`ev ew
`
`New Drug Targets and
`Therapies for Cancer
`
`Guest EditorS. Sebti
`
`Oncogene
`BI'IL Floo·l' 2
`UC !3.'\n Diego
`Received on: 03-07-01
`
`Volume 19 • Number 56 • 27 December 2000 • Review Issue 6
`
`PFIZER EX. 1593
`Page 1
`
`
`
`Volume 19 . Number 56. 27 December 2000. Review Issue 6
`ONCOGENE
`Reviews
`
`New Drug Targets and Therapies for Cancer
`
`Guest Editor Sai'd Sebti
`
`6549 Guest Editor
`Said M Sebti
`
`6550
`
`The EGF receptor family as targets for cancer therapy
`John Mendelsohn and Jose Baselga
`
`6566
`
`Design of grmfth factor antagonists with antiangiogenic
`and antitumor properties
`Sai'd M Sebli and Andrew D Hamilton
`
`6574
`
`From oncogene to drug: development of small molecule
`tyrosine kinase inhibitors as anti-tumor and anti·
`angiogenic agents
`Michael J Morin
`
`6584
`
`Farnesyltransfcruse and geranylgeranyltransfcrase I
`inhibitors and cancer therapy: Lessons from mechanism
`and bench-to-bedside translational s tudies
`Sa'id M Sebti and Andrew D Hamilton
`
`6594
`
`De,•elopment of anticancer drugs targeting the MAP
`kinase pathway
`Judith S Sebolt-Lcopold
`
`6600
`
`Small molecule modula tors of cyclin·dcpendent kinases
`for cancer therapy
`Adria n M Scnderowicz
`
`6607
`
`S mall molecule inhibitors of dual specificity protein
`phosphatases
`Katharine E Pestell. Alexander P Ducruet, Peter Wipf
`and John S Lazo
`
`6627 Bcl·2 family proteins as targets for anticancer drug
`design
`Ziwei Huang
`
`6632 Telomere maintenance mechanisms as a target for drug
`development
`David J Bearss. Laurence H H urley and
`Daniel D Von Hoff
`
`6642 Critical appraisal of the use of matrix mctalloproteinase
`inhibitors in cancer treatment
`Stanley Zucker, Jiao Cao and Wen·Tien Chen
`
`6651 Potential roles o( antisense technology in cancer
`chemotherapy
`Stanley T Crooke
`
`6660 Replication-selecti ve oncolytic adenm·iruses: virotherapy
`aimed at genetic targets in cancer
`David Kirn
`
`6670 ONYX·OIS selectivity and the pl4ARF pathway
`F rank McCormick
`
`6673 Dendritic cell vaccination for cancer therapy
`Frank 0 Nestle
`
`668() The rapamyein-sensitive signal t ransduction pathway as
`a target for cancer therapy
`Manuel Hidalgo and EricK Rowinsky
`
`6613
`
`STAT proteins: nonl molecular targets for cancer drug
`discovery
`J ames Turkso n and Richard Jove
`
`6687 :-Jew agents in cancer clinical trials
`Julian Adams and Peter J Ellio tt
`
`Copyright © 2000 Nature Publishing Group
`
`Subscribing organisat ions are encouraged to copy a n d distribute
`this table of contents for int ernal, non-commercial p u rposes
`
`This issue is now a vailable at:
`www.nature.com/onc
`
`PFIZER EX. 1593
`Page 2
`
`
`
`Oncogene (2000) 19. 6574- 6583
`© 2000 Macmillan Publishers Lid All rights reserved 0950-9132/00 $15.00
`
`From oncogene to drug: development of small molecule tyrosine kinase
`inhibitors as anti-tumor and anti-angiogenic agents
`
`Michael i Morin*·1
`1 !'ji:er Gloh(l/ R&D. Groton, Ct'mw<·flc·ur. C T 0113411, USA
`
`The cm1flucoce of two distinct but related activities in the
`past
`I 0 years has dramatically accelerated effort s
`towards the discovery and development of novel drugs
`first
`is a
`rapidly emerging
`treat cancer. The
`to
`understanding that a number of distinct tyrosine kinases
`play roles in diverse but fundamentally important aspects
`of tumor progression (gro\\1h, survival, metastasis and
`angiogenesis). The second is the discovery that small
`molecule compounds have the caJJacity to potently and
`selectively inhibit the biochemical function of tyrosine
`kinases by competing for ATP binding at the enzyme
`catalytic site. These observations have been conjoined in
`major efforts to bring forwa.rd into clinical development
`no,•el cancer drugs with the potential to provide both
`clinical efficacy and improved tolerability. The focus of
`this review is on the development of small molecule
`tyrosine kinase inhibitors, and does not extend to other
`approaches that could be applied to disrupt the same
`pathways in clinical tumors (receptor and/ or ligand(cid:173)
`competitive antibodies, intrabodies, antisense ribonucleo(cid:173)
`ddes, ribozymes. phosphatase inhibitors or SH2/SH3-
`directed agents). Selected
`tyrosine kinase inhibitors,
`to be in development in cancer
`known or believed
`treatment trials, are summarized as are some of the
`key issues that must be addressed if these compounds arc
`to be developed into clinically useful cancer chemother(cid:173)
`apeutic agents. On!'Oge11e (2000) 19, li574 - 6583,
`
`Keywords: tyrosine kinase inhibitors; anti-tumor: anti(cid:173)
`angiogenesis
`
`Origin of species- brief O\'ervicw of substrate-based
`inhibitors of protein tyrosine kinases
`
`Among all non-traditiomll (non-DNA-directed) cancer
`targets fo r which pharmacological
`interventio n
`is
`feasible. there are none that have genera ted as much
`interest, and have
`invoked as much
`widespread
`resource investment in both tile public and private
`sectors in the past 7 years, as have !he tyrosine kinases.
`Several excellent recent reviews have described the
`functions of various
`tyrosine kinases
`in
`the key
`that drive tumor progression, from
`pa thways
`fi rst
`genetic insuli to disseminated disease (Hanahan ;1nd
`Weinberg. 2000; H unter, 2000; Gibbs. 2000). Key
`among lhesc a re the recep!Or tyrosine kinases whirh
`initiate signal transduction in tumor cells or endothelial
`cells following the binding of the growth factors EGF,
`PDGF and YEGF. There <tre also several excellent
`reviews that provide detailed overviews o f the work
`
`•correspondence: !VIJ Mori11
`
`the molecular
`accomplished to date to understand
`pharmacology of small molecule inhibitors o f receptor
`tyrosine kinases (Sedlacek, 2000; Fry, 2000: Bridges.
`1999; Levitzki. 1999: Lawrence and Niu. 199!!). With(cid:173)
`m tt summarizing each of these important reviews, they
`provide a n appropriate context for understanding the
`obstacles and triumphs that have led, very recently, to
`the ftrst reproducible. objective clinical response,.; in
`cancer patients lre<tted with tyrosine kinase inhibitors.
`The catalytic function of pro tein tyrosine kinase~
`involves the simple transfer o f the gamma phosphate o l
`ATP
`to hydroxyl group of a
`tyrosine residue of
`pro teins (or peptides) encompassing a diversity of'
`primary sequences and tertiary structures (Songyang
`and Cantley, 1998). Each of the substrates in
`the
`phosphotransfer reaction, the tyrosine hydroxy grour
`and A TP, represenl reasonable pha rmacological start(cid:173)
`ing points for the design of substrate a nalogs <1t1d
`competitive .inhibito rs of tyrosine kinases. A diverSe SCI
`of pha rmacophorcs, including natura l products (lcwen(cid:173)
`dustins and erbstatins) and synthetic tyrosine mimetks.
`have a ll been characterized on the basis o f their abilit)
`to competitively
`inhibit
`tyrosine kinase
`functiou
`(Levitzki, 1999). These compounds tended to have
`poor potency (particularly in cells). to yield relatively
`Rat structure-activity relationships. and to be some·
`what non-specific in their kinase inhibition (Fry. 2000),
`Attacking
`this
`reaction
`from
`the o ther side, bv
`identifying compounds that mimic ATP, was o riginally
`thought to be even less tractable. As reviewed by
`Lnwrence a nd Niu ( 1998), the theoretical obstacles
`were immense. First. the primary sequence o f the ATP(cid:173)
`hinding pocket of all kinases is highly conserved. and
`therefore selectivity, if not ~pecificit y. represents a
`significant technical challenge. Secondly, the intracel(cid:173)
`lular concentration of ATP can exceed 5 m M.
`particularly in tumor cells, while the Km for ATP in
`most kinase active sites is in the micromola r ra nge.
`thus ensuring full-time saturation by ATP. A TP(cid:173)
`compctitive inhibitors would need to exhibit at lea$t
`nanomolar inhibitory kinetic constants to ell'ectively
`compete in
`this circumstance (Lawrence and Niu.
`1998). Finnlly. there are multiple no n-kinase AT P(cid:173)
`depcndcnt enzymes important to normal physiolog) ,
`and so an indi~criminant ATP mimetic would liketv
`thnt were phannacologicully
`<111;!
`toxicities
`have
`medically unacceptable.
`T his theoretical logjam was broken in convincing
`fashion when the tyrosine kinase inhibitory activities of
`a nilinoquinazolinrs were first described in 1994 bv
`three So!parate groups (Fry "' a/ .. 1994; Ward er a/ ..
`1994; Osherov and Levitzki. 1994). For example, the
`work of Fry er ul. ( 1994) at Warner La mbert revealeJ
`that 4-a nilinoquinazolines were potent (nM) inhibirors
`
`PFIZER EX. 1593
`Page 3
`
`
`
`6575
`
`t) f the EGFR tyrosine kinase with good cell activity
`11nd profound biochemical selectivity relative to other
`~tnases within
`the tyrosine kinase family. Furth~r
`.;laboration of structure-activity relationships rich in
`11CW possibilities resulted in ATP-competitive inhibitors
`nt' the EG FR tyrosine kinase with Ki values in the
`,,ngle digit picomolat' range. It is interesti ng to note
`that the Michaelis-Mentcn cqu;llion could not be used
`t<l derive the Ki values of these molecules. So avid was
`the binding of compound
`to
`the ATP site,
`the
`,·nnventional approximation that total and fr~e enzyme
`,·oncentrations were equivalent did not apply under
`these com.litions. These accomplishments. which may
`he among the most important in ph<irmacology for the
`IJst 10 years. were
`largely achieved by empirical
`,neening and iterative medicin<tl chemistry, Even more
`new chemotypes may emerge as strucwre-based design
`ll~comes more commonly applied to the identification
`,,f both active site- and allosteric site-directed inhibitors
`for an ever-widening ilate or tyrosine kinase targets.
`While these early lead mole.:ules had biopharmaceu(cid:173)
`tJcal properties which were by-and-large incompatible
`with oral bioavailability and good duration of exposure
`ill vivn, the results spurred on a number of groups,
`which have since identified and developed tyrosine
`ki nase inhibitors with significant potential to treat
`clinical cancer.
`
`:Selected development candidates-updates
`
`I' DGFR i11hibitnrs: ST/ 571 and SUJO!
`ST/571 ( CCP57148B) Among ull nf the candidates
`currently in clinical development, perhaps none has
`provided as much 'proof of concept' for the clinical
`dficacy and tolerability of small molecule tyrosine
`kinase inhibitors as has STI 571. Originally disclosed by
`Novartis as a multitrophic tyrosine kinase inhibitor.
`STI 571 was described by Druker el a/. ( 1996); and
`Druker and Lydon (2000) as having potent activity "·~
`the translocation product ha-abl, the transforming
`tyrosine kinase found in virtually all CM L cells
`<!'<pressing the Philadelphia chromosome ( K urzrock er
`ul.. 1988; Kelliher el a/., 1990). The inl1ibition of v-ah/.
`hcr-abl and PDGFR autophosphorylation by the 2.(cid:173)
`phenylaminopyrimidinc STI 571 (Figure l) at nanomo(cid:173)
`l:tr concentrations was found to translate to both ill
`l'fl'o anti-tumor activity. and
`to
`the
`inhibition of
`donogenicity of blasts from CML patients (le Coutre
`l/ at.. 1999; Druker et a/.. 1996). T he results of a
`clinical triul in which STI 57 I was administered to
`CML and ALL patients expressing hl'r-ahl in their
`leukemic blasts were mmt recently summarized in May
`2000 (Talpaz et 111 .• 2000). STI 571 was used to treat 33
`c~cute leukemia patients, which included 2 I myeloid
`blast crisis CM L patients and I 2 her-ubi-positive ALL
`lymphoid blast crisis CM L patients. Clinical
`lll'
`responses. as detined by a decrease in the percentage
`t~f patients achieving reduction in bone marrow blasts
`I•> 15% of pre-treatment levels, were observed in 55%
`t>f myeloid blast .:risis patients. with complete responses
`tn 22% of these patients. The response rates in patients
`with hcr-ahl positive ALL and lymphoid blast crisis of
`t ML were higher (82°1., with 55% complete responses),
`hut all of
`the patients with
`lymphoid
`leukemias
`
`Tyrosine kinase Inhibitors In cancer treatment trials
`MJ Mortn
`
`relapsed on drug between 45 and 81 days. Of 19
`responding patients. I 0 experienced Grade 3- 4 neu(cid:173)
`tropenia. This response rate. and the incidence of
`Grade 3- 4 toxicity, compares very favorably to the
`stundard of care cytotoxic chemotherapie.s for CM L.
`As such, more definitive tri<1IS assessing the efficacy and
`safeLy of STI 57 1 are ongoing in CML.
`It is interesting to speculate as to the biochemical
`basis for both the efficacy and the toleration profile of
`STI 571. Two other tyrosine kinases potently inhibited
`by STI 571. c-kir and PDG FR, are both believed to play
`important roles in maintaining bone marrow stroma (cid:173)
`progenitor cell interactions (Ashman, 1999; Sungaran e/
`al .. 2000). Thus. inhibition of c-kit and PDGFR could
`also account for some of the compelling clinical activity
`of STI 57 I in CM L, as well as for its toxicity profile
`£neutropenia). Treatment of a c-kit expressing a human
`myeloid leukemia cell line, M-07e, with STI 571 before
`stimulation with ki1 ligand inhibited c-kil atttopho(cid:173)
`sphorylation, activation of mitogen-activated protein
`(MA P) kinase, and activation of Akt. with an IC5o of
`I 00 nM (Heinrich et a/ .. 2000}. ST1 57 1 was even more
`potent in a human mast cell leukemia cell line (HMC- l)
`expressing an activated mutant form of c-kit. Similar
`results have also recently been reported
`in non(cid:173)
`hematopoietic tumor cells (Wang er al., 2000}. The
`dficctcy und safety hypotheses fo r in.l1ibition of c-ab/ io
`CM L tmty perhaps only be addressed with a more
`selective abl
`tyrosine kin<tse
`inhibitor. Given
`the
`appareht therapeutic benefit of ST1571 , this may be
`largely an academic question, but one with important
`implications as one tries to rationalize the desired
`selectivity profiles of tyrosine kinase inhibitors most
`likely to generate both diicacy and sctfety in humans.
`
`SU/01 ( lejlunomide: 1-IWA 486) Leflunomide was
`origi nally described and developed as an inhibitor of
`dihydroorotate dehydrog~:nase, a key enzyme in the de
`novo synthesis of py1imidincs, for use as an immuno(cid:173)
`(Bartlett and
`suppressive or anti-arthritic agent
`Schleyerbach, 1985; Kuo el . a!., 1996). Leflunomide
`hus shown significant activity as a
`treatment for
`rheumatoid arthritis (Smolen and Emery, 2000: Cohen
`1!/ a/ .. 2000b). and was launched by Aventis as Arava"'
`in the US and elsewhere beginning ln 1998. Extending
`the work of others (Matlar e/ a!.. I 'J93; Xu er al.,
`1995). Shawver and co-workers reported that micro(cid:173)
`the
`molar concentrations of 1etlunomide inhibited
`autophosphorylation of the tyrosine kinase receptors
`for PDGF and VEGF (Shawver el ul.. 1997). The
`compound was also eiTective at blocking mitogenesis
`stirnulated by both PDGF and EGF. but exogenous
`uridine could not reverse the effect of leOunomide on
`PDGF mitogenesis. suggesting that inhibition of the
`inhibition of
`tyrosine kinase. and not
`receptor
`pyrimidine pools. was a key phctrmacological activity.
`The inhibition of EGF-induced mitogenesis by letlu(cid:173)
`nomide was reversed in part by uridine (Shawver 1!1 al ..
`1997), despite the fact that leflunomide and close-in
`analogs also have inhibitory activity vs the EGFR
`tyrosine ki nase (Ghosh 1!1 ul .. 1999).
`tyrosine kinase
`Leflunomide/SU 101
`is clearly a
`inhibitor with multiple biochemical clfects. and readily
`generates a predominant active metabolite (SU0020 or
`A771726; Figure I) that has a comple.x. inhibitory
`profile of its own (Hamilton el ul .. 1999). SU 101 was.
`
`Onco&ene
`
`PFIZER EX. 1593
`Page 4
`
`
`
`6576
`
`Tyrosine kinase inhib~ors In cancer treatment trials
`MJ Morin
`
`ri('Nl
`Ny~y,Ay~lf"/ l.___,N,
`N _.,;V
`
`0
`
`N
`
`STI571
`
`F"YF
`HN~CI
`Ol
`l.___,N~Oxt.:"'N
`\ .o )
`'o
`N
`
`0l~n
`
`HO--{'CN I ,:; CF,
`
`Lenunomlde
`
`A771721>
`
`zo 1839
`(lressa1
`"')
`
`CP-358,774
`(0$1·774)
`
`X
`
`PD-183805
`(CI-1033)
`
`("""'yCI
`HN~
`
`Fig_ure I Structures of selected tyrosine kinase inWbitors in clinical d~velopment (nr c-.;nccr
`
`Z0-4190
`
`nonetheless, progressed into clinical trials by SUGEN
`(now part of P ham1acia). A Phase I study in cancer
`patients revealed that SU 101 was well-tolerated as a
`24 h continuous i.v. infusion at doses up to 443 mgj m~/
`wk. At this dose, the plasma concentratio11 of the
`active metabolite was maintained at levels sufficient to
`block both P D GFR and EGFR signaling, as well as
`pyrimidine biosynthesis (Eckhardt et a!., 1999). T oxi(cid:173)
`relatively minor (Grade 1- 2 nausea,
`cities were
`vomiting and fever
`in approximately 20% of aU
`courses given). Surprisingly, hematopoietic toxicities
`and hemolysis, which had been noted in the preclinical
`experience with SU 101, were not seen in this Phase I
`popula tion. One partial response was seen
`in 26
`patients receiving an average of two courses each; the
`responding patient received 13 courses (52 infusions) to
`treat an anaplastic astrocytoma, and had a notable
`(>50%) reduction in one measurable lesion (Eckhardt
`et al., 1999). SU 101 has been reported
`to be in
`advanced trials for multiple solid tumor types, but
`recent disclosures (Garber, 2000} indicate that P hase
`Ill trials in at least one tumor type (glioblastoma) have
`been abandoned. T he status of other trials (ongoing
`Phase II trials for ovarian and NSCLC; p lanned Phase
`III trials for prostate. colon and NSCLC) is uncertain
`at the present time.
`
`EGFR i11hibitors: Jressffi (ZD/839) . OSJ-774
`( CP-358.774 ) and Cl-1033 (PD/83805)
`!t·esscfo (ZDJ839) While STI 57l has provided no(cid:173)
`table clinical proof-of-concept for the clinical efficacy
`and safety of tyrosine kinase inhibitors, the early
`
`clinical findings with AstraZeneca·s ZDI839 ( L ressa~)
`have been equally compelling. T he pharmacological
`characteristics of lressa"' were first described in 1996
`(Wakeling et a!., 1996; Woodburn et a/., 1997) as a
`potenl and selective inhibitor of the EGFR tyrosine
`kinase. This quinazoline-based compound (Figure I) is
`an ATP-competitive inhibitor of the EGFR tyrosine
`kinase (IC 50 25 nM) with 50-fold selectivity relative to
`closely homolo&ous erbB family members (IC50 fo r
`erbB2 1- 3 JtM) and even greater selectivity for more
`It demonstrates good
`divergent
`tyrosine kinases.
`cellular potency (80 nM IC 50 for inhibition of EGF(cid:173)
`dependent mitogenesis) and robust. dose-dependent
`anti-tumor efficacy
`in a variety of human
`tumor
`xenografts (Woodburn et at .. 1997). These results have
`been most recently extended to show that [ressa'" has
`in vivo efficacy in a diverse human tumor xenograft
`models both with (Ciardello et a/ .. 2000) and without
`(Sirotnak et at., 2000) highly activated EGFR signaling
`pathways. Of equal interest a re the observ::ttions that
`lressae combines with standard cytotoxic agents
`(platinums. taxanes, topoisomerase I inhibitors, etc.)
`to produce additive or supra-additive anti-tumor
`efficacy in vivo without exacerbation of the toxicity of
`the co-administered cylotoxics. The findi ngs that tuuwr
`EGF R density does not predict efficacy when the
`compound is used in conjunction with cytotoxic agents
`have significantly impacted the development strategy
`employed by AstraZeneca as l ressa"' moves towards
`pivotal clinical trials.
`Multiple Phase T trials with
`lrcssa'"" have been
`revealed
`reasonable
`summarized, and
`the
`results
`pharmacokinetics. good toleration and the first signs
`
`Oncogene
`
`PFIZER EX. 1593
`Page 5
`
`
`
`of clinical efficacy when used as a single agent in
`p:~tients with advanced di$ease (Ferry et al., 2000;
`B:~selga et a/., 2000; Kelly et a/., 2000). Following oral
`udministration of a single dose (50 mg). maximum
`plasma drug concentrations (mean 45 ng/ml) occurred
`1 -5 h post-dose. The mean terminal t 10 was 34 h.
`Inter-subject variability in exposure was significant
`following single and multiple administration (up to
`sevenfold at each dose level), but exposure increased
`proportionally with dose, with no apparent change in
`terminal t 1 2 across the dose range tested (Kelly et a/.,
`2000). In a
`larger dose-e~ca lation trial. Ferry and
`coll:;tborators administered lressat<o at doses of 50 -
`700 mg once daily, given orally for 14 days followed by
`1~ days of observation (Ferry eta/., 2000). In total, 64
`patients with advanced disease. who had each
`progressed while on prior chemotherapy, completed
`145 cycles. C 11111x and A UCu.24 11 were proportional
`across
`the entire dose range (mean values 113 -
`2J55 ng/ml and 1.8- 3j!.5 mg.h/ml, respectively). As
`in single dose studies, I ressa"' showed a long terminal
`elimination half-life (mean of 46 h). l ressa"'~ was very
`well-tolerated in this study: the most common adverse
`events were diarrhea and acne-like skin rash (Grade 1-
`2). Acne-like skin rashes have emerged as a common,
`mechanism-based adverse event for EGFR inhibitors,
`but the specific toxicological effect in the skin is not yet
`well understood. Grade 3 - 4 adverse events were
`shown to be rare with lressa"' treatment. and were
`generally ascribed to disease progression. The dose(cid:173)
`limiting toxicity, defined at the 700 mg dose level, was
`Grade 3 diarrhea {Ferry et a/., 2000).
`A compelling level of etlicacy was also revealed in
`these early trials (Ferry et a/., 2000). Anti-tumor
`responses were most evident among the 1.6 NSCLC
`patients treated with lressa"'- two had an objective
`partial response, two patients had significant regression
`of disease and two patients had stable disease. Similar
`pharmacokinctic and safety profiles were noted in a
`separate study (Baselga et a/., 2000). one that also
`io
`revealed the p otential for efficacy from Iressa8
`pntients with advanced prostatic and head-neck
`cancers. These early results added importantly to the
`proof-of-concept that selective tyrosine kinase inhibi(cid:173)
`tors could have significant single agent efficacy, as
`measured by objective tumor regressions, in patients
`With advanced disease. T he clinical observations have
`therefore recapitulated rhe pre-clinical data showing
`l ressa~ increased apoptosis and regressions in
`that
`human tumor xenograft models (Ciardello et a/., 2000).
`The l ressa~ data indicate that the efficacy of these
`agents can be measured using more classically defined
`clinical endpoints. T her_e will undoubtedly be signifi(cid:173)
`cant value
`in
`the use of pharmacodynamic and
`surrogate endpoints to guide dose-intensification o r to
`pre-select patients for whom ot.her tyrosine kinase
`inhibitors might represent the most promising treat(cid:173)
`tnent option. Pharmacodynamic endpoints have not
`played a major role in the early development of EGFR
`ty1·osine kinase inhibitors. despite the fact that several
`r~:asonable options exist,
`including both
`invasive
`techniques (direct measurement o f tumor-derived or
`normal tissue-derived EGFR phosphotyrosine, phos(cid:173)
`signaling molecules:
`phorylation of down-stream
`apoptosis markers) and non-invasive techniques such
`us PET imaging of meta bolically modulated tumors
`
`Tyrosine kinase Inhibitors In cancer treatment trials
`MJ Mo11n
`
`ffi
`6577
`
`lPollack et ul., 1999; Goss et a/., 2000; Allen el at ..
`2000). Given the overall safety and toleration profile of
`lressa ,., AstraZeneca has committed to an aggressive
`development strategy, which includes two large Phase
`m studies to assess the use of l ressas in combination
`with cis-
`or carbo-platinum plus a
`taxane or
`gemcltabine in first-line therapy for NSCLC (trials 14
`and 17), as well as a Phase II trial (trial 16) to confirm
`the single agent activity of J ressa~ in patients with
`advanced NSCLC (Kelly et a!., 2000). ll is important
`to note tha t these trials do not call for a prospective
`selection for patients with tumors with some pre(cid:173)
`defined level of EGFR over-expression. All epithelial
`tumors express some EGFR. and in the disease target
`here, NSCLC, tumors often present with a high
`proportion of EGFR over-expression (11p to 80- 900;;,
`in advanced disease). T he strategy is also consistent
`with pre-clinical data suggesting that efficacy in drug
`combinations may not be determined in large part by
`the level of EGFR over-expression in tumors (Sirotnak
`et a/., 2000). Results are expected from these pivotal
`trials in a late-200 I or early-2002 timeframe.
`
`OS/-774 ( CP-358,774 ) C P-358, 774 is also a potent
`and selective quinazoline-based inhibitor o f the EG FR
`function (Figure 1). This compound is a reversible,
`ATP-competitive inhibitor (IC 50 of 2 nM) of the EG FR
`tyrosine kinase, with greater than 500-fold selectivity
`against other tyrosine kinases, such as the closely
`related erb 8 2 kinase, as well as v-src, c-ab/ and tbe
`insulin and JGF-1 receptors. (Moyer eta/., 1997). CP-
`358,774 inhibits the autophosphorylation of the EGF
`receptor in a variety of EGFR over-expressing tumor
`cells (l C 50= 20 oM). and produces cell cycle arrest and
`apoptosis in multiple cell types (Moyer et a!., 1997;
`Barbacci el a/., 1997; Iwata el al., 1997). In vivo, CP-
`tyrosine
`inhibits EG F R-specific
`358.774 effectively
`phosphorylation in human tumor xenografts (ED 50 or
`10 mg/kg p.o. when given as a single dose) with
`significant duration of action; daily dosing produces
`substantial growth inhibition and regressions in human
`tumor xenografts (Pollack el a/., 1999). Moreover, the
`dose-response for tumor growth inhibition shows good
`agreement with the d ose-response for inhibition of
`EGFR-phosphotyrosine in tumors from . treated ani(cid:173)
`mals. As with Lressa~, CP-358, 774 was found to
`generate additive anti-tumor activity when used in
`combination with cis-platinum and other cytotoxic
`agents, without exacerbating the toxicities of the other
`chemotherapeutants (Pollack et a/., 1999),
`Clinical studies with CP-358,774 have revealed that
`the agent is well-tolerated at oral doses that achieve
`plasma concentrations projected
`to be required for
`anti-tumor efficacy in humans (400 - 500 ng(ml). In one
`study, escalating doses were administered o rally once
`every week (Karp et (1/., 1999). Eighteen patients with
`advanced solid tumors were treated at five doses (100 -
`for a maximum period of 24 weeks.
`1000 mg)
`T oxicities were observed only at doses higher than
`200 mgj week, and included mild fatigue, Grade 2
`maculopapuiRr (ncneiform) rash. Grade 2 nausea, and
`Grade 2 diarrhea. Like lressa·"', C P-358, 774 exhibited
`intra- and inter-subject varia bility in exposure, but
`dose-proportional increases in exposure were observed
`throughout the 100- 1000 mg weekly dose
`r:Ulge.
`During the first 24 h following a single dose, the c.,V£
`Onco&ene
`
`PFIZER EX. 1593
`Page 6
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`ffi
`6578
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`Tyrosine kinase Inhibitor. In cancer treatment trials
`MJ Morin
`
`(0.9 - 4.8 mg/ml for 100-1000 mg doses. respectively)
`I O-f old above
`was some
`two-
`to
`the projected
`efficacious plasma concentration. No maximally toler(cid:173)
`ated dose or dose-limiting toxicity was discerned ip this
`study. In a second Phase I study (Siu c:l a/ .. 1999).
`patients were given CP-358.774 tablets in a variety of
`dose schedules. culminating in daily dosing at the
`maximally tolerated dose. The target C:o.g of 400-
`500 ngjml was achievable at doses at and above
`I 00 mgjday on a well-tolerated schedule (C,..~ values
`following continuous daily dosing at the 50, I 00 and
`200 mgfday levels were 432. 973 <md 2120 ng/ml.
`respectively). Dose-limiting diarrhea was encountered
`intermediate dose of
`at the 200 mgjday level. An
`150 mg/day was subsequently defined as the maximally
`tolerated dose (two of three patients had Grade l
`diaiThea \Vith loperamide support).
`Siu and co-workers also made efforts to understand
`the 'characteristic' Grade l - 2 acneifom1 rash seen in
`patients treated with CP-358,774, which was limited to
`regions of the upper body where adolescent acne is
`usually manifest (face, back and scalp). Histopathology
`of skin biopsies showed subepidermal neutrophilic
`infiltration and epidermal hyperproliferation (Siu 1!1
`a/., 1999). While the precise cytopat hie basis for the
`acneiform rash has not yet been determined, the
`consistent clinical observations with
`three difi'erent
`agents targeting EGFR function (CP-35!1. 774. l ressa'"
`and Jmclone·s C-225 antibody) suggest that this is a
`mechanism-based finding (Siu et a/., 1999; Ferry el a/.,
`2000; Cohen et al .• 2000b). Skin changes are consis(cid:173)
`tently noted in preclinical studies with rodents exposed
`to CP-358,774 for extended dosing periods, and these
`toxicological results are analogous to the skin changes
`seen in the waved-2 mouse. which has a mutated and
`marginally functional EGFR tymsine kinase (Luetteke
`et a/., 1994).
`readouts from ongoing Phase 1T
`Early efficacy
`clinical trials with CP-358, 774 have been compelling.
`The agent appears to have a broad potential to treat a
`variety of human solid tumors, including NSCLC.
`breast, ovarian and squamous head and neck tumors
`(Bonomi el a/., 2000; Allen eta/., 2000; Siu et a/ .. 2000;
`Hammond et a{., 2000). For example, in 34 NSCLC
`patients who had failed prior chemotherapy, daily oral
`doses of 150 mg CP-358,774 were well-tolerated. with a
`the most
`maculopapular
`(acneiform)
`rash being
`common adverse event reported. In 56 total patients
`evaluable for tumor response, there have been six
`partial responses in the lung andjor liver at 8 weeks
`and several patients with stable disease (Bonomi et nl ..
`2000).
`In 7 1 patients with
`refractory squamous
`carcinomas of the head and neck. CP-358,774 was
`again found to cause a reversible acneiform rash and
`G rade I - 2 diarrhea . Of 78 patients evaluable for
`response. there have been at least eight confirmed
`partial responses and 23 patients with stable disease
`(Siu et a/., 2000). These preliminary results indicate
`that CP-358. 774 is generally well-tolerated and demon(cid:173)
`strates evidence of single agent anti-tumor activity in
`patients with recurrent head and neck cancer. as well
`as in treatment-refractory NSCLC.
`Due to significant interests in both CP-358, 774 and
`C l-1033, Pfizer was directed to divest one of these two
`agents as a condition of their acquisition of Warner
`Lamben in 2000. As such, Oncogene Science (OS!P)
`
`has taken over complete responsibility for the devel(cid:173)
`opment of CP-358.774. which is now formally referred
`to as OSI-774.
`
`C/-/033 ( PD/838051 As described above, the selec(cid:173)
`tive and reversible inhibitors nf the EGFR tyrosine
`kinase appear to offer the promise of therapeutic
`is
`It
`eft1cacy coupled
`to
`reasonable
`tolerability.
`important to note. however. that the therapeutic index
`of neither l ressa· nor CP-35S,774 has yet to be fully
`elaborated. and that there may be significant proximity
`the
`tolerated dose~ and
`between
`the maximally
`cflk:1cious doses for both agent~ . Moreover.
`the
`efficacy of neither agent has yet to be established in a
`blinded, placebo controlled study. As such. there
`continues to be an opportunity to discover and develop
`distinctly different EG FR tyrosine kinase inhibitors
`with even greater potential for effic<tcy and a broader
`spectrum of activity. Cl-1033 is one such distinctly
`different development candidate. As recently reviewed
`former Warner Lambert
`by David Fry of the
`organization, signaling through the l'rhB family of
`tyrosine kinase receptor~ often involves complex cross(cid:173)
`talk among the members of that receptor fami ly (Fry.
`2000). The four family members (EGFR or erhB:
`erbB2. erbB3 and erhB4) are known to intensify their
`kimtse-dependent transforming signals via tbe forma(cid:173)
`tion of heterodimers with each other (Tzahar et a/ ..
`1996). There is, therefore. a compelling w tionale t.o
`consider the potential utility of nonspecific hut selective
`inhibitors that effectively block the function of the erhl:l
`family but do not inhibit more structurally diverse
`tyrosine kinases.
`i> also a strong
`to consider
`rationale
`T here
`irreversible tyrosine kinase inhibitors. Tht: reversible
`inhibitors have apparently generated clinical efficacy
`with dosing regimens designed Lo maintain plasma
`concentrations at fairly high levels for extended periods
`of tinJc. The optimal dosing paradigm
`for an
`irreversible inhibitor would he less likely to require
`prokmged exposure. Moreover. the 'absolute finalily"
`(Fry. 2000) of the irreversible inhibitors could con·
`ceivably provide significant advantages in terms of
`antitumor etlica,·y. To be balanced. a multi-tropic ami
`irreversible inhibitor would also have the potential to
`toxicity profil~ that was diflcrent and,
`generate a
`the mot•e
`perhaps, without advantages relati