
`Moreover, no difference in survival
`Sonve-encopsulateddoxorubicin (TLCD-99), animmunoconfugate linking
`lary tymph nodes, almost half of these
`ducted by Bezwoda et al, showed that
`patients later develop metastatic dis-
`was seen when only the patients who
`a chimeric human/mouse monoclonalantibody to doxorubicin molecules;
`high-dose therapysignificantly extend-
`received both the first- and second-line
`ease and eventually succumbto it, Met-
`MTA (LY231514), a multitargeted antifolate; and marimistat, a broad-
`ed the durations of response and
`ueatments were compared (P = .96), or
`survival.{11] However, the median fol-
`astatic breast cancer represents a
`Spectrum matrix metalloproteinase inhibitor. Tamoxifen (Nolvadex) re-
`when survival was calculated from
`historically incurable condition despite
`low-up was only 72 wecks, the study
`mains the most important hormonal agent, but new antiestrogens and
`was small, and the standard-dose che-
`the judicious use of various hormonal
`the beginning of second-line therapy
`selective estrogen receptor modulators (SERMs) mayprovide alternatives.
`manipulations, as well as surgical and
`(P = 56). Single-agent therapy was also
`motherapy arm has been criticized for
`Thepotentialroleofnewaromatase inhibitorsosfirst-line hormonalagents
`radiotherapeutic interventions, and the
`associated with less toxicity and better
`being suboptimal.
`requiresfurther study. Finally, the possible synergy between trastuzumab
`quality oflife.[5)
`application of active cytotoxic chemo-
`Atthe 1998 ASCO meeting, several
`(Herceptin), a recombinant humanized monoclonal antibody to the HER-
`presentations evaluated different trans-
`therapeutic agents for hormone-refrac-
`‘The second report, presented by the
`2/neu protein, andpaclitaxel (Taxol) is being studied in two clinical trials.
`tory disease. For most patients with
`Intemational Taxotere 304 Study Group,
`plant modalities, ie, single vs tandem
`
`Metastatic disease, treatment provides
`described the results of a phase I]
`high-dose chemotherapy, tandem vs tri-
`only temporary control of cancer
`study comparing single-ageat docetax-
`pie high-dose chemotherapy, and purg-
`¢l (Taxotere) therapy vs the combina-
`growth, Outside of experimental proto-
`ing oftumorcells from peripheral blood
`tion of mitomycin and vinblastine in
`cols, the goals of management, there-
`stem cells.(12,13] The exploratory na-
`patients with metastatic breast cancer
`Tore, arc to palliaie symptoms with as
`ture ofthese trials and preliminary re-
`little weatment-related toxicity as pos-
`whose disease had progressed fallow-
`sults underscore the need for large.
`
`prospective clinical
`trials to address
`ing an anthracycline-containing regi-
`‘One of two copies ofthis article for personal
`men. In this experience, single-agent
`these questions.
`of intercal use may be made at oo charge. Copies
`beyond that number require that 3 9¢ per page per
`capy fer be paid to the Copyright Clearance Cen-
`ter, 222 Rosewood Drive, Danvers, MA 01970.
`Specify ISSN 0890-9091. For further infarma-
`Won, contact the CCC at 508-750-8400. Write
`publisher for bulk quantities.
`
`“intensified CEF” arm actually received
`“an 80% increase in dosc intensity com-
`pared to those in the standard CEF
`arm.[8] Quality oflife was also assessed,
`In the 15) randonuzed patients, no
`differcnces between the two arms were
`observed with respectto response rates
`or progression-free survival. However,
`the intensified regimen was associated
`with more toxicity. Grade 3 and 4 events
`were more frequent with intensified
`CEF than with the standard regimen
`(anemia, 18% vs 3%; leukopenia, 26%
`vs 6%; thrombocytopenia, 8% vs 2%:
`and mucositis, 13% vs 3%).
`
`docetaxel therapy proved more effec-
`tive than mitomycin plus vinblastine,
`not only with respect to response rate
`and time to treatmentfailure, but, most
`Bratifyingly, with regard 10 survival.
`Median survival duration was 11.4
`months in the docetaxel group vs 8.7
`months in the. mitomycin-vinblastine
`group (P = .0097).[6}
`In this context,
`the experience of
`Sledge and colleagues, reported at the
`1997 ASCO meeting, should be con-
`sidered(7) In that study, Eastern Coop-
`erative Oncology Group Study (ECOG)
`1193, single-agent therapy with either
`doxorubicin or paclitaxel (Taxol) was
`compared with the combination ofdoa-
`orubicin and paclitaxel as first-line
`therapy in 739 patients with metastatic
`breast cancer. Patients recciving single-
`agent therapy were crossed overto the
`other agent at the time of disease pro-
`gression.
`Monotherapy with cither doxorubi-
`cin of paclitaxel had equivalent thera-
`peutic activity; the combination of the
`two drugs resulted in superior overall
`response rate and Lime to treatmentfail-
`ure. Despite this, combination therapy
`was not superior to sequential single-
`agenttherapy with regard to overall sur-
`vival and quality oflife.
`Taken together, these tials should
`prompt a reconsideration of the con-
`ventional wisdom that combination
`chemotherapy is the “gold standard”
`for the treatment of metastatic breast
`cancer.
`
`Uluimately, the treatmentof stage IV
`breast cancer often represents an attempt
`to reach an equilibrium between the pal-
`liation conferred by response to thera-
`py. on the one hand. and treat-
`ment-related toxicity, on the other.
`Thus, the issue of the value of dose
`intensification is of utmost importance,
`since increased doses are commonly as-
`sociated with greater toxicity.
`
`Dose-Intensified Regimens
`A uial of the Italian group Gruppo
`Oncologico Nord-Ouest (GONQ), re-
`ported at ASCO 1998 by Lionettoet al,
`is insiructive in this regard. This trial
`randomized patients to receive either
`standard doses of CEF orthe same reg-
`imen in an intensified manner with
`growth factor suppor; patients in the
`
`648
`
`ONCOLOGY = VOLUME 13 + NUMBER $
`
`
`
`
`Update on the
`|
`Managementof
`Advanced Breast Cancer
`
`MONICA FORNIER, MD
`PAMELA MUNSTER, MD
`ANDREW D. SEIDMAN, MD
`Breast Cancer Medicine Service
`Memoria! Sioan-Kettering
`Cancer Center
`New York, New York
`
`
`ABSTRACT
`
`
`
`sible and to extend the duration ofhigh-
`quality life.
`Metastatic breast cancer is moder-
`ately sensitive to chemotherapy, with
`25% to 40% of patients achieving a
`partial or, tess commonly, complete re-
`sponse to single-agent therapy; the du-
`vation of such responses averages 6
`months.(3] Historically, the most com-
`monly used cytotoxic agents in the man-
`agement of metastatic breast cancer
`
`have been cyclophosphamide (Cytox-
`an, Neosar), methotrexate, fluorouracil,
`doxorubicin, and, more recendy,
`the
`taxanes, When the discase progresses
`further, vinorelbine (Navelbine) and
`other vinca alkaloids, mitomycin
`(Mutamycin), mitoxantrone (Novan-
`trone), gemcitabine (Gemzar), etopo-
`side, and cisplatin (Platinol) represent
`some ofthe other frequently used cyto-
`toxic drugs.
`
`MAY1999 * ONCOLOGY
`
`647
`
`AstraZeneca Exhibit 2010 p. 1
`InnoPharma Licensing LLC v. AstraZeneca AB IPR2017-00904
`Fresenius-Kabi USA LLC v. AstraZeneca AB IPR2017-01910
`
`

`

`eR
`Table 3
`
`Randomized Trials of High-Dose Chemotherapy/Autoiogous Stem-Celi Rescue (HDC/ASCR)
`for Metastatic Breast Cancer
`Trial Number/
`Sponaor(s)
`P8T-O1 (Philadelphia
`Group, ECOG. SWOG,
`NCCTG}
`Duke University
`
`Control Arm
`CMFICAF x 4-6 4
`CMF x 2y7
`
`* AFM s 2-4-»
`Alrelapse: CEF
`CEFx4
`
`Sample She
`AccrusP
`$87(standard dosa)
`S16 (high dose)
`
`Target
`Completion Date
`Winter 1997
`.
`
`BO
`
`180
`
`Continue A (to dose Smit) 192
`or Tx (9 cycles)
`
`palicnt required hematopoietic growth
`factor support.
`A possible explanation for the noted
`uncoupling of drug delivery from my-
`elotoxicity in weekly | -hour paclitaxel
`maybe found in the pharmacodynamic
`observation that, with this schedule,
`plasma paclitaxel concentrations remain
`above 0.) pmol/L. for a relatively brief
`period after a dose of 100 mg/m?deliv.
`ered over} hour. Huizing et al have,in
`fact, previously reported thatto achieve
`an 80% decline from baseline absolute
`neutrophil count, plasma paclitaxel con-
`centrauon would necd to remain above
`the threshold concentration of 0.1
`}moW/L for upproximately 20 hours.[26}
`This, considered together with the cy-
`clic kinetics of neutrophil matura-
`tion, may explain the relative lack of
`myelosuppression.
`
`|
`
`
`
` AST
`
`with metastatic breast cancer.{21}
`velopment. Whilethe clinical develop-
`Another randomizedclinical trial led
`ment of docetaxel has largely involved
`by M. D. Anderson Cancer Center de-
`asingle administration schedule (]-hour
`tected no significant difference in ob-
`infusion) and a naow dose range (60
`jective responses of survival with
`to 100 mgm’), the range of paclitaxel
`pactitaxel at either 140 mg/m? via a
`doses and schedules has been broader
`96-hour infusion or 250 mg/m? via a
`(varying from 80 to 250 mg/m’infused
`3-hour infusion—the maximally toler-
`over } hour weekly to 3-, 24-, or even
`ated doses at these schedules.{22]
`96-hour infusions every 3 weeks).
`Two other trials have addressed op-
`Paclitaxed
`timal paciitaach scheduling. The ran-
`domized Bristol-Myers Squibb (BMS)
`© Optima! Dose and Schedule—Pre-
`O71 tial, in which women with meta-
`clinical data have suggested that
`the
`static breast cancer were treated with
`duration of paclitaxel exposure may be
`paclitaxel (175 mg/m’)infused overci-
`more important than dose for the cyio-
`ther 3 or 24 hours, allowing for intrapa-
`toxic activity of this drug. Depending
`ent dose escalation as tolerated, was
`an the duration of exposure, cellular
`AFM » 2-4 >
`conducted largely in Europe, Canada,
`cytotoxicity can be achieved at rela-
`HDG/ASCR: CBP
`and[srael. The two groups did not dif-
`tively low concentrations ofpaclitaxel,
`CEFx 4a +
`fer significantly with respect to response
`on the order of 0.01 pM_.[16,17} That
`rates (29% and 32%,respectively).{23)}
`HDGJASCA: CT
`duration of exposure can be an impor-
`Similar results were obtained by Na-
`tant element in the clinical activity of
`Avot Txx4—
`HOC/ASCR:
`¢@ Pactitaxel-Containing Combina-
`Uonal Surgical Adjuvant Breast and
`paclitaxel has also been demonstrated
`CMICb x 2
`Bowel Project (NSABP) wial B-26. In
`tion Regimens——Given the cavcats pre-
`by the activity of prolonged 96-hour
`continuous infusions in some patients
`this trial, response rates for paclitaxel
`viausly raised about combination
`
`
`iLENEEERIEIEEEEEEEeD
`with metastatic breast cancer soon after
`chemotherapy for metastatic breast can-
`(250 mg/m?) infused overeither 3 of 24
`Adapted trom Zujowshi J J Mat Cancer inst 90{3):200-209, 1998.
`their disease progressed during shorter
`hours were 40% and 56%,respectively,
`cer, at the 1998 ASCO meeting, Loesch
`A= Adriamycin; AFI « Adriamycin, ftuormuracil, methotrexate; CAF = Cyclophosphamide, Adnamycin,fuarouracit CBP = Cyclophosphamide, BCNU (car-
`infusions of the drug.[18,19) However,
`et al presented a phase {I study aimed at
`suggesting thal the more myclosuppres-
`mustine}, ciiptatin; CEF = Cyclophosphamide, epirubicin, fuorouracih CMF = Cyclophosphamide, methotraxate, Ruorouraci (CxinGb » Cyclophosphamide, m+
`sive 24-hour schedule does notresult in
`the administration of 96-hour continu-
`loxantrone, carboplatin: CT « Cyclophosphamide,thictapa; CTCb = Cyciophosphamida,thiotsps,,carboplatin; ECOG = Easiem Cooperative Oncotogy Group,
`determining the response rate anil safe-
`NCCTG = North Centra Cancer Treatmant Group; NCIC = Nationa! CancerInstinie of Canada; PBT = Philadetghia Transplant Group; PEGASE = Societe
`ous infusions of paclivaxel imposes a
`ty of a combination of paclitaxel (80
`a significant improvement in outcome
`Francaise De Gratte Ou Moelle, Federation Mational Oo Lute Corie Le Cancer, SWOG = Souttrrest Oncology Group: Tx » Taxol
`certain inconvenience for both the clin-
`mg/m? infused over | hour), fluorou-
`in the palliative setting.(24] The inctu-
`“asof June 1, 1997
`racil (425 mg/m’), and teucavorin (20
`ic and patient.
`sion of patients with stage {IB disease
`Manyclinical wials have addressed
`partly explains the higher response pro-
`mg/m’) administered weekly as first-
`the issue of both the optimal dosing and
`portions in the NSABP B-26 wial,
`line therapy in patients with metastatic
`breast cancer.{27] Full doses could be
`scheduling of the taxanes (Table 2).
`as compared to the aforementioned
`. Studies.
`administered in the fourth week to only
`With regard to dosing, the results of a
`randomized trial of paclitaxel doses of
`63% of patients, primarily due to diar-
`« Weekly Administration—Another
`rhea and neutropenia; a “3 week on,|
`135 vs 175 mg/m?on a 3-hourschedule
`method to provide extended curnula-
`week off" regimen subsequently over-
`in pretreated women with metastatic
`live drug exposure is frequent repeti-
`came this problem.
`breast cancer revealed no majordiffer-
`ences in response rates (22% and 29%,
`live drug administration, such as by a
`Thirtypatients were evaluated: The
`weekly schedule. Weekly dosing of
`overall response rate was 47%, with
`respectively) or median survival dura-
`10% compleie remissions and 37% par-
`Gens (10.5 and 11.7 months, respec-
`pactitaxel via a t-bour infusion has been
`demonsuated to be a welj-tolerated, fea-
`lial remissions. This activity is compa~
`tively). Progression-free survival was
`sible administration schedule.(25].
`table to other regimens in simitar
`slighly longer with the | 75-mg/m? dose
`patients.
`Weekly administration of paclitaxel is
`thanwith the lower dose (4.2 vs 3
`both dase-intense and dose-dense but
`months; P = .02), however{20}
`.
`Another abstract presented al ASCO
`1998 reported on the resulis of a ran-
`also has a favorable toxicity profite and
`in the Cancer and Leukemia Group
`domized trial comparing paclitaxel plus
`a remarkable degree of activity in pa-
`B (CALGB)trial 9342 reported at the
`ents with metasiatic breast cancer.
`losoxantrone, an anthrapycazole in
`1998 ASCO mecting, 450 patients were
`randomized to receive 175-, 210-, or
`clinical development, with structural
`In our experience at Memonial Sloan-
`similarities to both doxorubicin and mi-
`Kettering Cancer Center,the overall re-
`250-mg/m? doscs of paclitaxct on a
`toxantrone, vs paclitaxel alone.{28] In
`3-hour schedule. The three groups did
`MODACG
`sponse rate to a weekly administratian
`schedule was 53% (95% confidence in-
`.
`148 patients. a response rate of 54%
`not differ with respect to response rates
`was nated with the combination vs 15%
`terval [Cl], 34% to 72%), which com-
`of survival, but the higher doses were
`Docetaxel
`The taxanes,ic, paclitaxel and doce-
`with paclitaxe] alone (P < CQL}. Pro-
`pares favorably with the activity noted
`associated with greater toxicity, partic-
`taxel, are a relatively new addition to
`NA
`NA
`th
`100 mon?
`APR
`for 3-, 24-, and 96-hour regimens. In
`gression-free survival was significantly
`ularly peripheral neuropathy (26% rate
`the chemotherapeutic arsenal against
`75 mgfr
`contrast to these other regimens how-
`supenor with the combinalion regimen
`breast cancer. Their mechanism ofac-
`of grade 3 events). These data provided
`
`Lenene
`as well.
`litte compelling evidence to support
`ever, myclosuppression was insignifi-
`tua involves the formation of polymer-
`Toxicity was also higher with pacli-
`paclitaxel 3-hour infusion dosing of
`ized microtubulesandtheir stabilization
`BMS » Bristol-Myers Squibb; CALGB = Cancer and Leukemia Group 8; MDACC = 1. D. Anderson
`cant with weekly paclitaxcl, no febrile
`Cancer: Center, NA » Not applicable; NS = Nod rignificant; NSABP x National Adanert Surgical Breast
`taxel plus losoxantrone, however. Pa-
`greater than 175 mg/m?
`in women
`neutropenia was cncountered, and ao
`and Bowe! Project; RPA = Rhéne-Povienc Rorar
`against the forces that tead to depoly-
`merization. Proapoptouc effecis, as well
`as antiangiogenic actions, may also be
`clinically relevant.(14,15}
`The determination of optimal dos-
`ing and scheduling of taxancs has been
`an important objective during their de-
`
`HOC/ASCR Arm
`CMFICAF x 4-63
`HDG/ASCR: CTCb
`
`PEGASE
`
`NCIC
`
`.
`
`Onthe basis ofthe limited data avail-
`able to date frorn randomized, prospec-
`tive trials, high-dose chemotherapy
`cannotyet be considered “state-of-the-
`: ant”treatment for advanced breast can-
`cerand shouldbe offered only to patients
`in the setting ofclinical trials. The final
`results of such large prospective inals
`are eagerly awaited (Table 1).
`If multiagent chemotherapy and dose
`escalation prove to be suboptimal in
`conferring a consisient survival advan-
`tage in metastatic breast cancer, other
`strategies must be pursued. These in-
`clude the developmentof neweractive
`drugs, or the exploration of diffcrent
`aliematives, for example, biotogical
`therapies.
`
`Beyon
`
`Tabla 2
`Randomized Trials of Singie-Agent Taxanesin Metastatic
`Breast Cancer: Dose and Administration Schedule
`Dase
`Administration
`Response
`(gin?)
`Schedule (h})
`Rate (%)
`
`Study
`Paclitaxel
`BMS 048
`
`QMS 471
`
`,
`
`175 mom? -
`135 mg/m?
`175+ mgm"
`
`NSABP 8-26
`
`250 mg/m
`
`CALGB 9342
`
`175 mine
`210 magi?
`250 mom?
`140 mg/m?
`250 mg/m?
`
`3h
`
`ah
`24n
`3h
`24h
`3h
`
`96h
`an
`
`.
`
`.
`
`2%
`22%
`2%
`32%
`40%
`Sn
`21%
`20%
`22%
`29%
`23%
`
`P¥aiue
`
`108"
`
`NS
`
`02
`
`4
`
`NS
`
`650
`
`ONCOLOGY + VOLUME 13 + NUMBER 5
`
`MAY1999 + ONCOLOGY
`
`649
`
`AstraZeneca Exhibit 2010 p. 2
`
`

`

`
`
`Figure 1: Chemica! Structure and Mechanism of Action of Capecitabine—
`5'-DFCR = 5'-Deoxy-5-fluorocytidine; 5°-DFUR = S’-Deoxy-5-fluorouridine;
`dTHdPase = Thymidine phosphorylase; 5-FU = Fluorouracil
`
`|°
`
`
`
`tients treated wit the combination reg-
`imen had a 66% incidence of grade 3-4
`neutropenia, vs a rate of 32% with
`paclitaxel alone, and twocases of con-
`gestive heart failure occurred with the
`combination, vs one case with paclitax-
`et alone. Analysis of survival awaits
`longer follow-up, but these data are cer-
`lainly. provocative, if not surprising in
`light of the ECOG 1193 results with
`paclitaxel plus doxorubicia.(7)
`Doretaxel
`Regarding docetaxel, Loeffler et al
`reported their experience with weekly
`infusions in stage [V breast cancer pa-
`tients.{29}] Doses were escalated in in-
`crements of 5 mg‘m’ from 30 to 45
`me/m? weekly 6 with a 2-week break.
`The overall response rate was 50%, with
`15% complete remissions and 35% par-
`tial remissions, 38% ofpatients had sta-
`ble disease, Moreover,three out offive
`patients with a history of prior paclitax-
`el therapy responded to docetaxel. These
`investigators observed that weekly doc-
`etaxel has activity in chemotherapy-pre-
`treated breast cancerthat is comparable
`to 100 mg/m? of docetaxel every 3
`weeks, but with apparently less prade
`3-4 leukopenia.
`Another ASCO presentation by
`SjéstrSm et al focused on a phase II
`trial that compared docctaxel (100 mg/
`m*) every 3 weeks to methotrexate (200
`mg/m*) plus fluorouracil (600 mg/m?
`on days I and 8) every 3 weeks (MF
`regimen)in 199 patients with anthracy-
`cline-resistant breast cancer.(30) The
`overall response rate (partial and com-
`plete). was 42% in the docetaxel arm
`and 19% in the MF arm (P < .001);
`median time to progression was 6
`months in the docetaxel group and 3
`months in the MF group (P = .006).
`- These results thus demonstrated the su-
`periority ofsingle-agent docetaxel over
`MF forpatients with anthracycline-re-
`sistant metastatic breast cancer.
`
`taxanes, was evaluated in five mouse
`2 weeks, followed by 1 week of sest,
`and CMF was administered intravenous-
`xenograft models of humanbreast car-
`cinoma cells.(34) While the combina-
`ly on day | every 21 to 28 days.
`A total of 95 women were random-
`tion of fluorouracil and taxanes
`ized. Response rates were 25%in the
`demonstrated only additive efficacy,
`capecitabine-treated patients and 16%
`treatment with capecitabine and the tax-
`in the CMFrecipients, and time to pro-
`anes showed synergy and produced tu-
`gression was 132 days with capecitab-
`mor regression in some xenograft
`models. In fact, the taxanes increased
`ine vs 94 days with CMF.
`Regardingtoxicity, grade 3-4 clini-
`the tumorlevels of thymidine phospho-
`tylase by four- to eightfold within 4 to
`cal adverse events were reported by 44%
`of patients receiving capecitabine and
`10 days following the sitigte adminis-
`tration; the treatment did not increase
`20% patients treated with CMF. The
`the mouse enzyme levels in normal tis-
`difference between the two groups was
`sues (intestine and liver), however. Since
`due primarily to hand-foot syndrome
`(16% vs 0%) and diarrhea (8% vs 3%).
`tumoral thymidine phosphorylase lev-
`On the other hand, grade 3-4 hemato-
`els correlate with in vivo susceptibility
`to capecitabine, it is possible that the
`logic toxicity occurred more frequent-
`taxanes may enhance the efficacy of
`ly with CMF (479%) than with cape-
`citabine (20%).
`capecitabine by upregulating the en-
`Overall, within the constraints im-
`zyme ia human cancer cells.
`posed by relatively small sample sizes,
`Rei
`ing
`Old D
`it appears that home-based monothera-
`py with capecitabine appears to have at
`The continued search for newer
`least comparable efficacy to CMF com-
`New, Multitargeted Antifolate
`bination therapy in this older patient
`agents for coatrolof disease andpallia-
`MTA (LY231514) is a new, mulu-
`population.
`tion of symptoms in metastatic breast
`targeted antifolate that inhibits thymidy-
`cancerhas also led to the manipulation
`in a multicenter trial pre~
`Finally,
`sented by O'Reilly et al, the activity of
`late synthase and other folate-dependent
`of the more conventional drugs so as to
`capecitabine was compared to that of
`enzymes, inxluding dihydrofolate reduc-
`achieve equivalent or possibly greater
`paclitaxel
`in patients with advanced
`lase and glycinamide ribonucleotide
`activity with decreased toxicity.
`formyltransierase. It has potent antiw-
`breast cancer whase disease had pro-
`Liposamal Doxorubicin
`gressed following prior anthracycline
`mor activity in vitro and in vivo and
`therapy.(33] In this study, two sched-
`produced responses in phase 1 urials.
`One promising agentin this respect
`A phase [I study that evaluated the
`ules of capecitabine were planned:
`is liposome-encapsulated doxorubicin
`(1) 2,510 mp/m/dfar14 days, followed
`activity of MTA in 38 patients’ with
`(TLC D-99). A phase [I cial reported
`at ASCO 1998evaluated its use vs con-
`by 1 week of rest; or (2) a continuous
`locally recurrent or metastatic breast
`ventional doxorubicin, both at a dose of
`hand-foot syndrome (10%) were the
`converted to fluorouraci) by thiee cn-
`daily schedule of 1,331 mg/m. (The
`cancer was presented at the 1998 ASCO
`only ueatment-related adverse events
`75 mg/m? every 3 weeks.[35} This trial
`continuous arm ofcapecitabine was dis-
`meeting[37] Of the 38 patients, $ were
`zymes tocated in the liver and within
`that occured with a grade 3 or 4 inten-
`tumors, with the final conversion step to
`continued, however, after two patients
`randomized 69 patients who were stral-
`chemotherapy-naive, 14 had received
`were enrolled.[personal communication,
`sity in 2 10% of patients. Alopecia did
`ified on the basis of prior expasure to
`fluorouracil catalyzed by thymidine phos-
`adjuvant chemotherapy,|b had received
`Dr. Fabio Benedetti, Roche, Inc.. Feb-
`not occur and myelosuppression was
`chemotherapy for metastatic disease,
`doxorubicin. During the tial, patients
`phorylase, which is found preferendally
`minimal; there was 00 Ueatment-felat-
`Tuary 1999]) Paclitaxel was adminis-
`in breast cancer cells as compared to sur-
`underwent serial ventriculography at
`and 5 patients had had both. MTA was
`cumulative doses of 300, 400, and 500
`ed mortatity.
`:
`tered at a dosage of 175 mg/m? on
`rounding normal host tissues (Figure 1).
`administered at a dosage of 600 mg/m?
`Given these data and the historical
`day | of each 3-week cycle.
`mep/m? and then every cycle thereafter.
`every 2] days.
`An abswact presented by Blum et al
`context ofthe use of continuous intra-
`at the 1998 ASCO meeting described a
`Responses were documented in 11
`Patients were removed from the study
`With 4) evaluable patients, the in-
`venous infusions of fluorouracil as a
`termitient schedule of capecitabine
`if teft-ventricular ejection fraction
`patients (31%), with ! complete and 10
`_ phase II trial of twice-daily aral capecit-
`yielded a 36% response rate, as com-
`salvage therapy for metastalic breast
`(LVEF) declined by 2 20% from the
`abine (2,510 mg/m¥d) given for 2
`panial remissions. Of the [1 patients
`cancer, capecitabine was approved by
`baseline value (if this value was > 50%)
`pared with a 21% rate with paclitaxel.
`weeks, followed by a l-week rest peri-
`who responded, 5 had received prior
`the FDAfor use in patients with pacli-
`or by 2 10% from baseline (if < 50%),
`Median time to progression was 92 days
`taxane or amhracycline therapy. Medi-
`od, and repeated in 3-week cycles,
`taxel-refractory metastatic breast can-
`on the intermittent capecitabine sched-
`an duration of response was 8+ months.
`orif congestive bean failure developed.
`among patients with paclitaxel-refrac-
`cer in the spring of 1998. In summary,
`ule and 95 days on paclitaxel. Grade 3-
`Response cates were 33% in the
`Overall, 135 cyctes of MTA were de-
`tory metastatic breast cancer[31] A ta-
`TLC D-99 arm and 29% in the doxoru-
`livered with 28 dose reductions and 26
`4 events were reported in 22% of
`capecitabine can be considered an ac-
`tal of 163 patients were enrolled by 24
`tive drugin the treaumentof paclitaxel-
`delays. Reasons for reductions includ-
`bicin arm. Congestive heart failure de-
`centers; patents had received at least
`Patients eated with capecitabine and
`58% given paclitaxel.
`refractory advanced breast cancer with
`veloped in three patients (4%) weated
`two but no more than three prior che-
`ed neutropenia (39%), mucositis (18%),
`with doxorubicin but in none of those
`a relatively favorable toxicity profile.
`and ansaminase elevation (23%).
`motherapeutic regimens, one of which
`s Cspecitabine in Combination
`given TLC D-99. Also, TLC D-99
`Grade 2-3 nonhematologictoxicities
`contained pactitaxel as ueatment for
`NewerAgents
`
`metastatic disease.
`« Capecitabine vs Other Agents—A
`inctuded mucositis (34%), nausca and
`Regimens—lIn a relevant preclinical
`generally produced less emesis, stoma-
`second abstract reported at ASCO 1998
`vomiting (39%), and wansaminaseele-
`Japanese study,the efficacy of capecit-
`The primary study end point was
`litis, fever, and infection, suggesting
`Capecitabine
`abine and fluorouracil in combination
`that it may as effective as free doxoru-
`vation (88%). Also, a grade 2 skin rash
`tumor response in patients with mea-
`presented the results of a randomized
`Considering newer drugs for advanced
`surable disease. The response rate was
`with other cytostatic agents, including
`bicin but perhaps safer.
`developed in 50% ofpatients, a grade 3
`breast cancer, one of the most interesting
`phase II tial of capecitabine vs cyclo-
`phasphamide, methotrexate, and flucrou-
`20%, median response duration was 8.1
`agents is capecitabine (Xeloda). Capecit-
`racil (CMF) as first-line chemotherapy
`months, and median survival was 12.8
`abine is a novel, oral, selectively tumor-
`for advanced breast cancer in women
`months. Moreover,
`in patients with
`activated fluoropyrimidine carbamatethat
`> 55 yearsold (median age in both groups,
`baseline pain > 20 mm on a visual ana-
`has shown promising activity in breast
`69 years)[32] Capecitabine was given
`log scale, 47% showed a significant im-
`and colon cancers during phase ! and Il
`orally at a dosage of 2,510 mg/m?/d for
`provementin pain. Diarrhea (14%) and
`cvaluations. This agent
`is sequentially
`
`A Novel Immunoconjugate
`Tolcher et al described a phase II
`randomized tial in which a novel im-
`munoconjugate linking a chimeric hu-
`Man/mouse monoclonal antibody to
`approximately cight doxorubicin mole-
`cules was compared to doxorubicin.{36]
`This antibody is directed against the
`Lewis’ anugen, which is expressed in
`75% ofall breast cancers but has limit-
`ed expression in normal
`tissues, has
`shown promising antitumor activity in
`preclinical xenograft models.
`A total of 25 patients with metastat-
`ic breast cancer entered this trial. There
`was one partial remission in the [4
`patients (7%) on the immunoconjugate
`arm, showing thatits Clinical activity is
`limited. Also, two patients in this arm
`developed grade 3-4 toxicity with hem-
`omhagic gastritis, possibly reflecting the
`fact that the Lewis’ antigen unfortunate-
`ly is also expressed on some gastrointes-
`Unal mucosal cells.
`
`652
`
`ONCOLOGY + VOLUME 13 + NUMBER 5
`
`MAY 1999 » ONCOLOGY
`
`651
`
`AstraZeneca Exhibit 2010 p. 3
`
`

`

`ducted in Europe. Anastrozole was ad-|© Summary—lIt appears that the new-
`SERMs have shown very exciting pre-
`clinical and clinical results. One SERM,
`ministered at doses of either | or 10|e¢ aromutase inhibitors are as effective
`rafoxifene (Evista), approved for the
`me. Responses were seen in 34% of the|as megestro] acclate and perhaps tamox-
`treatment of osteoporosis in posimenc-
`patients in the 1-mg group, 33.9% in|ifen and are well tolerated. Theis role as
`the LO-mg group, and 32.8% in the}first-tine hormonal therapy,eitheralone
`pausal women, has also dramatically
`reduced the incidence of new breast can-
`Megestro} acetate-group.(63}
`or in combination with agents that mad-
`advantages. However,
`the patients
`cers,(61] with relatively short follow-
`These findings were confirmed