A Novel Approach in the Treatment of Cancer: Targeting the

Review

A Novel Approach in the Treatment of Cancer: Targeting theEpidermal Growth Factor Receptor1

Fortunato Ciardiello2 and Giampaolo TortoraCattedra di Oncologia Medica, Dipartimento di Endocrinologia eOncologia Molecolare e Clinica, Universita di Napoli “Federico II,”80131 Napoli, Italy

AbstractThe epidermal growth factor receptor (EGFR) auto-

crine pathway contributes to a number of processes impor-tant to cancer development and progression, includingcell proliferation, apoptosis, angiogenesis, and metastaticspread. The critical role the EGFR plays in cancer has led toan extensive search for selective inhibitors of the EGFRsignaling pathway. The results of a large body of preclinicalstudies and the early clinical trials thus far conducted sug-gest that targeting the EGFR could represent a significantcontribution to cancer therapy. A variety of different ap-proaches are currently being used to target the EGFR. Themost promising strategies in clinical development includemonoclonal antibodies to prevent ligand binding and smallmolecule inhibitors of the tyrosine kinase enzymatic activityto inhibit autophosphorylation and downstream intracellu-lar signaling. At least five blocking monoclonal antibodieshave been developed against the EGFR. Among these, IMC-225 is a chimeric human-mouse monoclonal IgG1 antibodythat has been the first anti-EGFR targeted therapy to enterclinical evaluation in cancer patients in Phase II and IIIstudies, alone or in combination with conventional therapies,such as radiotherapy and chemotherapy. A number of smallmolecule inhibitors of the EGFR tyrosine kinase enzymaticactivity is also in development. OSI-774 and ZD1839 (Iressa)are currently in Phase II and III development, respectively.ZD1839, a p.o. active, selective quinazoline derivative hasdemonstrated promising in vitro and in vivo antitumor ac-tivity. Preliminary results from Phase I and II trials inpatients with advanced disease demonstrate that ZD1839and OSI-774 have an acceptable tolerability profile andpromising clinical efficacy in patients with a variety of tu-mor types. This mini-review describes the EGFR inhibitorsin clinical development.

IntroductionRole of the EGFR3-driven Autocrine Pathway in

Cancer Development and Progression. Peptide growth fac-tors modulate signaling pathways, which control cell prolifera-tion and death in both normal and malignant cells. The EGF wasone of the first growth factors to be discovered and is theprototype of a large family of closely related growth factors,which includes TGF�, amphiregulin, heparin binding-EGF, andbetacellulin. Among these growth factors, TGF� has been iden-tified as a key modulator in the process of cell proliferation inboth normal and malignant epithelial cells. TGF� binds to itsspecific cell membrane receptor, the EGFR, with subsequentactivation of the EGFR tyrosine kinase enzymatic activity thattriggers the intracellular signaling pathway (1, 2).

The EGFR is part of a subfamily of four closely relatedreceptors: EGFR (or ErbB-1), HER-2/neu (ErbB-2), HER-3(ErbB-3), and HER-4 (ErbB-4; Refs. 3 and 4). The receptorsexist as inactive monomers, which dimerize after ligand activa-tion. This causes homodimerization or heterodimerization be-tween EGFR and another member of the erb receptor family.After ligand binding, the tyrosine kinase intracellular domain ofthe receptor is activated, with autophosphorylation of the intra-cellular domain, which initiates a cascade of intracellular events(4). The signaling pathway involves activation of ras and mito-gen-activated protein kinase, which activates several nuclearproteins, including cyclin D1, a protein required for cell cycleprogression from G1 to S phase (Ref. 5; Fig. 1). EGFR signalingis not only critical for cell proliferation. Several studies havedemonstrated that EGFR-mediated signals also contribute toother processes that are crucial to cancer progression, includingangiogenesis, metastatic spread, and the inhibition of apoptosis(4–7).

Activation of the TGF�-EGFR autocrine growth pathwayin cancer cells can be attributable to several mechanisms, suchas overexpression of the EGFR, increased concentration ofligand(s), decreased phosphatase activity, decreased receptorturnover, and the presence of aberrant receptors, includingEGFR gene alterations. In this context, the most common EGFRmutant found in human cancer is EGFRvIII (8). The rearrangedEGFRvIII gene is often amplified, thus resulting in tumor cellsoverexpressing EGFRvIII (9). The EGFRvIII is a truncatedEGFR that lacks domains I and II of the extracellular domainand is not capable of ligand binding (9). However, it has aconstitutively activated tyrosine kinase domain which stimulatescell proliferation independently of ligand interaction. TGF�and/or EGFR are overexpressed in many different solid human

Received 2/5/01; revised 4/10/01; accepted 6/15/01.The costs of publication of this article were defrayed in part by thepayment of page charges. This article must therefore be hereby markedadvertisement in accordance with 18 U.S.C. Section 1734 solely toindicate this fact.1 Supported by grants from the Associazione Italiana per la Ricerca sulCancro (AIRC).2 To whom requests for reprints should be addressed, at Cattedra diOncologia Medica, Dipartimento di Endocrinologia e Oncologia Mole-colare e Clinica, Universita di Napoli “Federico II,” Via S. Pansini 5,80131 Napoli, Italy. Phone: 39-081-7462061; Fax: 39-081-7462066;Fax: 39-081-2203147; E-mail: [email protected].

3 The abbreviations used are: EGFR, epidermal growth factor receptor;EGF, epidermal growth factor; TGF�, transforming growth factor �;TKI, tyrosine kinase inhibitor; MAb, monoclonal antibody; NSCLC,non-small cell lung cancer; VEGF, vascular endothelial growth factor;bFGF, basic fibroblast growth factor.

2958 Vol. 7, 2958–2970, October 2001 Clinical Cancer Research

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cancers, including NSCL, breast, head and neck, gastric, pros-tate, bladder, ovarian, colorectal carcinomas, and glioblastomas,in which it is generally associated with advanced disease andpoor prognosis (7, 10–12). Overexpression of EGFR has alsobeen associated with resistance to hormonal therapy, cytotoxicagents, and radiotherapy (12–15).

Inhibition of EGFR Signaling in Cancer Therapy. Alarge body of experimental and clinical work supports the viewthat the EGFR is a relevant target for cancer therapy. Twotherapeutic approaches have been shown most promising andare currently being used to inhibit the EGFR in clinical studies:(a) MAbs; and (b) small molecule inhibitors of the EGFRtyrosine kinase enzymatic activity. MAbs are generally directedat the external domain of the EGFR to block ligand binding andreceptor activation. TKIs prevent the autophosphorylation of theintracellular tyrosine kinase domain of the EGFR. Other ap-proaches currently in development for targeting the EGFR in-clude the use of recombinant proteins containing TGF� or EGFfused to toxins, such as Pseudomonas aeruginosa toxin, EGFconjugated to genistein (a natural broad-spectrum TKI), EGFR-directed vaccine approaches, and the use of antisense oligonu-cleotides to the EGFR mRNA (Ref. 7; Fig. 1).

MAbs to the EGFR. The development of blockingMAbs to the EGFR as a cancer therapy was first proposed by J.Mendelsohn in the 1980s (16, 17). Mendelsohn’s group hasgenerated two blocking anti-EGFR MAbs which inhibit the invitro and in vivo growth of human cancer cell lines that expressTGF� and EGFR. MAb 528 and MAb 225 are two mouse MAbsthat have been characterized extensively for their biological and

preclinical properties, and represent the first series of anti-EGFRblocking agents that have entered clinical evaluation in cancerpatients (16, 17). MAb 528 and MAb 225 bind to the EGFRwith affinity similar to EGF and TGF�, compete with theseligands for receptor binding, and block EGF- or TGF�-inducedactivation of EGFR tyrosine kinase. In addition, it has beenshown that the combined treatment of nude mice bearing well-established human A431 epidermoid and MDA-MB-468 breastcancer xenografts with MAb 528 or with MAb 225 and withcytotoxic drugs, such as doxorubicin or cisplatin, significantlyincreases the antitumor activity of these drugs (Fig. 2; Refs. 18and 19). To avoid human antimouse Ab production that caninterfere with the therapeutic efficacy of repeated administra-tions of mouse MAbs in humans, a chimeric human-mouseMAb 225 (IMC-C225) that contains the human IgG1 constantregion has recently been developed and purified for clinical use(16, 20).

IMC-C225: Preclinical Studies. IMC-C225 binds theEGFR with a greater affinity (Kd � 0.39 nM) than MAb 225 andis able to block EGF-induced autophosphorylation of the EGFRin cell lines in vitro (20, 21). In vitro studies demonstrated thatIMC-C225 induces dimerization and internalization of theEGFR (21, 22). In this respect, removal of the EGFR from thecell surface may contribute to the inhibitory effects of thisantibody. IMC-C225 also perturbs cell cycle progression byinducing a G1 arrest through an increase in the protein levels ofthe p27kip1 inhibitor of cyclin-dependent kinases (23, 24). IMC-C225 significantly inhibits the growth of epidermoid, prostate,colon, and renal cell carcinoma xenografts in vivo, and this

Fig. 1 EGFR signaling pathway and approaches to inhibiting the EGFR (adapted and modified from Ref. 6).

2959Clinical Cancer Research



effect is generally accompanied by a significant increase insurvival of mice (20, 21, 25–27). Studies using human cancerxenografts growing either s.c. or orthotopically in nude micehave demonstrated that IMC-C225 inhibits tumor-induced an-giogenesis (25, 28–31). This is probably attributable to reducedtumor expression of numerous angiogenic factors, includingTGF�, VEGF, interleukin-8, and bFGF (Table 1; Refs. 25 and28–31). A dose-dependent additive increase in growth inhibi-tion has been observed when cancer cells have been treated withIMC-C225 plus various cytotoxic agents, including doxorubi-cin, cisplatin, paclitaxel, gemcitabine, and topotecan in vitro(16, 26, 29, 31). In addition, EGFR blockade with IMC-C225 incombination with gemcitabine, topotecan, or paclitaxel resultedin regression of human pancreatic, colon, or bladder carcinomaxenografts in nude mice, respectively (Refs. 26, 29, and 31; Fig.3). In two orthotopic models of human pancreatic carcinoma andhuman bladder transitional carcinoma in nude mice, this wasmediated in part by the inhibition of tumor-induced angiogen-

esis, leading to endothelial and cancer cell apoptosis and tumorregression (29, 31). These effects were potentiated when micewere treated with IMC-C225 in combination with gemcitabineor paclitaxel, respectively (29, 31). Several in vitro experimentsand in vivo animal studies have also shown an enhancement oftumor response to ionizing radiations by IMC-C225 in humanepidermoid, head and neck, and colon cancer xenografts (Fig. 4;Refs. 32–36). Among the potential mechanisms that contributeto the increased radiation sensitivity by treatment with IMC-C225, various studies have suggested an accumulation of cancercells in the more radiosensitive cell cycle phases (G1, G2-M), ablockade of radiation-induced DNA repair mechanisms, and areduction of VEGF production by cancer cells with inhibition oftumor angiogenesis (33, 34, 36).

IMC-C225: Clinical Studies. Three consecutive Phase Iclinical trials have been carried out, in which IMC-C225 wasadministered as a single i.v. infusion, weekly infusions for 4weeks, and weekly infusions in combination with cisplatin (37).

Fig. 2 Antitumor activity of cisplatin and MAb 225 on established A431 tumor xenografts (reproduced from Ref. 18). A431 cells (107) wereimplanted s.c. into nude mice and allowed to grow for 8 days. In A, the mice were given i.p. injections of either PBS (F), two injections of cisplatin(150 mg/mouse) on days 8 and 18 (Œ), or MAb 225, 1 mg/mouse, twice a week for 4 weeks, with (f) or without (�) two injections of cisplatin (150mg/mouse) on days 8 and 18. The data are expressed as the mean tumor size �SE (seven mice per group). In B, the mice were observed for 6 monthsfor survival.

Table 1 Immunohistochemical analysis of GEO colon cancer xenografts after treatment with IMC-C225a

A. Analysis performed on day 21 after tumor cell injection (2 weeks of treatment)

Tumor size (cm3) Ki67 (%) bFGF (%) VEGF (%) TGF� (%)Factor VIII-related antigen

(microvessels per field � SD)

Control 0.76 45 55 (��) 60 (��) 70 (��) 20 (�2)IMC-C225 0.20 20 25 (�) 25 (�) 35% (�) 10 (�2)

B. Analysis performed on day 28 after tumor cell injection (3 weeks of treatment)

Tumor size (cm3) Ki67 (%) bFGF (%) VEGF (%) TGF� (%)Factor VIII-related antigen

(microvessels per field � SD)

Control 1.98 60 55 (��) 65 (��) 75 (��) 21 (�3)IMC-C225 0.40 20 30 (�) 30 (�) 25 (�) 8 (�2)

a Modified from Ref. 30. Mice were injected s.c. with 107 GEO cells that had been resuspended in 200 �l of Matrigel. After 7 days, whenestablished tumors of �0.2–0.3 cm3 in diameter were detected, 10 mice/group were treated i.p. with IMC-C225 (0.5 mg/dose, twice weekly on days1 and 4 for 2 or 3 weeks). Both the percentage of specifically stained cells and the intensity of immunostaining was recorded. Microvessel count wasscored by averaging the five field counts of five individual tumors for each group.

2960 Targeting the Epidermal Growth Factor Receptor



All were open-label, dose-escalation studies (5, 20, 50, and 100mg/m2). IMC-C225 was additionally escalated to 200 and 400mg/m2 in the combination study with cisplatin (100 mg/m2, laterreduced to 60 mg/m2). Overall, 52 patients were included inthese studies. All patients were immunohistochemically deter-mined to have EGFR tumor overexpression (37). Antibodiesagainst IMC-C225 were detected in only 1 of 52 patients.IMC-C225 toxicity was minimal and was not dose related orrelated to the number of cycles administered (37). The mostfrequent IMC-C225-related adverse events were skin toxicities(20.9%), fever and chills (13.5%), asthenia (13.5%), transient

transaminase elevations (11.5%), and nausea (11.5%; Ref. 37).Skin toxicities were mainly flushing or acneiform rashes. Fourgrade 3–4 adverse events occurred when IMC-C225 was incombination with cisplatin 100 mg/m2 [diarrhea (1 patient),epiglottis (1 patient), dyspnea (1 patient), and anaphylactoidreaction (1 patient)]. The maximum tolerated dose was notreached in any of these three Phase I studies (37). IMC-C225has nonlinear pharmacokinetics, with antibody doses in therange of 200–400 mg/m2 being associated with complete satu-ration of systemic clearance (37). Clearance did not change withrepeated administration or with coadministration with cisplatin

Fig. 3 Antitumor activity of topotecanand IMC-C225 on established GEO tumorxenografts (reproduced from Ref. 26).Mice were injected s.c. into the dorsalflank with 107 GEO cells. After 7 days(average tumor size, 0.2 cm3), the micewere treated i.p. with topotecan alone (2mg/kg/dose, twice weekly on days 1 and 2of each week for 2 weeks), with IMC-C225 alone (0.25 mg/dose, twice weeklyon days 3 and 6 of each week for 5weeks), or with both drugs. Each groupconsisted of 10 mice. Results are shownas mean �SD.

Fig. 4 Antitumor activity ofIMC-C225 in combination withradiotherapy in squamous cellcarcinoma xenografts (repro-duced from Ref. 36). SCC-1(106) or SCC-6 (5 � 105) cellswere injected s.c. into the dor-sal flank of athymic mice andtreated with IMC-C225 (0.1mg/dose) on days 10 and 13.Radiotherapy (XRT) was de-livered with 12 Gy on day15. Each group consisted ofsix mice. Values representmean �SE.




(37). On the basis of the doses for complete saturation ofantibody clearance, the recommended maintenance dose forPhase II studies has been 250 mg/m2. Single-agent IMC-C225treatment resulted in disease stabilization at 4 weeks for 7 of 12(58%) and 11 of 16 (69%) patients, respectively (37). In com-bination with cisplatin, 9 of 13 (69%) patients treated withIMC-C225 doses � 50 mg/m2 completed 12 weeks of therapy.Two patients with head and neck cancer had a partial response(37). A Phase Ib clinical trial with IMC-C225 and cisplatin in 12patients with advanced head and neck cancer has been reportedrecently (38). Tumor EGFR saturation after treatment withIMC-C225 was demonstrated by immunohistochemistry. Addi-tionally, inhibition of EGFR tyrosine kinase activity after IMC-225 treatment within the tumor mass was demonstrated in somepatients. The recommended loading dose was 400 mg/m2 with amaintenance dose of 250 mg/m2. Six of 9 evaluable patientsachieved a major response, including two complete responses(38). In patients with EGFR-positive tumors refractory to, or inrelapse from, previous therapeutic regimens, including surgery,radiotherapy, or chemotherapy, IMC-C225 (maintenance dose100 or 250 mg/m2) in combination with cisplatin has shownpositive antitumor activity (39). One patient with head and neckcancer and 1 patient with colorectal cancer had complete re-sponses. In addition, 4 patients with head and neck cancer hadpartial responses. In a Phase II study of IMC-C225 monotherapyin 54 patients with metastatic renal cell carcinoma, there wasone partial response and disease stabilization for �6 months in�25% of treated patients (40). An additional study evaluatingIMC-C225 in combination with radiotherapy showed that of 15patients with locally advanced head and neck cancer, 13 patientsexperienced a complete response, whereas an additional patienthad a partial response when treated with IMC-C225 and radio-therapy, a response rate significantly higher than the expected30–45% with radiotherapy alone (41). The median duration ofresponse in this study was 17 months, with a range of 1–32�months. Preliminary results of a Phase II study of IMC-C225 incombination with gemcitabine in 41 advanced pancreatic cancerpatients have been reported (42). Antitumor activity has beenobserved in 5 (12%) patients with a partial response and in 16(39%) patients with a stable disease. The 1-year patient survivalin this study was 32%. Results from two Phase II clinical trialsof therapy with IMC-225 in combination with CPT-11 or cis-platin in patients with diseases refractory to these cytotoxicdrugs have also been reported recently. Saltz et al. (43) haveshown that treatment with IMC-225 plus CPT-11 in advancedcolorectal cancer patients that have failed a previous treatmentwith CPT-11 determines partial responses in 27 of 120 patients(22.5%) with a median duration of response of 186 days anddisease stabilization for �12 weeks in 9 other patients (7%). Inthis study, IMC-C225 treatment was well tolerated and did notincrease the toxicity attributable to CPT-11. Hong et al. (44)have treated with IMC-C225 plus cisplatin advanced head andneck cancer patients that had stable disease (41 patients) orprogressive disease (27 patients) after two cycles of a cisplatin-based combination chemotherapy. In the first group of patients,the authors observed one complete response, nine partial re-sponses, and 25 disease stabilizations, with a median duration ofthe response of 24 weeks. In the second group, 5 patientsexperienced a partial response, and 6 patients had a disease

stabilization for �12 weeks. Phase II and III clinical trials ofIMC-C225 in combination with a range of chemotherapeuticdrugs, such as cisplatin or CPT-11, or with radiotherapy inpatients with head and neck or colorectal cancers are currentlyin progress (45).

Other EGFR MAbs. ABX-EGF is a fully human IgG2MAb specific for the EGFR, which inhibited the spontaneousproduction of angiogenic factors in vitro and caused significantgrowth inhibition of EGFR-positive tumors in vivo (46). APhase I study of ABX-EGF has been initiated (46). Y10 is aMAb which recognizes both human and murine mutated EGFR-vIII. It inhibits cellular proliferation and induces cell-mediatedcytotoxicity in vitro. Intratumoral injection of Y10 in micebearing human brain tumor xenografts expressing the mutatedEGFRvIII increased median survival by �3-fold with �25% ofmice achieving long-term survival (47).

Small Molecule Inhibitors of the EGFR TyrosineKinase. In the past 10 years, hundreds of TKIs have beensynthesized and evaluated for potential preclinical activity (48–57). These molecules are generally reversible competitors withATP for binding to the intracellular catalytic domain of thetyrosine kinase. Pharmacore modeling of the binding of com-pounds in the ATP pocket of tyrosine kinases has been used tosuccessfully design potent and selective EGFR-TKIs (57). Themost promising small molecule selective EGFR-TKIs are cur-rently three series of compounds, which include 4-anilinoquina-zolines, 4-[ar(alk)ylamino] pyridopyrimidines, and 4-phe-nylaminopyrrolo-pyrimidines (Fig. 5). A variety of these smallmolecule inhibitors has shown encouraging in vivo antitumoractivity in preclinical models, including ZD1839 (Iressa), OSI-774, PD183805/CI-1033, PKI-166, CGP-59326A, GW2016,and PD153035 (Table 2). Of these EGFR-TKIs, ZD1839, OSI-774, CI-1033, and PKI-166 are currently in clinical develop-ment in cancer patients.

ZD1839: Preclinical Studies. ZD1839 [4-(3-chloro-4-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy) quinazoline]is a low molecular weight (447), synthetic anilinoquinazoline.ZD1839 is a p.o. active, selective reversible inhibitor of EGFRtyrosine kinase. ZD1839 inhibited autophosphorylation ofEGFR isolated from A431 vulval carcinoma cells, with an IC50

Fig. 5 Small molecule inhibitors of the tyrosine kinase domain of theEGFR.




of 0.023–0.079 �M (51). By contrast, ZD1839 exhibited mini-mal activity against other tyrosine kinases and several serine/threonine kinases. A generally cytostatic growth inhibiting ac-tivity of ZD1839 has been demonstrated in a wide range ofhuman cancer cell lines that express functional EGFRs, includ-ing prostate, breast, ovarian, colon, epidermoid, small cell lung,and NSCL (13, 72, 73–76). In addition, ZD1839 treatment canalso be associated with a dose-related increase in apoptosis invitro (72). ZD1839, like IMC-225, has been shown to induce G1

arrest in human head and neck squamous cell carcinoma celllines, via a dose- and time-dependent up-regulation of p27Kip1

cyclin-dependent kinase inhibitor (77). In vivo experiments havealso demonstrated that ZD1839 inhibits EGFR signaling, e.g.,after administration of ZD1839 to mice bearing A431 xe-nografts, there was a time- and dose-dependent decrease in c-fosmRNA, which can be considered a downstream nuclear biomar-ker for EGFR mitogenic signaling activation (78). Moreover,daily p.o. administration of single-agent ZD1839 (12.5–200mg/kg) to athymic nude mice caused marked reductions intumor growth in a variety of human cancer xenografts, includinghormone-resistant prostate, ovarian, ductal carcinoma in situ ofthe breast, colon, vulval, small cell lung, and NSCL (72, 73, 76).Administration of ZD1839 (1.25–5 mg/mouse/day) to nudemice bearing human GEO colon cancer xenografts for 4 weeksproduced a dose-dependent inhibition of tumor growth that wasreversible, because tumors resumed a growth rate comparablewith that observed in controls once treatment with ZD1839ceased (Fig. 6; Ref. 72). ZD1839 demonstrates similar antitumoractivity in xenograft models with differing levels of EGFRexpression (76), suggesting that factors other than simply thenumber of EGFR per cell may influence cancer cell sensitivityto EGFR-targeted therapies. These include the levels of expres-sion of the EGFR-specific ligands and of the other EGFR-related receptors that could form heterodimers with the EGFR.Enhancement of cell growth inhibition, induction of apoptosis,and increased antitumor activity in vitro and in vivo wereobserved when ZD1839 was combined with cisplatin, carbopla-tin, oxaliplatin, paclitaxel, docetaxel, doxorubicin, etoposide,

topotecan, and raltitrexed (72, 76, 79). In some cases, ZD1839in combination with cytotoxic agents produced tumor regressionin nude mice bearing prostate, lung, and colon cancer xenografts(76, 80). After 4 weeks of treatment, ZD1839 combinationtherapy was associated with a significant increase in survival ofnude mice with GEO tumor xenografts, especially with pacli-taxel (Fig. 7; Refs. 72 and 80). Additionally, it has been shownrecently that ZD1839 has a growth inhibitory effect and couldrestore the sensitivity to taxanes in MCF-7 ADR bcl-2 cells, amodel of hormone-independent, multidrug-resistant humanbreast cancer cells (81). Preliminary data have been reported onthe combination of ZD1839 and radiotherapy. ZD1839 treat-ment has an additive or frankly synergistic effect when com-bined with ionizing radiations in several human NSCL cancer

Table 2 Summary of small molecule inhibitors of the EGFR tyrosine kinase domain

DrugInhibition of EGFR

kinase (IC50)

Antitumor activityDevelopment

stage ReferencesIn vitro (IC50) In vivo

ZD1839 23 nM 80 nM � (�12 mg/kg)a Phase III Woodburn et al., 1996 (51)Kris et al., 2000 (57)Tamura et al., 2000 (58)

OSI-774 20 nM 100 nM � (�10 mg/kg) Phase II Moyer et al., 1997 (59)Pollack et al., 1999 (60)Karp et al., 2000 (61)Siu et al., 1999 (62)

PKI-166 0.7 nM � � (�10 mg/kg) Phase I Traxler et al., 1999 (63)Bruns et al., 2000 (64)

PD183805 7.4 nM � � Phase I Sherwood et al., 1999 (65)Driscoll et al., 1999 (66)

CGP-59326A 27 nM 138 nM � (�1.5 mg/kg) Preclinical Lydon et al., 1998 (67)GW2016 9.2 nM 150 nM � (�30 mg/kg) Preclinical Mullin et al., 2001 (68)CI-1033 pan-erbB inhibitor 40 nM � Phase I Modjtahedi et al., 1998 (69)

Shin et al., 2001 (70)Garrison et al., 2001 (71)

a �, activity.

Fig. 6 Dose-dependent effects of ZD1839 treatment on tumor growthin nude mice with established GEO tumor xenografts (reproduced fromRef. 72). Mice were injected s.c. into the dorsal flank with 107 GEOcells. After 7 days (average tumor size, 0.25 cm3), the mice were treatedi.p. on days 1–5 of each week for 4 weeks with ZD1839 at the indicateddaily doses. Each group consisted of 10 mice. Results are shown asmean �SD.




cell lines in vitro (82). Additionally, ZD1839 enhances theefficacy of radiotherapy in the LoVo human colon carcinomaxenograft model (83). A recent study has demonstrated thatZD1839 blocks tumor-induced angiogenesis (80). In fact,ZD1839 treatment determined a dose- and time-dependentgrowth inhibition accompanied by the decrease of VEGF,bFGF, and TGF� production in vitro and in vivo in severalhuman cancer cell lines (Table 3). This effect was potentiated bythe combination with paclitaxel (80). Finally, preliminary datafrom three independent groups have suggested that ZD1839treatment prevents c-erbB-2 signaling in human breast cancercell lines that overexpress c-erbB-2 and that express functionalEGFRs, possibly by preventing EGFR/c-erbB-2 heterodimeriza-tion (84–86). Additionally, a cooperative or frankly synergisticantitumor activity in vitro and in vivo in these models has beendemonstrated after treatment with ZD1839 in combination withtrastuzumab (Herceptin; Refs. 84–86).

ZD1839: Clinical Studies. Five Phase I trials have beenconducted to assess either intermittent ZD1839 (14 days treat-ment followed by 14 days observation; Refs. 57, 58, and 87) orcontinuous ZD1839 (28 consecutive days treatment) adminis-tration (58, 88, 89). ZD1839 was administered as a once-daily,p.o. dose (50–1000 mg/day). Nearly all of the 254 patients inthese Phase I trials were heavily pretreated, with �30% failingmore than two prior chemotherapy regimens. Both intermittentand continuous dosing of ZD1839 were well tolerated. The mostfrequently reported National Cancer Institute-CTC grade 1–2adverse events were diarrhea and an acneiform skin rash (57).Adverse events were reversible on discontinuation of treatment,and the skin rash resolved without scarring. Grade 3–4 adverseevents were rare and usually related to disease progression (57).Intermittent ZD1839 treatment was also well tolerated in aJapanese study; grade 3 elevation of hepatic transaminases wasobserved in 3 patients, and grade 3 diarrhea was observed in 1patient (58). Grade 3 diarrhea was dose limiting at the 700-mgdose level after intermittent dosing and 1000 mg after continu-ous dosing (87, 88). Pharmacokinetic assessments confirm thatZD1839 is suitable for once-daily dosing; the mean eliminationhalf-life was 46 h (86). Steady-state plasma concentrations wereachieved by day 7. Exposure to ZD1839 increased approxi-mately linearly with dose, although exposure varied within eachdose group (87). Antitumor activity has been observed in pa-

tients with colorectal, ovarian, NSCL, head and neck, renal, andhormone-resistant prostate cancers (57, 87, 88). In particular,encouraging results have been reported in patients with NSCLC.Of 99 patients with NSCLC, 8 patients have had a partialresponse lasting from 1 to 16 months, and 2 patients have hadregression of nonmeasurable evaluable disease (57, 58). Inaddition, approximately one-third of patients have had long-lasting stable disease for �3 months, and preliminary quality oflife assessment data suggest this corresponds with symptomaticrelief (57). A pilot study has shown that ZD1839 in combinationwith carboplatin/paclitaxel appears feasible and well tolerated inpreviously untreated patients with advanced NSCLC (90). Pre-liminary pharmacokinetic data suggest that coadministration ofZD1839 does not affect the clearance of either carboplatin orpaclitaxel (90). Preliminary antitumor activity data of this com-bination have been reported recently (91). Of 24 patients af-fected by advanced NSCLC and treated with carboplatin/pacli-taxel plus ZD1839, 1 patient had a complete response (�8months), 5 patients experienced partial responses (range, 3.1–12.4 months), and 8 patients obtained a disease stabilization(91). Recently, preliminary results of a Phase I study of p.o.ZD1839 in combination with 5-fluoruracil and leucovorin inpatients with advanced colorectal cancer have been reported(92). This study included 26 patients that were treated withZD1839 doses from 250 to 500 mg/day. No significant increasein the frequency and the severity of diarrhea or skin toxicitybeyond that seen with chemotherapy alone was observed in thistrial (92). Two large multicenter Phase III studies of ZD1839(250 or 500 mg daily) in combination with cytotoxic agents(carboplatin/paclitaxel or cisplatin/gemcitabine) have beenstarted as first-line treatment in nonoperable stage III and stageIV NSCLC patients (Fig. 8). For both studies, patients accrual(�1030 patients in each trial) has been completed in March2001.

OSI-774: Preclinical Studies. OSI-774 [6,7-bis(2-methoxy-ethoxy)-quinazolin-4-yl-(3-ethynylphenyl)amine, for-merly CP358,774] is a quinazoline derivative which reversiblyinhibits the kinase activity of purified EGFR (IC50 � 2 nM) andautophosphorylation in intact cells (IC50 � 20 nM) in vitro. Theproliferation of DiFi human colon tumor cell lines is inhibitedby OSI-774 at submicromolar concentrations, and OSI-774 alsoblocks the cell cycle in G1, resulting in significant accumula-

Table 3 Immunohistochemical analysis of GEO colon cancer xenografts after treatment with ZD1839a

Dose of ZD1839(mg/day)

Tumor volume(cm3 � SD)

% positive cells (�SD)Factor VIII-related

antigenbKi67 TGF� bFGF VEGF

0 0.92 � 0.15 75 � 10 55 � 8 45 � 10 50 � 4 19 � 31.25 0.68 � 0.08 50 � 7 40 � 6 25 � 3 35 � 2 8 � 22.5 0.44 � 0.05 40 � 5 25 � 2 10 � 2 15 � 4 5 � 13.75 0.31 � 0.07 35 � 5 20 � 2 5 � 3 5 � 1 4 � 25 0.16 � 0.04 25 � 2 5 � 1 5 � 1 3 � 2 4 � 1

a Reproduced with modifications from Ref. 80. Mice bearing GEO tumor xenografts were treated as follows. Briefly, 107 cells were injected,after being suspended in 200 �l Matrigel, into the dorsal flank of 4–5-weeks-old nude mice on day 0. Treatment was started on day 7 after tumorcell injection, when tumor volume was �0.25 cm3. Mice were treated i.p. daily from days 1 to 5 with the indicated doses of ZD1839 for 2 weeks.Analysis was performed on day 21 after tumor cell injection. Each group consisted of six mice. The percentage (�SD) of specifically stained GEOcancer cells for Ki67, TGF�, bFGF, and VEGF was recorded. The number of microvessels for field (�SD) was measured using a monoclonal antibodyraised against the human factor VIII-related antigen and was scored by averaging five field counts of three individual tumors for each group.

b Figures for factor VIII-related antigen are the numbers of positively staining microvessels.




tions of cell cycle inhibitor p27Kip1 (59). OSI-774 inducesapoptosis in vitro and has activity against various human tumorxenografts in vivo (59, 60, 93, 94). OSI-774 in combination withcisplatin produced substantial growth inhibition of human can-cer xenografts with no detectable effects on body weight orlethal toxicity in mice (61).

OSI-774: Clinical Studies. OSI-774 has been evaluatedin two Phase I dose-escalation pharmacokinetic trials in patientswith advanced solid tumors (61, 62, 95). p.o. OSI-774 (100–1600 mg) was administered once weekly every 3 of 4 weeks(n � 28; Ref. 61), on 3 consecutive days for 3 weeks, or everyday for 3 weeks (n � 27; Ref. 62). All these treatment scheduleswere followed by a week of rest. All of the patients had prior

treatment for advanced solid tumors. The maximum tolerateddose was not reached in the once-weekly schedule, and 1600 mgweekly was a well-tolerated dose (61). Like ZD1839, dose-limiting toxicity was diarrhea (at the 200-mg dose level) in thecontinuous once-daily dose schedule (62). Half of the patients inthe continuous dose schedule have reported grade 1–2 acne-iform skin rashes (62). Preliminary pharmacokinetic analysisshowed large intra and interpatient variability but dose-propor-tional increases in exposure (61, 62). Of 28 patients receivingOSI-774 weekly, 12 patients remained alive (9–22 months),including 5 of 11 with lung cancer and 3 of 5 with head and neckcancer (61). OSI-774 is currently in Phase II development inadvanced head and neck, NSCL, and ovarian cancer. Prelimi-nary results of a Phase II study of OSI-774 in patients withpretreated, advanced head and neck cancer have been presentedrecently (96). A group of 124 patients (98 patients with EGFRoverexpressing cancer as detected by immunohistochemistry)received OSI-774, 150 mg daily. Major toxicities were skin rashin 74.2% patients (11.3%, grade 3) and diarrhea (3.2%, grade 3).Partial responses were observed in 7 patients (5.6%), and stabledisease occurred in 39 patients (33.9%). The median survivalwas 5.8 months, with a 1-year survival of 24% patients. A PhaseII study in ovarian cancer patients has also been reported re-cently (97). Patients (34) with advanced, heavily pretreated,ovarian cancer received p.o. OSI-774, 150 mg daily. Majortoxicities were skin rash (88% patients, 9%, grade 3) and diar-rhea (35% patients, 6%, grade 3). Two patients had partialresponses, and 16 experienced disease stabilization. The mediansurvival for the patients in this study was 242 days (97). Finally,evidence of antitumor activity of OSI-774 in patients withadvanced NSCLC that had failed a platinum-based therapy wasreported recently (98). A complete response occurred in 1 of 57patients, and partial responses were recorded in 6 other patients.An additional 17 patients had stable disease.

PD183805/CI-1033. PD183805 [4-(-3-(chloro-4-fluoro-phenylamino)-7-(3-morpholin-4-yl-propoxy)-quinazolin-6-yl)-acrylamide dihydrochloride] is an irreversible inhibitor of theEGFR (IC50 � 7.4 nM against EGF-stimulated A431 cells) andof the other EGFR family members (65). PD183805 has dem-onstrated antitumor activity against A341 and H125 tumors invivo (66). PD183805 is currently in Phase I development inpatients with head and neck, breast, and NSCL cancer. Thewater-soluble analogue of PD183805, CI-1033, inhibited EGFRtyrosine kinase in vitro and p.o. CI-1033 suppressed humanepidermoid A431 xenografts in nude mice. A Phase I trial inadvanced cancer patients has been reported recently (70). Pa-tients (50) were treated with escalating doses of CI-1033 (50–650 mg p.o., daily for 7 days, every 3 weeks). Toxicitiesincluded skin rash and diarrhea, whereas the dose-limiting tox-icities were grade 3 hypersensitivity at 560-mg dose level andgrade 4 thrombocytopenia at 650-mg dose level. A similar PhaseI study was reported (71). Also in this trial, hypersensitivity andthrombocytopenia were the major toxic side effects. A diseasestabilization for �12 weeks was observed in 6 of 53 patientstreated in this study (71).

PKI-166. PKI-166 is a reversible pyrrolo-pyrimidine in-hibitor of the EGFR tyrosine kinase in vitro (IC50 � 1 nM; Ref.63). PKI-166 inhibited EGFR autophosphorylation, c-fosmRNA expression, and cell proliferation in the submicromolar

Fig. 7 A, antitumor activity of ZD1839 in combination with paclitaxelin nude mice with established GEO (colon) tumor xenografts. B, theeffects of ZD1839 treatment in combination with paclitaxel on thesurvival of GEO tumor-bearing mice (reproduced from Ref. 72). Micewere injected s.c. into the dorsal flank with 107 GEO cells. After 7 days,the mice were treated i.p. on days 1–5 of each week for 4 weeks withZD1839, 2.5 mg/dose, alone or in combination with paclitaxel, 20mg/kg/dose on day 1 of each week for 4 weeks. Each group consisted of10 mice. Results are shown as mean �SD.




range (63). PKI-166 demonstrated antitumor activity in fourEGFR-expressing tumor xenograft models in nude mice (63). Inaddition, PKI-166 decreased the growth and metastasis of ahuman pancreatic cancer growing orthotopically in nude mice,increased survival via reduced production of proangiogenicmolecules, and increased apoptosis (64). PKI-166 is planned toenter Phase I trials in patients.

GW2016. GW2016 is a 6-thiazolylquinazoline deriva-tive that selectively inhibits with equimolar potency both theEGFR and the ErbB-2 tyrosine kinases (IC50 � �10 nM for bothkinases in vitro; Ref. 99). Recently, data have been presented onthe antitumor activity of GW2061 in nude mice bearing humanHN5 squamous carcinoma xenografts (68). GW2016 is plannedto enter Phase I trials in cancer patients.

Conclusions. Considerable experimental evidence overthe last decade has shown that the EGFR-driven autocrinepathway is a rational target for cancer therapy. The identifica-tion of selective and potent inhibitors of EGFR activation thatcould be developed as anticancer agents has been one of themost successful areas of translational research in cancer treat-ment. All of the EGFR inhibitors described above have shownefficacy in relevant preclinical models, such as human cancercell lines in vitro and human tumors xenografted to immuno-deficient mice in vivo.

Three different inhibitors of EGFR signaling, IMC-C225,ZD1839, and OSI-774, have shown in vitro and in vivo antitu-mor activity, as well as encouraging results in clinical trials.Although IMC-C225 and the small molecule EGFR-TKI havedifferent mechanisms of action, they all ultimately lead to G1

arrest via accumulations of p27kip1. IMC-225 administered i.v.and ZD1839 or OSI-774 administered p.o. displayed differentpharmacokinetic profiles. IMC-C225 demonstrated nonlinearsaturable pharmacokinetics, whereas ZD1839 and OSI-774showed linear pharmacokinetics.

The hope for new agents targeting the EGFR is that spe-cific inhibition of the EGFR will have therapeutic efficacywithout the toxicities associated with virtually all currentlyavailable anticancer cytotoxic drugs. Toxicities associated withIMC-C225, ZD1839, and OSI-774 were similar and very mild.Grade 1–2 rash-like, skin toxicity was common with IMC-C225,ZD1839, and OSI-774. In this respect, skin toxicity is oftenviewed as an indirect marker of clinically relevant EGFR tar-geting in vivo. Although the IMC-C225, ZD1839, and OSI-774dose-escalation Phase I trials were not designed to specifically

analyze clinical response, they have all shown encouragingclinical results. Moreover, preliminary results from Phase IIstudies with these agents confirm antitumor activity of anti-EGFR-directed therapies in advanced human cancer. In fact,treatment with IMC-C225, ZD1839, or OSI-774 as single agentsresulted in disease stabilization, as well as in a number of majorresponses in a variety of cancers.

Preclinical results with IMC-C225, ZD1839, and OSI-774and preliminary clinical results with IMC-C225 suggest that thepotential of these agents will increase when combined withstandard cytotoxics and/or radiotherapy. Taken together, thesestudies support the hypothesis that cellular damage induced bychemotherapy or by ionizing radiations can convert EGFR li-gands from growth factors into survival factors for cancer cellsthat express functional EGFR (100, 101). In this situation, theblockade of EGFR signaling in combination with cytotoxicdrugs or with radiotherapy could cause irreparable cancer celldamage leading to increased programmed cell death. The en-hancement of anticancer activity of conventional cytotoxic treat-ments by interfering with EGFR activation may have relevantclinical implications. In this respect, treatment with conven-tional doses of cytotoxic drugs or of radiotherapy in combina-tion with signal transduction inhibitors, such as the anti-EGFRselective agents, could be an effective novel anticancer strategy,which is less toxic and more tolerable than other clinical ap-proaches for increasing the activity of cytotoxic drugs, such ashigh-dose chemotherapy (100, 101).

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