Combinations of two, thrw, or more
`Chcmothuapculic agents are occasion-
`ally employed based on prxlinical data
`suggesting improved antimmot activity
`(ie, additive or synergistic effects);
`manyofthme cornbinatinrtsarte derived
`empirically, however. Alihough 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 suidies presented at
`the 34th annual meeting of the Ameri-
`can Society of Clinical Oncology
`(ASCO) in I998.
`The first study, conducted by the
`Finnish Breast Cancer Group, random-
`ized303 breast cancer-patients with dis-
`taut metastases to one of two regimens:
`(l) single-agent chemotherapy with epi-
`nrbicin (20 tug/m‘ weekly until disease
`pmgtefiion or a atmulalive dose of
`l,(XXl mg/m’). followed by mitomycin
`(8 mglm’ every 4 weeks) as second-line
`therapy; or (2) the CEF polyt:hemotlter-
`apy regimen. consisting of cyt:lophos-
`phamide (500 mg/m’), epiruhicin (60
`mg/tn’), and fluorouracil (50) mglm’)
`every 3 weeks. followed by mitomycin
`(8 tnglm’) and vinblastine (6 mg/m’)
`every 4 weeks. Although responses to
`CE.Ftendedtolastmodcstlylongerthan
`responses to epirulticin alone (med.ian
`duration. I2 vs 105 months: P: .07).
`no significant difference in time to pro-
`gression (P =.28) or overall survival (P
`=.65)wasfound betweenthetwo arms.
`Moreover. no difference in survival
`was seen when only the patients who
`received both the fir:t- and second-line
`treatmet-_in were compared (F = .96). or
`when survival was calculated from
`the beginning of second-line therapy
`(P: 56).Sing1e-agent therapy was also
`tnsociared with less toxicity and better
`quality of lil’e.[5]
`The second report, presented by the
`Inl.ernal.i0na|Taxotn'e 304Sutdy Group,
`described the results of a phase 11]
`study comparing single-agent dooetax-
`el (Taxotere) therapy vs the combina-
`tion of mitomycin and virtblastine in
`patients with metastatic breast utncer
`whose disease had progressed follow-
`ing an aothracycliue-containing regi-
`men. In this experience, single-agent
`
`docetaxel thctapy proved more effec-
`tive than mitomycin plus vinblastine,
`not only with respect to response rate
`and time to treatment failure, but. must
`gnutytngly. with regard to survival.
`Median survival duration was I [.4
`months in the docetaxel group vs 8.7
`months in the ntitornycin-vinblastine
`E'°11PU’=-0097)-[5]
`In this context,
`the experience of
`Sledge and colleagues. reported at the
`1997 ASCO mating, should be con-
`sidt-.red.[7] In that study, Eastern Coop
`erative Oncology Group Study (ECOG)
`H93. single-agent thaapy with either
`dmtontbicin or paelitaxel (Taxol) was
`compared with the combination ofdo1-
`orubicin and paelitaxel as first-line
`therapy in 739 patients with metastatic
`breastcancer. Patients receiving single-
`agent therapy were crossed over to the
`other agent at the titne of disease pro-
`gression.
`Monotherapy with either doxorubi-
`cin or paclitaxel had equivalent thera-
`peutic activity; the combination of the
`two drugs resulted in superior overall
`response rue 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 trials should
`prompt a reconsideration of the con-
`ventional" wisdom that combination
`chemotherapy is the “gold.stalnda.tt:l"
`for the tn-‘sument of metastatic breast
`cancer.
`
`l.€_M2z:_BelZet:Z
`
`Ultimately. the treatment of stage IV
`breast cancer often represents an anempt
`to reach anequilibriurn 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 imponance.
`since increased doses are oommonly as-
`sociated with greater toxicity.
`
`Dose-lnlensified Regimens
`A trial of the Italian group Gruppo
`Oncologico Nord-Ouest (GONG), re-
`ported at ASCO 1998 by Lionetto et al.
`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 supprtn; patients in the
`
`“intensified CEF' arm actually received
`'an 30% il‘lCl'I'£lSC in dost: intensity corn-
`panzd to those in the standard CEF
`arrn.1l£] Quality oflife was also assessed.
`in the i5] rtndontizul palienls. no
`differeneu between the two anns were
`observed with respect to 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
`(anetnia. 18% vs 3%; leulropcnia. 26%
`vs 6%; thrombocytopenia, 8% vs 2%;
`and mucositis, 13% vs 3%).
`
`High-Dose Chemathenpy.
`With Stem-Cell Support
`Regarding dose 5t;ilau'on,.the po-
`tential role of high-dose chemotherapy
`with stem-cell rc_st:uc still awaits tkfi-
`tuition. Although some authors have re-
`ported 5-year disease-free survival
`proponions of approximately 20% in
`selected pa.LlclILS treated with such regi-
`rneus.[9.l0] 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 II trials. often accompanied by the
`irresistible. but problematic and unfor-
`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 autolngnus bone marrow or pe-
`ripheral blood stern-cell supporL con-
`ducted by Bezwutla et al, showed that
`high-dose therapy significantly extend-
`ed the durations of response and
`survivalll l I] However, the rntzdian 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. seven]
`presentations evaluated different trans-
`plant modalities. ie, single vs tandem
`highdose che
`y, tandem vs tri-
`ple highaiose chemotherapy, and purg-
`ing oftumor cells from peripheral blood
`stem cells.[l2,l3] The exploratory na-
`ture of these trials and preliminary re-
`sults underscore the need for large.
`prospective clinical
`trials to address
`these questions.
`
`648
`
`oNcot.ocv - voume I3 - NUMBERS
`
`Astrazeneca Ex. 2010 p. 1
`Mylan Pharms. Inc. V. Astrazeneca AB IPR2016-01325
`
`
`
`MOMCA FORMER, MD
`PAMELA MUNSTER. MD
`ANDREW D. SEIDMAN. MD
`Breast Cancer Medicine Sernce
`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 cattse ofcancer dcath.[l] Over
`the past several decades, there has been
`a fairly steady increase in the incidence
`of the disease. Epidcmiologic 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 disease at
`some point during her life.[2)
`Although approximately 30% of
`breast cancer patients present with dis-
`ease limited to the breast andlor axil-
`lary lymph nodes. almost halfofthese
`patients later develop metastatic dis-
`ease and eventually succumb to it. Met-
`astatic breast cancer represents a
`historically incto-able condition despite
`the judicious use of various hormonal
`manipulations. as well as surgical and
`ntdiotherapeutic interventions, and the
`application of active cytotoxic chemo
`therapeutic agents for homtone-reFrae-
`tory disease. For most patients with
`metastatic disease. treatment provides
`only temporary control of cancer
`growth, Outside ofexperimental prottr
`cols, the goals of management, there-
`fore. an: to pailiate symptoms with as
`little treatment-related toxicity as pos-
`On: 01 two copies of this article in personal
`or internal use may be made at no charge Copies
`beyond that number require that a 9: pa page per
`copy fee be paid to the Copyright Clearance Cen-
`Ier, 222 Rosewood Drivc. Danters. MA 01970.
`Specify ISSN 0S9t}909|. For iurttu ii-ifonna-
`tion. contact the EEC at 503-150-3411). Write
`publisher for bulk quantities.
`
`ABSTRAC|'
`
`Recent trials comparing tingle-agent vs combination therapy in meta-
`sum’: breml cancer suggest that it may be time to reconsider the beliefthat
`combination clurnothuropy it the goldstandardoftrznnncnt. Based on the
`limited randomized trial data available to date, high-dart chemotherapy
`with sum-cell rescue should not be viewed as “stole-of-the or!” treatment
`for metastatic d.i.t¢ose and shooldbe used only in the context ofclinical
`triatt. Recent trials have explored the optimal dosing and Ichaduling of
`the mrantx, as well or the possible role of Ihac ogenu in eootbinntion
`regimens. Copecitabine (Xelodn), a new omlfluoropyr-iotidinc, appear: to
`be comparable in eflicoey to CMF (cyelophosplutnudc, mellxatrexale, and
`fluoroumcil). and prtclirtical data suggest possible ryncrgy between this
`agent and the lautnu. Other promising agent: under nod; include lipo-
`roonz-znmpsulotcddarontbicio (TLCD-99), on immunocottfugnu linking
`a chimeric human/tuouu moooclonalatuibodyto doxorttbicin molecules;
`MTA (LYZJISI4), o rrtultitorgelzd ortnfolatc; and moriotirtar, a broad-
`rpectrum matrix tnet'al.lopmt¢t'na.re
`Tnmnrtfen (Nolvodzx) re-
`mains the marl intpunant hormonal agent, but new andlslrognu and
`relative estrogen receptor modulators (SERM:) moypnrrida alternatives.
`1'hepotenlz'alrolen[ncwm-ontotase inltibilarxosfirsl-liru kormonalogenls
`require:further mzdy. Finally, the possible synergy between mzxtuzmnnb
`(Hareptin), a recombinant humanized monoclonal arttibody to the HER-
`2/ncu protein, andpocfilnrel (Tno!) it being studied in two clinical b-ials.
`
`
`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. leg commonly. complete re-
`sponse to single-agent therapy; the du-
`ration of such responses averages 6
`monil-is.[3] Historically. the most corn-
`monly used cytotoxic agents in the man-
`agcmenl of metastatic breast cancer
`
`have been cyclophosphatriide (Cytox-
`an. Ncosar), methotrexate. fluorouracil,
`doxorubicin, and. more recently,
`the
`taxanes. When the disease progresses
`further, vinorelbinc (Navelbine) and
`other vinca alkaloids. mitomycin
`(Mutamycin). mitoxantroue (Novan-
`oone). gemeitabine (Gemzar), empo-
`side. and cisplatin (Platinol) represent
`some ofthe outer frequently used cyto-
`toxic drugs.
`
`MAY 1999 - ONCOLOGY
`
`647
`
`

`
`Randomized Trials of High-Dose Chemotherapy/Autologous stem-cell Rescue (HDCIASCR)
`tor Metastatic Breast Cancer,
`Trlal Number]
`590'-wlu)
`PET-Ol (Philadelphia
`Group, ECOG. SWOG.
`NCCTG)
`Duke University
`
`‘
`
`Table l
`
`.
`
`HDCIASCR Ann
`CMF/CAF x #-6.;
`HDCJASCR: CTCII
`
`contlolAn-n
`fl-6—o
`CMF/CAFH
`CMF X Z )7
`
`' AFM 2: 2-4-9
`At relapse: CEF
`CEF-xb
`
`Continua A (to dose limit)
`orTtr (9 cycles)
`
`AFM to 2-1 —~
`HDC-/ASCR: CE?
`CEFX 4 —i
`HDCIASCRI CT
`A or Tit ~< 4 -9
`HDG’ASCFl:
`CMICI) x 2
`__:._:—_?
`Adapted from Zuiowilu J 4 Han CancarlnsI90(3):200-209. 1995.
`A = Atkiarnyoin; AFM . Adlriamycm, ltuorouroal, meoioumn; out = Cyelophospnmruno,AntumYI1l|.lbrorotuodl; can .D . ocuu (car-
`mustlne), ohrlalln; CEF . c1¢tnphoa,pnamion.|hiuo\uac’l;CIAF -c rrutriotrtuato. Iuolourlci; cuncn -c , ml-
`ta-antrone. r.amapI.1tln:CY : Cychcttosuhatnldo. tnlotupa. ctou - cydounosnnamld-. tnirtopl.asrooplairi; ECOG =E1uomt:mpaauvo0-Izahuyarnqr:
`NCCTG:NormCorttralCa.r\cuTrIatrrtorI6Itru:t.MGlCurhlhmalCvtoIImmtmo1CutAda:PBT-PvihddwJaTtamuamGrnv:PEGASE-Sodom
`FruncalslDIGIahaDuMaelLc.FaonratkxtNauu1al0uuflnC<xIuILtCIIce1ZS7NOG-5nu¢tviI!t(lfl£¢0SV5'°||91T|‘7|3°l
`-IuatJuruI,t997
`
`PEGk5E
`
`NCIC
`
`On the basis ofthc limited data avail-
`able to date from randomized. prospec-
`live trials. high-dosc chemotherapy
`cannot yet be considered "stale-of-the-
`. art" treatment for advanced brvast can-
`ccr and sliotddbe offered only to patients
`in the setting ofclinical trials. The final
`results of such large prospective trials
`are eagerly awaited (Tabli: 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. 'l'hr_se in-
`clude the development of newer active
`drugs, or the exploration of different
`:lll¢l'n3llVC$, for example, biological
`therapies.
`
`Be‘rr
`
`The la.lan:S_ ic, paclitaxcl and draco-
`tutcl. are a relatively new addition to
`(ht: clternothctapeutic arsenal against
`breast cancer. Their mechanism of ne-
`liun involves the fomtation of polymer-
`izcd microtubulcs and their stabilization
`against the forces that load to deputy-
`meriution. Proapoptoti: effects. as well
`as antiangiogenic actions, trtay also be
`clinically relevanl.[l4,l5]
`The tlclcnnlnalion of optimal dos-
`ing and scheduling of taxancs has been
`an irnponant objective during their dc-
`
`Sample Slzn
`Aoauar
`587(standart1 dose)
`516 (high dose)
`ED
`
`‘raiuut
`Completion Date
`Wln1ar1997
`'
`
`150
`
`.192
`
`velopment. While the clinical develop-
`men! of doceuuel has largely involved
`asingle adrninistrmiort st:ltcdt1lc(l-hour
`infusion) and at narrow dose range (60
`to l00 mglm’), the range of paclilaxel
`doses and schedules has been broader
`(varying from 80 to 250 mg/m’ infused
`over I hour weekly to 3-. 24-. or even
`96-hour infusions every 3 ween).
`Puclitaxd
`. optimal Dose and Schedulc.~—Pre-
`clinical data have suggmted that
`the
`duration ofpaclitaxel exposure may be
`more important than dose for the cyto-
`toxic uctivity of this drug. Depending
`on the duration of exposure, cellular
`cytotuxicity can be achieved at rela-
`tively low concentrations of paclitaxel,
`on the order of 0.0] p.M.[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 inftuions in some patients
`with metastatic breast cancer soon after
`their disease progressed during shorter
`infusions of the dntg.{l8,l9] However,
`the adtrtinistnttion of 96-hour continu-
`ous ittfusiotls of paclitttxel imposes a
`cznairr inconvenience forboth the clin-
`ic and patient.
`Many clinical trials have addressed
`the issue ofboth dteoptimnl dosing and
`scheduling of the taxanes (Table 2).
`With regard to dosing, tlte results of a
`randomized trial of paclitaxel doses of
`135 vs I75 mg/m’ on a 3-hour schedule
`in pretreated women with metastatic
`breast cancer revealed no major differ-
`ences io response rates (22% and 29%,
`respectively) or median survival dura-
`tions (l0.5 and ll.7 months, respec-
`tively). Progression-free survival was
`slightly longerwith the I75-mg/m’ dose
`than with the lower dose (4.2 vs 3
`months; P = .07.), howcver.[20}
`'
`In the Cancer and Leukemia Group
`B (CALGB) trial 9342 reported at the
`I998 ASCO meeting, 450 patients were
`mndotrtizui to receive I75-. 210-. or
`250-mglm* doses of paclilaxcl on a
`3-hour schedule. The three groups did
`not differ with respect to rmponse rates
`or survival, but the higlter doses were
`associated with greater toxicity, panic-
`ularly 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 cancer.l2l)
`Another randomized clinical trial led
`by M. D. Anderson Cancer Center de-
`tected no significant difference in ob-
`jcelive responses or survival with
`pacliiaxel at either N0 mg/nt‘ via in
`96-hour infusion or 250 mg/m’ via a
`3-hour inl’usion—tht: maximally toler-
`ated doses at these sdieduli-.s.[22]
`Two other trials have addressed op-
`timal paelitaxcl scheduling. The ran-
`domized Bristol—Myct-s Squibb (EMS)
`07l trial, in which women with meta-
`static breast cancer were treated with
`paclilaxcl (175 mg/m‘) infused over ei-
`ther 3 or 24 hours. allowing for intrapa-
`tient dose escalation as tolerated. was
`conducted largely in Europe. Canada.
`and lsrncl. The two groups did not dif-
`fu significantly with respect to response
`rates (29% and 32%. re5pectively).[23)
`Similar results were obtained by Na-
`tional Surgical Adjuvant Breast and
`Bowel Project (NSABP) trial B-26. in
`this trial, response rates for paclitaxel
`(250 mglm‘) infused over either 3 or 24
`hours were 40% and 50%. respectively,
`Suggesting that the more myclosttppres-
`sive 24-hour schedule does not result in
`it significant improvement in outcome
`in the palliative setting,[24] The inclu-
`sion of patients with stage IIIB disease
`partly explains the higher response pro-
`portions in the NSABP B-26 trial,
`as ' compared to the aforementioned
`.sutdtes.
`
`I Weekly Ad.tninlsi.ratlon—Another
`method to provide extended cumula-
`tive drug exposure is frequent repeti-
`tive drug adrninistntion, such as by at
`weekly schedule, Weekly dosing of
`paclitaxel viaa I-hour ittfusionltasbeen
`demonsurtted to be a well-lolcta1od.fe:t~
`sible administration schedule.[251_
`Weekly administration of paclitaxcl is
`both dose-intense and dose-dense but
`also has a favorable toxicity profile and
`a remarkable degree of activity in pa-
`tients with rnetasuatic breast cancer.
`In our expu-iaice at Memorial Sloan-
`Kertering CancerCenter, theovemll re-
`sponse tale to a weekly administration
`schedule was 53% (95% confidence in-
`terval [Cl]. 34% to 72%). which oom-
`pares favorably with the activity noted
`for 3-, 24-, and 96-hour regimens. ln
`contrast to these other regimens how-
`ever. myelosupprcssion was insignifi-
`cant with weekly paclitaxel. no febrile
`netttropenin was encountered. and no
`
`patient required hcrnatopoietic growth
`factor suppon.
`A possible explanation for the noted
`uncoupling of drug delivery from my.
`clutoxtctty in weekly l-huur paclitaxel
`may be found in the phztrmaeodynamic
`observation that. with this schedule,
`plasma paclitaxel concentrations remain
`above 0.1 ttmol/L for a relatively brief
`period after a dose of 100 mg/m' deliv.
`cred ovcr l hour. Huizing et al have, in
`fact. previously rcponed that to achieve
`an 80% decline front baseline absolute
`neutrophil count. plasma paclitaxcl con-
`centration would need to remain above
`the threshold concentration of O.l
`ttmolll. for approximately 20 hours.l26]
`This. considered together with the cy-
`clic kinetics of ncutrophil matura-
`tion. may explain the relative lack of
`myelosupprcssion.
`
`.
`
`0 Puclitaxel—Contalnlng Combina-
`tion llegimrns—Ciiven the cavt-sits pfl:-
`viously raised about combination
`chemotherapy for metastatic breast can-
`cer, at the I998 ASCO meeting. Loesch
`ct al presented a phase ll study aimed at
`dctennining the response rate and safe-
`ty of a combination of paclitaxel (Sf)
`mgjm’ infused over I hour), fluorou-
`racil (425 mg/m’). and leucovorin (20
`mglm’) administered weekly as first-
`lint: therapy in patients with metastatic
`breast c:tncer.[27] Full dnscs could be ‘
`administered in the fourth week to only
`63% of patients, primarily due to diar-
`rhea and ncutropenia; a “3 week on,
`I
`week off" regimen subsequently over-
`came this problem.
`Thiny patients were evaluated: The
`overall response rate was 47%, with
`lofiicornplete remissions and 37% par-
`tial remissions. This activity is compa-
`rable to other regimens in similar
`patients.
`Another abstract prt'.re.ntecl at ASCO
`1998 teponrd on the raults of a ran-
`domized trial comparing paclitaxel plus
`losoxantronc. an anthrapyrazole in
`clinical development with structural
`similarities to both doxoruhicin and mi-
`loxantrone, vs pnclilaxcl alone.[2ll] ln
`I43 patients. a rfiponse rate of 54']:
`was noted with thecombination vs l5‘7o
`with paclitaxel alont; (P < .001). Pro-
`gression-frec survival was significantly
`superior with the combination regimen
`as well.
`Toxicity was also higher with pacli-
`taxel plus losoxantrone. however. Pa‘-
`
`650
`
`ONCOLOGY - VOLUME 13 - NUMBER 5
`
`
`Tabla?
`Randomized 1’rials of Slngle-Agent Taxaites In Metastatic
`Breast Cancer: Dose and Admlnlatratlon Schedule
`D030
`Attmlnixtrntlon
`Response
`Sfitodulollt)
`RINGS)
`(fl\§lm'l
`
`PVIIUO
`
`Study
`Paclltuel
`ams 048
`
`EMS 071
`
`NSABP B-26
`
`CALGB 9342
`
`t‘r'5m9fm’,
`tasmglrn‘
`l75~mg/rn-'
`
`250 rn9’m'
`
`t7SrI'lglm‘
`Ztomglm’
`250mgIrrr'
`t40rno’m*
`250 rnglrrt’
`
`an
`
`3h
`24n
`an
`24h
`an
`
`I
`
`star:
`{In
`
`In
`
`29'.’-
`22%
`297-
`32%
`40%
`50%
`ztx
`28%
`22%
`29%
`23%
`
`NA
`
`.108‘
`
`NS
`
`NS
`
`NA
`
`MDACC
`Dooetaul
`HPR
`I00 rnglm’
`75 rnglml
`:j.j_.
`Bus-Bnstnt-MyouSqidnu;cALGa=cmemuu1LouherriaGmi.ipB:MDAGC= H.D.Ariderwrt
`cuumcuunNA.uuaupiuu-;Ns.nu-umuzrmnsnarxnuth-mnamuusawcuoroast
`arIdBoaolP'°i£fiRPR-Rh¢1io—Pou!Iul:Flovur
`
`MAY I999 ' ONCOLOGY
`
`649
`
`Astrazeneca Ex. 2010 p. 2
`
`

`
`tients treated with the combination reg-
`itnen had a 66% incidence of grade 3-4
`neutropenia, vs 2 rate of 32% with
`paclitaxcl alone. and two cases of con-
`gestive heart failure occurred with Lltc
`combination. vs one case with pttclitax-
`el alone. Analysis of survival awaits
`longer follow-up, but these data are cer-
`tainly pmi-ocative, if not surprising in
`light of the ECOG 1193 results with
`paclitaxel plus tloxorubicin.[7]
`Docelaxel
`Regarding docetaxel. Loefller et at
`reported their experience with weekly
`infusions in stage IV breast cancer pa-
`ricm_r,,[29] Doses were escalated in in-
`crements of S mg-‘m’ front 30 to 45
`mglm’ weekly x 6 with a 2- week break.
`The overtll response rate was 50%, with
`IS% complctc remissions and 35% par-
`tial remissions; 38% ofpatiet-its 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
`3-‘v lcukopcnia.
`Another ASCO presentation by
`Syostriim et al focused on a phase ~lII
`trial that compared docctaxel (I00 mg]
`m:) every 3 weeks to methouexate (200
`mg/m‘) plus fluorouracil (600 mglrn'
`on days I and 8) every 3 weeks (MF
`regimen) in l99paticnts with anthncy—
`cline-resistant breast cancer.[30] The
`overall response rate (partial and com-
`plete) was 42% in the docctaxel arm
`and I97: in the MF arrn (P < .00I);
`rnedian time to progression was 6
`months in the tlocetaxel group and 3
`months in the Ml‘ group (P = -005)-
`' These results thus demonstrated the su-
`periority ofsinglc-agent docet.-rxel over
`MF for patients with arithracycline-re
`sistant metastatic breast cancer.
`
`Aimccdgeztts
`Capecitahine
`Coruidczing ncwur drugs [or advanced
`breast cancer. one of the mos interesting
`agents is capccitabine fxeloda). Capecit-
`abine is a novel. oral. selectively tumor-
`activatcd fluoropyriniidinc carbarnarcthru
`hu shown promising activity in breast
`and colon cancers during phase l and ll
`evaluations. This agent
`is sequentially
`
`
`
`Figure 1; Chemical Structure and Mectranisin of Action of Cepec|tnbin_e—
`5'-orcn = S’-Deoxy-5-tluorocytidine: 5'-orurt = 5-Peary-Erfluurvundtnaz
`dTHdPase = Thymictine r>hosphory1ase:5+FU = Flwmumc-'
`
`convened to fluoroui-.icil by three en-
`zytrtcslocatedititheliverarrdwithin
`tumors. with the final conversion step In
`lluorotnarcil catalyzed by thyrnidirte phos-
`phtxylase, which is found preftacntially
`in lxeastcancercells as compared to sit-
`rounding normal host tissues (figure 1)-
`An abstract presented by Blum et al
`at the l998 ASCO meeting dcscribeda
`,phase II trial of ntvice-daily oral mpecit—‘
`abine (2,510 mg/m’Id) given for 2
`weeks, followed by a l-week rat peri-
`od. and repeated in 3-week cycles,
`among patients with paclitax:l-refrac-
`tnry metastatic breast canccr.[3 I] A to-
`tal of 163 patients were enrolled by 24
`centers; patients had received at least
`two but no more than tluee prior clic-
`motherapeutic regimens. one of which
`contained paclituel 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 I28
`months. Moreover,
`in patients with
`baseline pain > 20 mm on a visual ana-
`log scat; 4711-, showed a significant im-
`provement in pain. Diarrhea (14%) and
`
`‘
`
`hand-foot syndrome (10%) were the
`only treatment-related adverse events
`thatoocurred with a grade3or4 inten-
`sity in 2 |0‘i2 of patients. Alopccia did
`not occur and myelosuppressian was
`minimal; there was no t:t'c'.ttrnent—r'clat-
`ed mortality.
`.
`Given these data and the lti5lOrlC1l
`context of the use of continuous intra-
`vcnous infusions of lluorouracil as a
`salvage uierapy for metastatic breast
`cancer. capecitabine was approved by
`the FDA for use in patients with paell-
`taxct-rcfnictnry metastatic breast can-
`oer in the spring of 1998. In sumrnttry.
`rapecitabine can be considered an ac-
`tive drug in the treatment of paclitaxel-
`refractory advanced breast cancer with
`a relatively favorable toxicity profile.
`- Capedlablne vs Other Agents-—A
`smond abstract repormd at ASCO 1998
`presented the results of 3 randolltizf-4
`phase II trial of capccitabine vs cyclcr
`phasphamidc. rnethotrutatz. and fluorou-
`iacil (CMF) as first-line cl'iernotlr.mP)'
`for advanced breast unfit-I’ in WOMEN
`>55y¢arsold(rnedianageinbothgro_ups.
`69 yt-ars).[32] Capecitabine was gtvfll
`orally at a dmage M1510 ms/ml/Cl 5°’
`
`my .999 . ONCOLOGY
`
`651
`
`2 weeks. followed by 1 week of RSI,
`mdClVl'F was administered intravenous-
`lyonday l every2l to28 days.
`A total "of 95 women were random-
`ized. Response rates were 25%'in the
`capecitabine-treauad patients and I695
`in the CMF recipients, and time to pro-
`gression wm 132 days with capt:citab-
`ine 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 trmted with CMF. The
`difference between the two groups was
`due primarily to hand-foot syndrome
`(l6% vs 0%) and diarrhea (8% vs 3%).
`On the other hand, grade 3-4 hemato-
`logic toxicity occuned more l'mqucnt-
`ly with CMF (47%) than with cape-
`citabine (20%).
`Overall, within the constraints im-
`posdl by relatively small sample sizes,
`it appears that borne-based monothera-
`py with capecitabine appears to have at
`least comparable efficacy to CMF com-
`bination therapy in this older patient
`population.
`in ii multicenter trial pre-
`Finally.
`sented by O‘Reilly et al, the activity of
`capecitabine was compared to that of
`paclitaxel
`in patients with advnncal
`brmst cancer whose disuse had pro-
`grcssed following prior lmthmcyclinc
`therapy.[33] In this study, two sched-
`ules of capecitabine were planned:
`(1) 2,5 10 mg/m’ld for I4 days, followul
`by 1 week of rest; or (2) a continuous
`daily schedule of L3]! nrgIrn'lcL (The
`continuous arm ofcapecitabine was dis-
`continued. however, after two patients
`waeen.t:olled.[persooalcomnumiration_
`Dr. Fabio Bcnedetti. Roche. Inc.. Feb-
`ruary 1999]) Pnclitaxel was adminis-
`tered at a dosage of 175 mglm’ on
`day I of each 3-week cycle.
`With 4l evaluable patients. the in-
`termittent schedule of capecitabine
`yielded a 36% response rate, as oom-
`pared with a 21% rate with paclitariel.
`Median time to progression was 92 days
`on the intermittent capccitabine sched-
`ule and 95 days on paclitaxel. Grade 3-
`4 events were reported in 22% of
`patients treated with capecitabine and
`58% given paclitaxel.
`I Capecitahln: in Cumhiltallon
`Regimens-—ln a rcle'vnnl preclinical
`Japanese study. the efficacy ofcapecit-
`abide and lluorouracil in combination
`with other cytostatic agents. including
`
`taxancs, was evaluated in five mouse
`xenograft models of human breast car-
`cinoma celIs.[34l While the Combina-
`tion of lluorouracil and taitanes
`demonstrated only additive efficacy.
`treatment with capecitabinc and the tax-
`anes showed synergy and produced tu-
`mor regression in some renograft
`models. In fact, the taxanes increased
`the tumor levels of thymidine phospho-
`rylasc by four- to eightfold within 4 to
`10 days following the single adminis-
`uatiori; the treatment did not increase
`the mouse enzyme levels in normal tis-
`surs (rntr-_stine and livu), however. Since
`tumoral thymidine phosphorylase lev-
`cls correlate with in vivo susceptibility
`to capazilabine, it is possible that the
`tax-aries may enhance the cfficacy of
`capccitabinc by uprcgulating the en-
`zyme in human mncer cells.
`E.
`. mm
`Thr: continued search for newer
`agents for control ofdiscasc and pallia-
`tion 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
`aclivily with decreased toxicity.
`Liposomal Doxonrhlcin
`One promising agent in this respect
`is liposome-encapsulated doxorubicin
`(TLC D-99). A phase ll] trial reported
`at ASCO 1998 evaluated its use vs con-
`ventional doxonrbicin. both at a dose of
`75 mglml every 3 \IIccks.[35lTltis trial
`randomized 69 patients who were strat-
`ified on the basis of prior exposure to
`doxorubicin. During the trial. patients
`underwent serial ventriculogritphy at
`cumulative doses of 3M. 400. and 500
`mg/in’ 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 l0‘!> from baseline (il'< 50%),
`or ifcongestive heart failure developed.
`Response rates were 33% in the
`TLC D-99 arm and 29% in the doxo:u-
`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 errtesis. stoma-
`titis, fever, and infection, suggesting
`that it may as clfcctive as free doxoru-
`bicin but perhaps safer.
`
`A Novel lrnruunoconjugate
`Tolchcr et al described a phase It
`randomized trial in which a novel im-
`munoconjugate linking a chimeric hu-
`man/mouse monoclonal antibody to
`approximately eight doxorubicin mole.
`cules was compared to doxnrubicixi.(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 patients with metastat-
`ic breast cancer entercd this trial. There
`was one partial remission in the M
`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 hern-
`orrhagic gastritis, possibly reflecting the
`fact that the Lewis’ antigen ut'rl'orlunate-
`ly is also expressed on some gastrointes-
`tinal mucosa] cells.
`
`New, Multitargeted Antilolrtte
`MTA (LY23l5l4) is a new. multi-
`targeted antifolatc that inhibits thymidy-
`late synthase and other fal:ite—dependent
`enzymes. including dihydrofolatc reduc-
`tase and glycinamide ribctnucleotide
`furmyluansfer-ase. ll has potent antiw-
`mor activity in vitro and in vivo and
`produced responses in phase I uials.
`A phase II study that evaluated the
`activity of MTA in 38 patients'with
`locally recurrent or metastatic breast
`cancer was presented at the I998 ASCO
`moeting.[37] Of the 38 patients. 8 were
`cheruotherapy-na.'t've, I4 had received
`adjuvantchcmothcrapy, 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 ll
`patients (3|%). with I complete and I0
`partial remissions. Of the It patients
`who responded. 5 had received prior
`taxane or anthracycline therapy. Medi-
`an duration of response was 8+ months.
`Overall. 135 cycles of MTA were de-
`livered with 28 dose reductions and 26
`delays. Reasons for reductions includ-
`ed neutropenia (39%). mucositis (18%),
`and uansaminase elevation (23%).
`Grade 2-3 nonhematologic toxicities
`included mucositis (34%), nausea and
`vomiting (39%). and uiftnsarninase ele-
`vation (88%). Also. a grade 2 skin rash
`developed in 50% of patients, a grade 3
`
`652
`
`ONCOLOGY - vowms I1 - Nururatts
`
`Astrazeneca Ex. 2010 p. 3
`
`

`
`SERMs have shown very exciting pre-
`clinical and clinical results. One SERM.
`filollfcnc (Evista). approved for the
`lrmtmcnt of osteoporosis in postmeno-
`pausal wutnctt, has also tlrrintatically
`reduced the incidence of new breast can-
`oers.[6ll with relatively short follow-
`up. A “third-generation" SERM
`(LY35338l) has entered phase it trials
`for the treaunent of metastatic cancer
`after a phase I trial showed activity in
`women whose disease had progressed
`during tamoxifen therapy.
`Aromalase inhibitors
`Arornatase inhibitors block the pe-
`ripheral conversion of androstendione
`to cstronc. This effect is not specific to
`the ovaries. but rather. occurs in multi-
`ple organs. such as adipose tissue. mus-
`cle. and liver-the latter being important
`sites of estrogen production in post-
`
`! AI