Combinations of two, thra. or more
`chemotherapeutic agents an: occasrou-
`ally employed based on prxlinical data
`suggesting improved antimmor activity
`(ie. additive or synergistic effects);
`manyoftlrtse combinatinnsare derived
`empirically. however. Although com-
`bination regimens may sometimes yield
`higher response proportions than sin-
`gle-agent therapy. 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
`the 34th annual meeting of the Ameri-
`can Society of Clinical Oncology
`(ASCO) in [998.
`The first study, condch by the
`Finnish Breast Cancer Group. random-
`ized303 breast eaucerpatients with dis-
`tant metastases to one of two regimens:
`(l) single-agent chemotherapy with epi-
`nrbicin (20 rug/m‘ weekly until disease
`progression or a cumulative doso of
`Lt“) mg/m’). followed by mitomycin
`(8 mg/m’ every 4 weeks) as second-line
`tlraapy; or (2) the CEF polychemotluz-
`apy regimen. consisting of cyclophos-
`phamide (500 mg/m’), epirubicin (60
`mg/m’). and fluorouraeil (50) mgjm’)
`every 3 weeks. followed by mimmycin
`(8 mglm’) and vinblastine (6 mg/m’)
`every 4 weeks. Although responses to
`CEFtendedtolast modestly longerthan
`responses to epiruhicin alone (median
`duration. l2 vs 10.5 months: P: .07).
`no significant difference in time to pro
`greasion (P =28) or overall survival (P
`=.65)wasfound betweenttretwo arms.
`Moreover. no difference in survival
`was seen when only the patients who
`received both the first- and second-line
`treaunenn were compared (F = .96). or
`when survival was calculated from
`the beginning of second—line therapy
`(P: 56). Single-agent therapy was also
`associated with less toxicity and better
`quality of lifeli]
`The second report. presented by the
`InternatiomlTuotue 304$tudy Group.
`described the results of a phase Lll
`shady compann'g single-agent dooetax-
`el (Taxmere) therapy vs the combina«
`tion of mitomycin and virtblastinc in
`patients with metastat'e breast GUICCI
`whose disease had progressed follow.
`ing an anthracyetine-containing regi-
`men. In this experience. singleagenr
`
`docetaxel therapy proved more effec-
`tive than mitomycin plus vinblastine.
`not only with respect to response rate
`and time to treatment failure. but. must
`gnutyngly. Willi ttgttttl to survival.
`Median survival duration was t [.4
`months in the docuaxel group vs 8.7
`months in the mitornycin-vinblastine
`group (P= -0097)At61
`In this context.
`the experience of
`Sledge and colleagues. reported at the
`1997 ASCO mating. should be con—
`sideredl‘l] In that study. Eastern Coot»
`erative Oncology Group Study (ECOG)
`H93. single-agent thaapy with either
`doxorubicin or paclitaxel (Taxol) was
`compared with the combination ofdox-
`ombicin and paelitzutel as first-line
`therapy in 739 patients with metastatic
`breastcancer. Patients receiving single-
`agent therapy were crossed over to the
`other agent at the time of disease pro-
`grassron
`Moootherapy with either doxorubi-
`cin or paclitaxel had equivalent theraA
`peutic activity; the combination of the
`two drugs resulted in superior overall
`response rate and time to treatment fail-
`ure Dspite this. combination therapy
`was not superior to sequential single-
`agent therapy with regard to overall sur-
`vival and quality of life
`Taken together. these uiats should
`prompt a reconsideration of the con-
`ventional wisdom that combination
`chemotherapy is the “gold.th
`for the Militant of metastatic breast
`miner.
`
`Walled
`
`Ultimately. the treatment of stage D]
`breast cancer often reprcsmts an anempt
`to reach anequilibrium between the pat-
`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 at dose
`intensification is of utmost importance.
`since increased doses are commonly as
`sociated with greater toxicity.
`
`Dose-Intensified Regimens
`A trial of the ltalian group Gruppo
`Oneologico NordAOuest (GONG), re-
`ported at ASCO 1998 by Lionetto et at.
`is instructive in this regard. This trial
`randomized patients to receive either
`standard doses of CEF or the same reg-
`imen in an intensified manner with
`growth factor support; patients in the
`
`“intensified CEF‘ arm actually received
`'an 80% inert-25¢ in dose intensity com.
`pared to those in the standard CEF
`anTLlll] Quality oflil'e was also assessed.
`in the lit randomized paliEnls. no
`differencu between the two arms were
`observed with respect to response rates
`or progression-free survival. However.
`the intensified regimen was miated
`with more toxicity. Grade 3 and 4 events
`were more frequent with intensified
`CEF than with the standard regimen
`(anemia. 18% vs 3%; leukopcnia. 26%
`vs 6%; thrombocytopenia. 8% vs 2%;
`and mucosttis. 13% vs 3%).
`
`High-Dose Chemotherapy.
`With Stem-Cell Support
`Regarding dose wlation..the po-
`tential role of high-dose chemotherapy
`with stern-cell rescue still awaits tkfi-
`uition. Although some authors have re-
`ported 5-year disease-free survival
`propom'ons of approximately 20% in
`selected patients treated with such regi-
`rneos,[9.t0] to date there has been no
`demonstration of clear superiority of
`highdosc consolidation over other Strat-
`egies in the management of stage IV
`breast cancer.
`Most studies of high—dose chemo
`therapy have been uncontrolled phase I
`and H trials. often accompanied by the
`irresistible. but problematic and unlora
`tunate. comparisons with historical con-
`trols. Moreover. the inherent bias of
`patient selection for these trials has also
`been an issue. The first reported ran-
`domized trial of standard chemothera-
`py vs high~dose chemotherapy with
`either autolognus bone marrow or pe-
`ripheral blood stern-cell supporL con-
`ducted by Bezwuda et al. showed that
`high-dose therapy significantly extend-
`ed the durations of response and
`survival.[ 1 I] However. the median fol-
`low-up was only 72 weeks. the study
`was small. and the standard-dose che~
`motherapy arm has been criticized for
`being suboptimal.
`At the I998 ASCO meeting. several
`presentations evaluated different trans-
`plant modalitirs. ie. single vs tandem
`Nghdose chemotherapy, tandem vs tri-
`ple bighdose chemotherapy. and purg-
`ing oftumor cells from peripheral blood
`stem cells.[12.13] The exploratory na-
`ture of these trials and preliminary re-
`sults underscore the need for large.
`prospective clinical
`trials to address
`these questions.
`
`648
`
`ONCOLOGY - VOLUME l3 - NUMBERS
`
`
`
`MOch FORMER. MD
`PAMELA MUNSTER. MD
`ANDREW D. SEIDMAN. MD
`Breast Cancer Medicine Service
`Memorial Sloan—Kcttenng
`Cancer Center
`New York. New York
`
`Update on the
`Management of
`Advanced Breast Cancer
`
`
`
`roast cancer is the most frequent
`ly diagnosed cancer in Ameri-
`can women. and the second most
`common cause ot‘cancer dcathlt] Over
`the past several decades. there has been
`a fairly steady increase in the incidence
`of the disease. Epidcntiotogic data from
`the United States analyzed between
`1988 and 1990 indicate that the lifetime
`risk of developing breast cancer is
`12.2%. or, stated in another way. one in
`eight women will develop the diseasr: at
`some point during her life.[2)
`Although approximately 30% of
`bn‘ast cancer patients present with dis~
`ease limited to the breast and/or artil-
`lary lymph nodes. almost halfofthese
`patients later develop metastatic dis-
`ease and eventually succumb toil. Met-
`astatic breast cancer represents a
`historically incur-able condition despite
`the judicious use of various hormonal
`manipulations. as well as surgical and
`radiotherapeutic interventions, and the
`application of active cytotoxic chem
`therapeutic agents for hormone~refrac-
`tory disease. For most patients with
`metastatic disease. treatment provides
`only temporary control of cancer
`growth. Outside ofexperimcntal proto-
`cols. the goals of management. there—
`fore. an: to palliate symptoms with as
`little treaunent-rclated toxiciry as pos~
`
`On: or two copies of this article for personal
`or internal use may be made at no charge Copies
`beyond that number require that a 9: pa page per
`copy fee bc paid to the Copyright Clearance Cen—
`IH. 222 Rosewood Drivc. Danten. MA 01970.
`Emily ISSN 0890909L For font-u inforrm-
`tion. contau the CCC at 503—15on. Write
`publisher for bulk quantified
`
`
`ABSTRACT
`
`Recent trials comparing tingle-agent vs combination tlumpy in meta-
`some bremt cancer suggest that it may be time to reconsider the belizfthat
`combination clurnotltrropy is the goumndardoft‘rrotmcnc Based on the
`limited randomized trial clam availisz to date. high-dart chemotherapy
`with sum-cell rescue should not be viewed as ‘Wemf-th: or!” treatment
`for metastatic disease and shooldbe used only in the context ofclinical
`t'rt'aLt. Recent tner have explored the optimal dosing and Ichaduling of
`the wants, as well or the possible role a] lhar ogetm in combination
`regimens. Copecirnbi'nc (Xeloda), it new omlfluoropyfimidinc, appears to
`be comparable in emcee, to CMF (cyclophosphamldc, methatrcxate, and
`fluoroumct'l). and preclinical data suggest possible synergy between this
`agent and the taunts. Other promising agent: under study include lipo-
`roore-cnmpsuloteddarontbiciu (TLL‘099), on t'mmunocmtfugou linking
`a chimeric human/mouse monoclonolantibodyto doxorubt‘cl'n molecules;
`MTA (LYZJISN), a muhitnrgcled mfolatc,‘ and mar-imistnt, a broad-
`.rpectrum matrix metallopmtcimse
`Tamoxifen (Nolvodex) re-
`mains the mt important hormonal agent, but new anda‘lrogertt and
`relative estrogen recepaar modulators (SERMI) mpnm'da alternatives.
`nepotenlialrolenfnewmntatase inhibitorxasfirat-linc homonalqgcnts
`requires-further mdy. Finally, the possible 3'me between amt-annual:
`(Hareptin), a recombinant humanized monoclonal antibody to the HER-
`2/nur protein, andpot-Elner (Tno!) is being studied in two clinical mu.
`
`
`sibte and to extend the duration ofhigh-
`quality life.
`Metastatic breast cancer is moder-
`ately sensitive to chemotherapy, with
`25% to 40% of patients achievrng a
`partial or. leg commonly. complete re-
`sponse to single~agcnt therapy; the du-
`ration of such responses averages 6
`months.[3] Historically. the most corn-
`monly used cytotoxic agents in the man~
`agement of metastatic breast cancer
`
`have been cyclophosphamide (Cytox-
`an. Neosar). methotrexate. fluorouracit.
`doxoruhicin. and. more recently,
`the
`taxanes. When the disease progressu
`further. vinorelbinc (Navelbine) and
`other vinca alkaloids. mitomycin
`(Mutamycin). mitoxantrone (Novan-
`none). gemCitabine (Gemzar), empo—
`side. and cisptatin (Platinol) represent
`some ofthe other frequently used cyto-
`toxic drugs.
`
`MAY I999 - ONCOLOGY
`
`647
`
`AstraZeneca Exhibit 2010 p. 1
`InnoPharma Licensing LLC V. AstraZeneca AB IPR2017-00900
`
`

`

`
`
`PEGkSE
`
`Mac
`
`On the basis ofth limited data avail-
`able to date from randomized. prospec-
`tive trials. high‘dose chemotherapy
`cannot yet be considered "stale-of—the—
`. art" treatment for advanced breast can—
`cot and shouldbe offered only to patients
`in the setting ofclinical trials. The final
`results of such large prospective trials
`are eagerly awaited (Table I),
`If multiagent chemotherapy and dose
`escalation prove to be suboptimal in
`conferring a consistent survival advan-
`tage in metastatic breast cancer. other
`Strategies must be pursued. These in-
`clude the development of newer active
`drugs, or the exploration of different
`alternatives, for example, biological
`therapies,
`
`32‘"
`
`The rasanes, ic. paclitaxel and three-
`tatel, are a relatively new addition to
`the chemotherapeutic arsenal against
`breast cancer. Their mechanism of ac-
`liun involves the fomtation of polymer-
`ized microtuhulcs and their stabilization
`against the forces that load to depoly-
`mnrization. Proapoptotic effects. as well
`as antiangiogcnic actions, may also be
`clinically relevantllmljl
`The dctcmtination of optimal dos—
`ing and scheduling of taxanes has been
`an iniponant objective during their do
`
`
`
`_________————————-
`Tabla?
`Randomized Trials of Single-Agent Taxa’nes in Metastatic
`Breast Cancer: Dose and Administration Schedule
`Dose
`Administration
`Response
`Winn!)
`Rah“)
`(“SM”)
`
`Panuo
`
`Study
`Paelltuel
`EMS ma
`
`EMS 071
`
`NSABP 8-26
`
`CALEB 9342
`
`l75mgl'm’.
`rasmw
`l75~mg/m‘
`
`250 mg’m'
`
`175 ntng
`210m
`250mng
`montan
`250 rnglm’
`
`3h
`
`3h
`zan
`an
`tab
`3h
`
`96!!
`3h
`
`Hi
`
`29%
`22%
`29‘7-
`32%
`40%
`50%
`2m
`28%
`22%
`29%
`23%
`
`NA
`
`.108‘
`
`NS
`
`NS
`
`NA
`
`mace
`Dooetaxol
`HPR
`too mghn’
`75 rug/tnI
`_______—__————————
`Bus-m-WW:CALGBIWWUUWGWEW= “Jim
`momnNA-Nmappiuuums-Nuswmtmnmwwwm
`mmea-mmm
`
`650
`
`ONCOLOGY 0 VOLUME 13 - NUMBER 5
`
`MAY |999 ' ONCOLOGY
`
`649
`
`AstraZeneca Exhibit 2010 p. 2
`
`___________'____________.___—__—
`Table ‘l
`
`HDCIASCR Arm
`CMF/CAF x 4-8»
`HDCJASCR: CTCh
`
`ControlAr-m
`56—.
`CMF/CAFK
`CMF x Z Y7
`
`Randomized Trials of High-Dose Chemotherapy/Autologous Stem-Cell Rescue (HDCIASCR)
`tor Metastatic Breast Cancer
`Trial Number]
`Spun-min)
`PET-01 (Philadelphia
`Group, ECOG. SW06.
`NCCTG)
`Duke University
`
`Sample Sin
`w
`587 (standard dose)
`516 (high dose)
`ED
`
`Target
`Cermolollon Data
`Winter 1997
`'
`
`150
`
`.192
`
`' AFM R 24—)
`At relapse: CEF
`CEFxb
`
`Continua A (to dose limit)
`orTr (9 cycles)
`
`AFM v 24 —.
`HOG/ASch CBP
`CEFx 4 —)
`HDC/ASCR: CT
`A or Tit x 4 —v
`HDG’ASCH:
`03.4le x 2
`__________.__.___'__________———————-—
`Adapted from Zw'ow‘ilu J J Han Cancer Ina 90(3):?00—209. 1995.
`A = Ataiamyein; AFM - Adriim mammal, morale; CAF = Cyclopnospnamme, Aonamydn. minimum; CBP - Eyehphoxmamioe. BCNll lear—
`mustloe). e’nrlalln; CEF - Cyclophoeohamide.
`Wadi; CW - (2me MM. ‘uolulrlci; culer - Cyaumaspnarrm. mi<
`Imam-one. campbun: cr : Cyewnsohawida, moon. Cleo - cvdouhosommldl. Mp5..auooplath; E006 =Ewornompoauvo0'mhuv6mim:
`"com:mammoutmunmmm.nac-erlmmmormm;mT-Wrrmumzm.5odem
`normals-pawnnamueeuesfmmuawmummnumswoc-WMMfinTuol
`‘AlafJnnIL1997
`
`
`
`velopment. While the clinical develop-
`ment of doutaxel has largely involved
`asingle administratim schedule (1-hour
`infusion) and a narrow dose range (60
`to l00 mg’m’), the range of paclitaxel
`doses and schedules has been broader
`(varying from 80 to 250 mg/m2 infused
`over I hour weekly to 3-, 24-. or even
`9&hour infusions every 3 ween).
`Paclitaxel
`o Optimal Dose and Sdledflle—Plt-
`clinical data have suggmted that
`the
`duration ofpaclitaxel exposure may be
`more important than dose for the cyto-
`toxic activity of this drug. Depending
`on the duration of exposure, cellular
`cytotoxicin can be achieved at rela-
`tively low concentrations of paclitaxel,
`on the order of 0.0] pM.[l6,l7] That
`duration of exposure can be an impor-
`tant element in the clinical activity of
`paclitaxel has also bun demonstrated
`by the activity of prolonged 96-hour
`continuous infusions in some patients
`with metastatic breast cancer soon after
`their disease progressed during shorter
`infusions of the dnig.{18.l9] However,
`the administration of 96-hour continu-
`ous infusions of paclitaxel imposes is
`certain inconvenience forboth the clin-
`ic and palian
`Many clinical trials have addressed
`the issue ofboth dieoptimal dosing and
`scheduling of the taxancs (rable 2).
`With regard to dosing. the results of a
`randomized trial of paclitaxcl doses of
`135 vs I75 mg/m‘ on a 3-hour schedule
`in pretreated women with metastatic
`breast cancer revealed no major differ-
`ences in response rates (22% and 29%,
`respectively) or median survival dura-
`tions (l0.5 and “.7 months, respec-
`tively). Progression-free survival was
`slightly longerwilh the l7Sl-mg/n'tz dose
`that with the lower dose (4.2 vs 3
`months; F = .01), howeverllol
`'
`In the Cancer and Leukemia Group
`a (CALGB) trill 9342 rcponetl at the
`1998 ASCO meeting, 450 patients were
`mndomizul to receive 175-. 210-. 0r
`Zfifl-rnglml doses of paclitaxel on a
`3-hour schedule. The three groups did
`not differ with respect to moons: rates
`or survival. but the higher doses were
`associated with greater toxicity, panic-
`ular‘ly peripheral neuropathy (26% rate
`ofgrade 3 events). These data provided
`little compelling evidence to support
`paclitaxcl 3-hour infusion dosing of
`greater than 175 mg/m'
`in women
`
`with metastatic breast canccrfll)
`Another randomized clinical trial led
`by M. D. Anderson Cancer Center de-
`tected no significant difference in ob-
`jective responses or survival with
`pacliiaxel at either NO trig/ml via a
`96—hour infusion or 250 mym’ via a
`3—hour infusion—the maximally toler-
`ated doses at these sdreduleleZ]
`Two other trials have addressed op-
`timal paelitaxel scheduling. The ran-
`domized Bristol—Myers Squibb (EMS)
`07l trial. in which women with meta-
`static breast cancer were treated with
`paclilaxcl (I75 mglm') infused ovcr ci-
`thcr 3 or 24 hours. allowing for intrapa—
`tient dose escalation as tolerated. was
`conducted largely in Europe. Canada.
`and lsmcl. The two groups did not dif-
`fa significantly with respect to response
`rates (2996 and 32%. respectively).[23)
`Similar results were obtained by Na
`unnal Surgical Adjuvant Breast and
`Bowel Project (NSABP) tn'al 3-26. in
`this trial, response ran-s for paclitaxel
`(250 mg/m‘) infused over either 3 or 24
`hours were 40% and 50%. respectively,
`suggesting that the more myclosuppres-
`sive 24«hour schedule does not result in
`a significant improvement in outcome
`in the palliativo setting,[24] The inclu-
`sion of patients with stage lllB disease
`partly explains the higher response pro-
`portions in the NSABP 8-26 trial,
`as ' compared to the aforementioned
`.studies.
`
`o Weekly Administration—Another
`method to provide extended cumula-
`tive drug exposure is frequent repeti-
`tive drug administration. such as by a
`weekly schedule, Weekly dosing of
`paclitaxel viaa 1-hour infusionhasheen
`demonstrated [0 be a well-tolerated. fea~
`sible administratiOn Schedule.[251.
`Weekly administration of paclitaxcl is
`both dose-intense and dosedense but
`also has a favorable toxicity profile and
`a remarkable degree of activity in pa-
`tients with mastetic breast canceri
`In our cxpu-iaice at Memorial Sloan-
`Kcttering Cartcchentcr, theoverall re-
`sponse tale to a weekly administration
`schedule was 53% (95% confidence in‘
`terval [Cl]. 34% m 72%), which dom-
`pares favorably with the activity noted
`for 3-, 24-, and 96-hour regimens. in
`contrast to these other regimens how-
`ever, myelosupprcssion was insignifi-
`cant with weekly paclitaxcl. no febrile
`neumpenia was encountered. and no
`
`patient required hematopoietic ngth
`factor suppon.
`A possible explanation for the noted
`uncoupling of drug delivery from my-
`eloloxicuy in weekly l‘huur paclilaxel
`may be found in the pharmaeodynamic
`observation that. with this Schedule,
`plasma paclitaxel concentrations remain
`above 0.1 pmol/L fur a relatively brief
`period after a dose of 100 mg/m' deliv.
`cred over I hour Huiling et al have, in
`fact. previously reported that to achieve
`an 80% decline from baseline absolute
`neutrophil count. plasma paclitaxel con-
`centration onId need to rcmatn above
`the threshold concentration of 0.1
`ttmolll. for approximately 20 hourleé]
`This. Considered together with the cy-
`clie kinetics of ttcutrophil matura-
`tion. may explain the relative lack of
`myelos'uppression.
`
`.
`
`o Puditaxel—Contalning Combina-
`tion Regimens—Given the caveats pre-
`viously raised about combination
`chemotherapy for metastatic breast can~
`err. at the I998 ASCO meeting. Locsch
`ct a1 presented a phase it study aimed at
`dcten'nining the response rate and safe-
`ty of a combination of paclitaxel (8f)
`mgjm2 infused over I hour), fluorou-
`racil (425 mg/m’). and lwcovorin (20
`mglm’) administered weekly as first-
`lint: therapy in patients with metastatic
`breast cancer.|27] Full doses could be '
`administered in the fourth week to only
`63% of patients. primarily due to diar-
`rhea and neurropenia; a “3 week on,
`I
`week off" regimen subsequently over-
`came this problem,
`Thiny patients were evaluated: The
`overall response rate was 47%, with
`l0%cornplete remissions and 37% par~
`lial remissions. This activity is compa-
`rable to other regimens in similar
`palicnls.
`Another abstract presented at ASCO
`1998 reported on the raults of a ran»
`domizerl trial comparing paclitaxel plus
`losorantronc. an anthrapyrazole in
`clinical development, with structural
`similarities to both doxorubicin and mi-
`loxantrone, vs paclitaxcl alone.[28] in
`143 patients. a rfiponse rate of 54‘]:
`was noted with thecombination vs l5‘7o
`with paclitaxel alone (P < .001). Pro
`grassion-frec survivale significantly
`supcnor with the combination regimen
`as well.
`Toxicity was also higher wrth pacli-
`taer plus losoxantrone. however. Pa-
`
`

`

`
`
`2 weeks. followed by 1 week of 0.51.
`MM was administcrui intravenous-
`lyonday l every2i 1028 days.
`A total of 95 women were randoms
`lied. Response rates were 25%in the
`capmitahine-treatad patients and 16%
`in the CMF recipients. and time to pro
`gression wm 132 days with captzcitah-
`in: vs 94 days with CMF.
`Regarding toxicity. grade 3-4 clini-
`cal adverse events were reported by 44%
`of patients receiving capecitabine and
`20% patients mead with CMF. The
`difference between the two groups was
`due primarily to hand-foot syndrome
`(I617 vs 0%) and diarrhea (8% vs 3%).
`0n the other hand. grade 3-4 hemato-
`logic toxicity occurred more fruiuenl-
`ly with CMF (47%) than with tape-
`citabine (20%).
`Overall, within the constraints im-
`posa‘l by relatively small sample sizes.
`it appears that home-based monothera-
`py with capecitahine appears to have at
`least comparable efficacy to CMF com-
`bination thuapy in this older patient
`population.
`in a multicenter trial pre-
`Finally.
`senrm by O‘Reilly :1 a]. the activity of
`capuitabine was compared to that of
`paclitaxel
`in patients with advancal
`brass cancer whose dim had pro-
`gressed following prior anthracycline
`therapy.[33] in this study. two sched-
`ules of capecitahine were planned:
`(1)2,510 mg/m’ld for 14 days. followed
`by l wink of rest; or (2) a continuous
`daily schedule of 1.331 mglrn'ld (The
`continuous arm ofcapecitahine was dis
`continued. however. after two patients
`waeeomlledlpqsonaleommuniration.
`Dr. Fabio Benedctti. Roche. Inc.. Feb-
`ruary 1999]) Paclitaxel was adminis-
`tered at a dosage of 175 mglm2 on
`day I of each 3-week cycle.
`With 4i evaluable patienLt. the in-
`termittent schedule of capecitabine
`yielded a 36% response rate. as com
`pared with a 21% rate with paelitmtel.
`Median time to progression was 92 days
`on the intermittent capacitabine sched-
`ule and 95 days on paelitaxel. Grade 3-
`4 events were reported in 22% of
`patients treated with capecitabine and
`58% given paclitarel.
`I Capecitahlne in Combination
`Regimens—in a rcle'vnnl preclinical
`Japansc study. the efficacy ofcapecit-
`abide and fluorouracil in combination
`with other cytostatic agents. including
`
`taxartes. was evaluated in five mouse
`xenogral't models of human breast car-
`cinoma cells.[34) While the combina-
`tion of fluorouracil and tartanes
`demonstrated only 'additivc efficacy.
`treatment with capecitabine and the tax-
`anes showed synergy and produced tu-
`mor regression in some xenografl
`models. In fact, the tartanes increased
`the tumor levels of thymidine phospho—
`rylasc by four— to eightfold within 4 to
`10 days following the single adminis-
`tration; the treatment did not increase
`the mouse enzyme levels in normal tis-
`surs (intestine and liva), however. Since
`Iumoral thymidine phosphorylase lev-
`els correlate with in vivo susceptibility
`to capuzitahine, it is possible that the
`taxaries may enhance the efficacy of
`capccilab'rnc by upregulaling the en-
`zyme in human mncer cells.
`E.
`. mg
`The continued search for newer
`agents for control ofdisease and pallia-
`tiun of symptoms in metastatic breast
`cancer has also led to the manipulation
`of the more conventional drugs so as to
`achieve equivalent or possibly greater
`activity with decreased toxicity.
`[Jpnsomal Domnthltio
`One promising agent in this respect
`is liposome-encapsulated doxorubicin
`(TLC D99). A phase [ii trial reported
`at ASCO 1998 evaluated its use vs con-
`ventional doxunrbicin. both at a dose of
`75 niglrn:l every 3 weeks.[35)'l‘his trial
`randomized 69 patients who were strat-
`ified on the basis of prior exposure to
`doxorubicin. During the trial. patients
`underwent serial ventriculography at
`cumulative doses of 300. 400. and 500
`mg/m’ and then every cycle thereafter.
`Patients were removed from the study
`if left-ventricular ejection fraction
`(LVEF) declined by 2 20% from the
`baseline value (ifthis value was 2 50%)
`or by 2 lO‘b from baseline (if< 50%).
`or ifcungestive heart failure developed.
`Response rates were 33% in the
`TLC D~99 arm and 29% in the datum-
`bicin arm. Congestive heart failure de-
`veloped in three patients (4%) treated
`with doxorubicin but in none of those
`given TLC D-99. Also. TLC D-99
`generally produced less ernesis. stoma-
`iitis. fever, and infection. suggesting
`that it may as effect.ch as free doxoru-
`hicin but perhaps safer.
`
`A Novel lrnrnunocanjugate
`Tolcher cl :1 described a phase 1]
`randomized trial in which a novel im-
`munoconjugate linking a chimeric hu.
`man/mouse monoclonal antibody to
`approximately eight doxarubicin mole.
`cules was compared to doxombicin.(36|
`This antibody is directed against the
`Lewis’ antigen. which is expressed in
`75% of all breast cancers but has limit-
`ed expression in normal
`tissues. has
`shown promising antitumor activity in
`preclinical xenograft models.
`A total of 25 patian with metastat—
`ic breast cancer entered this trial. There
`was one partial remission in the 14
`patients (7%) on the immunoconjugate
`arm. showing that its clinical activity is
`limited. Also. two patients in this arm
`developed grade 3-4 toxicity with ham
`onhagic gastritis. possiny reflecting the
`fact that the Lewis’ antigen unfortunate-
`ly is also expressed on some gastrointes—
`tinal mucosa] cells.
`
`New, Multitargeted Antitolrtte
`MTA (LY231514) is a new. multi-
`targeted antitolatc that inhibits thymidy~
`late synthase and other relate-dependent
`enzymes. including dihydrofolatc reduc-
`tase and glycinamide ribonucleou'de
`formyluansferase. It has potent antitu-
`mor activity in vitro and in vivo and
`pdechd responses in phase I trials.
`A phase II study that evaluated the
`activity of MTA in 38 patients'with
`locally recurrent or metastatic breast
`cancer was presented at the 1998 ASCO
`meeting.[37] 0f the 38 patients. 8 were
`chemouierapy-na'i've, 14 had received
`adjuvantchcmodtcrapy. II had received
`chemotherapy for metastatic disease.
`and 5 patients had had both. MTA was
`administered at a dosage of600 mg/m'
`every 2] days.
`Responses were documented in 11
`patients (3I%). with I complete and 10
`partial remissions. 0f the 11 patients
`who responded. 5 had received prior
`tartaric or anthracycline therapy. Medi-
`an duration of response was 8+ months.
`Overall. 135 cycles of MTA were de-
`1ivered with 28 dos: reductions and 26
`delays. Reasons for reductions includ-
`al neutropenia (39%). mucositis (18%).
`and uansaminase elevation (23%).
`Grade 24 nonhematologic toxicities
`included mucositis (34%). nausea and
`vomiting (39%). and tritnsaminase ele-
`vaiion (88%). Also. a grade 2 skin rash
`developed in 50% of patients, a grade 3
`
`652
`
`ONCOLOGY - voumr i1 - NUMBERS
`
`AstraZeneca Exhibit 2010 p. 3
`
`
`
`Figure 1; Chemical Structure and Mechanism at Action or capecltnbtrie—
`5’—DFCR = S’-Deoxy-5»lluorocytidine: 5’»DFUR = 5'-l?ooxy-5«fluoroundtno;
`dTHdPaso = Thymidtne phosphorylase; 5-H) = Fluorouractl
`
`convened to fluoroumcil by thrm en—
`zymcslocaiedinthcliverandwithin
`tumors. with the futal conversion 51m to
`“mil catalyzed by thymidine phos-
`phtxylase, which is found preferentially
`in txeastcancercells as compared to su-
`rounding normal host tissues (figure 1).
`An abstract prescntcd by Blum et a]
`at the [998 ASCO meeting descriheda
`.phase II trial of Mice-dain oral mpeeit;
`abine (2.510 mg/m’ld) given for 2
`weeks, followed by a 1—week rest peri-
`od. and repeated in 3-week cycles.
`among patients with paclitaxel-refiac-
`tory metastatic breast cancer.[31] A to-
`tal of 163 patients were enrolled by 24
`centers; patients had received at least
`two but no more than titrtae prior che-
`motherapeutic regimens. one of which
`contained pactituel as treatment for
`metastatic disease.
`The primary study end point was
`tumor response in patients with mea-
`surable disease. The response rate was
`20%. median response duration was 8.l
`months, and median survival was 12.8
`months. Moreover.
`in patients will
`baseline pain > 20 nun on a visual ana-
`log scale. 47% showed a significant im-
`provement in pain. Diarrhea (14%) arid
`
`‘
`
`hande syndrome (10%) were the
`only treatment-related adverse events
`thatooctn-red with a grade30r4 inten-
`sity in 2 10% of patients. Alopccia did
`not occur and myelosuppression was
`minimal; there was no mohair—relat-
`ed mortality.
`.
`Given these data and the historical
`context of the use of continuous intta‘
`venous infusions of fluorouracil as a
`salvage Uierapy for metastatic breast
`cancer. capecitabine was approved by
`the FDA for use in patients with pacli-
`incl-refractory metastatic breast can-
`cer in the spring or1998.1n summary.
`rapecitabine can be considered an ac-
`tive drug in the treatment of paclitaxel-
`rcfractory advanced brcaét cancer with
`a relatively favorable toxicity profile.
`- Capedlablne vs Other Agents—A
`smom‘l abstract repormd at ASCO 1998
`presented the results of a randomized
`phase 1] trial of capecitabine vs cyclo-
`phosphamide. methotrutate. and fluorou-
`iacil (CMF) as first-line chernotlrrapy
`for advanced breast cancer in women
`>55y¢arsold(medianageinbothgrmps.
`69 yrars).[32] Capecitabirie was givui
`orally at a dmage of 2.510 mg/mlld for
`
`MAY 1999 - oucomov
`
`651
`
`Macadam
`Capecitabine
`Considering new; drugs [or advanced
`breast cancer. one of the mos interesting
`agents is capecitabine (Xeloda). Capecits
`abine is a novel. oral. selectively tumor-
`activated fluoropyrimidint: camamatcthat
`hm shown promising activity in breast
`and colon cancers during pbaSc l and II
`evaluations. This agent
`is sequentially
`
`tients treated with the combinaan reg-
`imen had a 66% incidence of grade 3—4
`neutropenia. vs a rate of 32% with
`paclitaxel alone. and two cases of con-
`gestive hean failure occurred with the
`combination. vs on: case with pactitax—
`el alone. Analysis of survival awaits
`longer follow-up. but these data are cer-
`tainly provocative, if not surprising in
`light of the ECOG 1193 results with
`paclitaxel plus doxorubicinl‘l]
`Dooelaxel
`Regarding docetaxel. Loetflcr et :1
`reported their experience with weekly
`infusions in stage 1V breast cancer pa~
`ticnts.[29] Doses were escalated in in-
`crements of 5 mg’m‘ from 30 to 45
`mglm2 weekly x 6 with a 2-week break.
`The overall response rate was 50%. with
`15% complete remissions and 35% par-
`tial remissions; 38% of patients had sta-
`ble disease. Moreover, three out of five
`patients with it history of prior paclitait-
`el therapy responded to docetaxel. These
`investigators observed that weekly doc-
`etaxel has activity in chemotherapy-pre-
`treated breast cancer that is comparable
`to 100 mg/m‘ of docetaxel every 3
`weeks. but with apparently less grade
`341cukopcnia.
`Another ASCO presentation by
`SJostrom et al focused on a phase 111
`trial that compared docctaxel (100 mg]
`nfl every 3 weeks to methouexate (200
`mg/m‘) plus fluorpuracil (600 mglm’
`on days 1 and 8) every 3 weeks (MF
`regimen) in l99paticnts with anthracy-
`Cline-resistant breast cancer.[30] The
`overall response rate (partial and corn
`pleic) was 42% in the deceiaxel arm
`and 197a in the MF arm (P < .001);
`inedian time to progression was 6
`months in the docuaxel group and 3
`months in the MP group (P = .006).
`' These results thus demonstrated the su»
`perior-lty ofsingle—agerit docetaxel over
`MF for patients wtth antl‘tracycline-re»
`sistanl metastatic breast cancer.
`
`

`

`
`
`the patients
`advantages. However.
`who received concomitant
`tamox-
`ifen and gosctclin experienced more
`tonicity.[50]
`o Tamoxifen Raistance—Unfonu-
`nately. breast cancer in most patients
`will eventually become resistant
`to
`tamoxifen. Tamoxifen resistance is not
`fully understood. None of the proposed
`mechanism. such as the emergence of
`tamoxifen—dependent cell
`lines and
`loss or mutations of the ER. its func~
`tions. and interactions. appear to com-
`prehensively explain resistance to
`tamoxifenljljl]
`Other Antlestrogens
`The significant activity and relative-
`ly modest toxicity oftanwxifen (ie. high
`therapeutic index) when compared with
`cytotoxic chemotherapy has led to an
`intensive search for other hominnal
`agents.
`‘
`- Toremitene (Fareston), an anties-
`tmgen with properties similar to those
`of tamoxifen. was recently approved in
`the United States for the treatment of
`metastch breast cancer. Large Ameri-
`can and European randomized studies
`found no significant differences in the.
`efficacy and safety of toremifene and.
`tamoxifen when the two therapies were
`compared in posuncnopausal women
`with ER positive or unknown tu-
`mors.153-57] The reported rfiponse‘
`rates were between 29% to 50%,
`Toremifene doses higher than 60 mg/d
`did not offer any advanutgr-s over lower
`doses. A crossover u-ial demonstrated
`cross-resistance o