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Int. J. Radiation Oncology Biol. Phys., Vol. 59, No. 2, Supplement, pp. 11–20, 2004Copyright © 2004 Elsevier Inc.

Printed in the USA. All rights reserved0360-3016/04/$–see front matter

doi:10.1016/j.ijrobp.2003.11.042

GFR-LUNG CANCER

POTENTIAL ROLE FOR EPIDERMAL GROWTH FACTOR RECEPTORINHIBITORS IN COMBINED-MODALITY THERAPY FOR NON–SMALL-CELL

LUNG CANCER

DONG WOOK KIM, M.D., PH.D.,* AND HAK CHOY, M.D.†

*Department of Radiation Oncology, Vanderbilt University Medical Center, Nashville, TN;†Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX

There has been a surge of interest in the translation of discoveries in molecular biology into clinically relevanttherapies in the field of hematology/oncology. The epidermal growth factor receptor (EGFR) has been amolecular target of significant interest and investigation, and preclinical and clinical studies support a role fortargeted therapy in a variety of cancers, including non–small-cell lung cancer (NSCLC) via compounds thatspecifically inhibit EGFR. ZD1839, IMC-C225, and OSI-774 are the most clinically developed of these com-pounds. Interestingly, preclinical studies have demonstrated that EGFR inhibitors may have radiation-sensitiz-ing properties, as well as increased cytotoxic activity in combination with chemotherapeutic agents, suggesting apotential role for EGFR inhibitors as an adjunct to the current combined-modality approach for therapy ofStage III NSCLC. Therefore, clinical trials have been proposed and initiated to address the issue of determiningthe impact of the addition of EGFR inhibitors to the standard combined-modality regimen (chemotherapy/radiation therapy � surgery) for Stage III NSCLC. This article reviews preclinical and clinical data supportingthe role for EGFR inhibitors alone or in combination with chemotherapy/radiation therapy for locally advancedNSCLC. Also, it will provide an overview of ongoing and proposed clinical studies investigating the potential rolefor EGFR inhibitors in Stage III NSCLC. © 2004 Elsevier Inc.

Epidermal growth factor receptor (EGFR), Non–small-cell lung cancer (NSCLC), Combined-modalitytreatment.

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INTRODUCTION

lthough significant progress has been made in the tent of lung cancer, the overall survival rate for patieith all stages of lung cancer in the United States is 15years(1). Advances in radiation therapy (RT) techniqu

hemotherapeutic regimens, and different combined-mty approaches have yielded only a modest impact onrognosis of patients with advanced lung cancer. T

here is clearly a need for additional strategies. Oneroach involves using the identification of a numberolecular targets that may be responsible for the resisf cancer cells to radiation or to other cytotoxic agentsuch, these molecular determinants may serve as targeugmentation of the RT or chemotherapy response

hese, the epidermal growth factor receptor (EGFR)een a molecular target of considerable interest and in

igation, and there has been a tremendous surge of inn pursuing targeted therapy of cancers via inhibition ofGFR.

Reprint requests to: Hak Choy, M.D., Department of Radiancology, University of Texas Southwestern Medical Cen801 Forest Park Rd, Dallas, TX 75390-9183. Tel: (214)600; Fax: (214) 645-7622; E-mail: Hak.Choy@utsouthwesdu

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The overexpression of EGFR has been demonstrateumber of human tumor types, including head-and-nancer, colon cancer, breast cancer, gliomas, pancancer, and lung cancer(2–10). Since the first publisherticle of EGFR expression in lung cancer in 1984(5), thereave been numerous reports of EGFR overexpressio

mmunohistochemical (IHC) methods in non–small-ung cancer (NSCLC) (Table 1) (11).

Theoretically, there are four main strategies for inhibif EGFR: (1) monoclonal antibodies to the extracelluomain of the receptors, (2) small molecules that inhibeceptor autophosphorylation by inhibiting ATP bindi3) antisense oligonucleotides, and (4) toxins attached tGFR ligands/antibodies(12). Of these, the former twtrategies are currently being investigated in clinical triaarious types of cancers, including NSCLC. Clinical coounds developed of these include ZD1839 (Iressatinib; AstraZeneca Pharmaceuticals, LP, WilmingtE), IMC-C225 (Erbitux, cetuximab; ImClone Systemsorporated, New York, NY and Bristol-Myers Squibb Co

Received Jul 22, 2003, and in revised form Nov 6, 20ccepted for publication Nov 10, 2003.

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12 I. J. Radiation Oncology ● Biology ● Physics Volume 59, Number 2, Supplement, 2004

any, New York, NY), and OSI-774 (Tarceva, erlotinibCl; OSI Pharmaceuticals, Inc, Melville, NY). These

gents are being developed for use as single agents or inombination with other cytotoxic agents, including radia-ion (13). The rationale for investigation of EGFR inhibitorss radiation sensitizers in cancer therapy is based on theollowing observations: (1) positive correlation betweenGFR expression and cellular resistance to radiation inany cell types (14–18); (2) the degree of radioresistance

orrelates positively with the magnitude of EGFR overex-ression (16); (3) cell survival and repopulation during aourse of radiotherapy are influenced by activation ofGFR/transforming growth factor–� that is induced afterxposure to radiation (19); and (4) inhibition of EGFRignaling-enhanced radiation sensitivity (20, 21).

ZD1839

ZD1839 is a small-molecule EGFR-specific tyrosine ki-ase inhibitor that has been shown to exhibit potent activityn vitro in the nanomolar range. Preclinical studies havehown that in vitro, ZD1839 causes a dose-dependent inhi-ition of colony formation in soft agar, and an in vivoenograft model showed a dose-dependent cytostatic effectn tumor growth (22, 23), with apoptosis at higher doses.ost recently, Raben et al. (24) have investigated the

rowth inhibitory properties of ZD1839 in NSCLC in vitro.s reported in other cell types, administration of ZD1839

aused a dose-dependent growth inhibitory effect in theung cancer cell lines. A small but significant (10% to 15%)hift of cells into the G0/G1 phase of the cell cycle washown in several NSCLC cells at 72 h after treatment withD1839, with the higher EGFR–expressing cells having theigher shifts (10–15%), whereas moderate EGFR–express-ng cells had lower shifts (4–5%). Overall, minimal apop-otic effects were noted in these preliminary studies (24,5). Furthermore, in vitro combination of ZD1839 witharious cytotoxic agents such as vinorelbine, paclitaxel, andisplatin resulted in synergistic to additive effects inSCLC cells (24).Several preclinical studies have indicated that ZD1839

lso enhances the radiation effect in a variety of cancer cellypes, including NSCLC. Synergistic to additive interac-ions have been reported when ZD1839 is added 24 h before

single fraction of RT (2 to 6 Gy) in NSCLC cells (24).

Table 1. Epidermal growth factor receptor expression in lungcancer by histology (adapted from Ref. 11)

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n vivo, Williams et al. (26) found an enhanced therapeuticffect when ZD1839 was combined with radiation in theuman colon carcinoma xenograft model. Huang et al. (21)emonstrated that in human head-and-neck squamous cellarcinoma cells, ZD1839 produced a dose-dependent de-rease in proliferation, and clonogenic analysis demon-trated decreased cell survival when cells were treated withadiation and ZD1839 compared with radiation alone. Fur-hermore, ZD1839 was shown to increase the radiation-nduced apoptosis of these cells. In models using squamousell carcinoma xenografts, profound tumor regression andegrowth delay were demonstrated in mice treated withadiation and ZD1839. Radiation therapy was administeredn 3 Gy fractions, twice weekly for 7 fractions, and 0.5 mgf ZD1839 was administered orally daily for 2.5 weeks.urthermore, ZD1839 was implicated as having antiangio-enic activity (21).In the clinical setting, a number of Phase I studies have

een conducted with doses of ZD1839 ranging from 50 to,000 mg/day (27–30). Four trials have been completedith a total of 252 patients receiving at least one dose ofD1839 (100 of whom had advanced NSCLC). Adverse

eactions included dose-related skin changes (mainly rash,ost often involving the head, neck, and upper trunk),

ausea, vomiting, diarrhea, and rare transaminase eleva-ions. Dose-limiting toxicity with diarrhea occurred at00 mg daily in one trial and at 1,000 mg daily in aompanion, nearly identical, Phase I trial. Among patientsith NSCLC, 10 of 100 (10%) exhibited partial responses

PRs), and 13 (13%) had stable disease (SD). Seventeenatients with NSCLC remained on study for 6 or moreonths (31). Six patients continued on ZD1839 from 11 to

3� months. There was no dose–response effect, withesponses occurring at doses ranging from 150 to 700 mg/ay. Based on safety and antitumor activity data, doseselected for evaluation in Phase II testing were 250 mg/daynd 500 mg/day. Both doses were shown to be safe, toler-ble, and to have antitumor activity.

Two monotherapy Phase II studies, Iressa Dose Evalua-ion in Advanced Lung Cancer (IDEAL 1 and IDEAL 2),nvolving advanced NSCLC have been reported (32, 33). InDEAL 1, 208 patients (from Europe, Australia, South Af-ica, and Japan) with locally advanced/metastatic NSCLCere randomized to receive either 250 mg or 500 mg ofD1839 daily (32). Entry criteria included one to two priorhemotherapy regimens, one of which contained a plati-um-based agent. Adverse reactions were generally mild,ncluding Grade 1/2 rash, diarrhea, pruritus, and dry skin.here was less Grade 3 (8.7% vs. 30.2%) and 4 (1.9% vs..4%) toxicity with the 250-mg regimen compared with the00-mg regimen (Table 2). Response rates were 18.4% vs.9%, and overall survival was 7.6 vs. 8.1 months for the50- and 500-mg doses, respectively (Table 2). Efficacyas not affected by previous chemotherapy regimens.In IDEAL 2 (33), 216 patients (from the United States)

ere randomized to receive either 250 mg or 500 mg ofD1839 daily. Entry criteria for IDEAL 2 included greater

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han or equal to two prior chemotherapy regimens, includ-ng a platinum-based regimen and docetaxel administeredoncurrently or as separate regimens. Response rates for the50-mg and 500-mg arms were 11.8% and 8.8%, respec-ively (Table 2). Response duration ranged from 3 to� months, and symptom response rates were 43%250 mg) and 35% (500 mg). Median survival was 6.1onths and 6 months for the 250-mg and 500-mg arms,

espectively. The toxicity profile was similar to IDEAL 1,ith Grade 3/4 toxicities occurring in 6.9% and 17.5% ofatients receiving the 250-mg and 500-mg dose, respec-ively. Both studies indicated that 250 mg is a well-toleratedose, with evidence of clinically significant antitumor ac-ivity in patients who had failed one or two previous che-otherapy regimens. Many patients in both IDEAL 1 and

DEAL 2 reported significant improvement in disease-re-ated symptoms and quality of life (40.3% and 43.1% forDEAL 1 and IDEAL 2, respectively) (34, 35).

Two Phase I studies involving ZD1839 with two differenttandard chemotherapy regimens have been reported. Therst study combined ZD1839 with carboplatin and pacli-

axel in 24 chemotherapynaive patients with advancedSCLC (36). Six (25%) patients showed a partial response

PR), and 8 (33%) patients had SD without new or increasedoxicity. The second study involved ZD1839 in combinationith cisplatin and gemcitabine in 18 chemotherapynaiveatients with advanced solid tumors, including NSCLC37). Of 17 evaluable patients, 9 (5 of whom had NSCLC)ad a PR, and 7 (4 with NSCLC) had SD. There was noignificant increase in overall toxicity with the addition ofD1839 to the regimen.Finally, two Phase III studies, the Iressa NSCLC Trial

ssessing Combination Treatment (INTACT) 1 and 2, haveeen conducted. The three arms of these studies included:1) chemotherapy plus 250 mg/day ZD1839, (2) chemother-py plus 500 mg/day ZD1839, and (3) chemotherapy pluslacebo, all of which were to be followed by continuation ofD1839 or placebo until disease progression. The chemo-

herapeutic regimen was gemcitabine and cisplatin inNTACT 1 and paclitaxel and carboplatin in INTACT 2.

ore than 1,000 patients have been treated in each of thesetudies. The primary endpoint for both trials was survival.ata from INTACT 2 were presented at the Europeanociety for Medical Oncology in October 2002 (38). Me-ian survival was 9.92 months for the placebo arm, 9.82onths for the ZD1839 250-mg arm, and 8.74 months for

Table 2. Response and toxic

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esponse rate 18.4%edian survival 7.6 monthsrade 3 toxicity 8.7%rade 4 toxicity 1.9%rade 3 or 4 toxicities

he 500-mg arm. Therefore, it was concluded that ZD1839howed no added benefit in survival for these patients whoere being treated with a standard chemotherapy regimen.he toxicity profile was also as predicted from the previoustudies. INTACT 1 showed similar results. The optimal usef ZD1839 in NSCLC patients must be further researched.

IMC-C225

IMC-C225 is a mouse–human chimerized monoclonalntibody that specifically binds to the EGFR, thereby inhib-ting downstream signal transduction pathways (39). In pre-linical studies, IMC-C225 has been shown in vivo andn vitro to enhance radiosensitivity, to promote radiation-nduced apoptosis, to decrease cell proliferation, to inhibitadiation-induced damage repair, and to inhibit tumor an-iogenesis. This was demonstrated in head-and-neck cancerell lines and in colon cancer cells (10, 40–44). In head-nd-neck cancer cells, IMC-C225 and radiation seem to beynergistic. An in vivo study of A431 squamous carcinomaell xenografts treated with radiation therapy (RT) andMC-C225 3 h prior, 3 days after, and 6 days after RT18 Gy) was performed. With the addition of the 3 doses ofMC-C225, tumor growth delay was noted with a radiationnhancement factor (defined as normalized tumor growthelay in mice treated by IMC-C225 plus RT divided by thebsolute growth delay in mice treated with RT alone) of.62 (44) (For definitions of absolute growth delay andormalized tumor growth delay, please refer to [44]). Theechanism of action appeared to be tumor necrosis, and an

ntiangiogenic effect was demonstrated. Other mechanismsncluded inhibition of tumor cell repopulation and retarda-ion of tumor growth. Furthermore, IMC-C225 has beenhown to enhance the cytotoxic effect when combined witharious chemotherapeutic agents (39).In the clinical setting, Phase I studies of IMC-C225 alone

nd in combination with cisplatin have been reported (45).aselga et al. (45) have reported a summary of three initial

tudies, which included a single-dose trial of IMC-C225CP02-9401), a weekly multiple-dose trial (once weekly for

weeks) (CP02-9502), or a weekly dose in combinationith cisplatin (CP02-9503). In CP02-9503, patients were

equired to have head-and-neck cancer (n � 16) or NSCLCn � 6). A total of 52 patients were treated in these threetudies. In the CP02-9401 and CP02-9502 studies, IMC-225 doses ranged from 5 to 100 mg/m2 i.v. In CP02-9503,

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MC-C225 doses ranged from 5 mg/m2 to 400 mg/m2 giveneekly with the addition of cisplatin every 4 weeks at0 mg/m2 1 h after IMC-C225 administration. Initially, 3atients were treated with 100 mg/m2 of cisplatin, but 2 ofhe 3 patients experienced Grade 3 or higher toxicities, andherefore, the dose was reduced to 60 mg/m2. Treatmentas continued for up to 12 weeks if there was no diseaserogression and if the patient was experiencing less thanrade 3 toxicity. Overall, IMC-C225 was well toleratedith five episodes of Grade 3 or higher toxicity occurringith 317 doses of IMC-C225. There was also no relation-

hip of toxicity to the dose level or number of cyclesdministered, with the possible exception of the acneiformashes that occurred. The most frequent adverse reactionsncluded fever and chills, asthenia, transaminase elevations,ausea, and skin toxicities (flushing [4 cases], seborrheicermatitis [1 case], and acneiform rash [6 cases]). Theashes were seen with doses greater than 100 mg/m2 andere Grade 1 in severity. Allergic reactions occurred in 4atients (urticaria, anaphylaxis). Antibodies against IMC-225 were detected in only 1 patient. Among the fivepisodes of Grade 3 or higher toxicity, 1 patient developedseptic meningitis with IMC-C225 alone, and the other 4atients received IMC-C225 and cisplatin and developediarrhea, epiglottitis, dyspnea, and anaphylactoid reaction,espectively. Except for the anaphylactic event, the otherhree events were associated with the higher dose of00 mg/m2 of cisplatin. Nine of the 13 patients treated withn IMC-C225 dose of 50 mg/m2 or greater and cisplatinompleted 12 weeks of therapy, and 2 PRs were reported.verall, in these studies, the maximum tolerated dose wasot reached. IMC-C225 systemic clearance vs. drug doseevels were pooled and analyzed from these three studies.MC-C225 clearance decreased with increasing concentra-ions, up to 200 mg/m2, and at 200 and 400 mg/m2 thelearance levels were similar, indicating that complete sat-ration of drug clearance occurred at this dose range.A Phase I study of IMC-C225 � RT was reported in 16

atients with advanced head-and-neck cancer (46). Patientseceived conventional RT doses (70 Gy in 2 Gy/day frac-ions), with IMC-C225 given in a dose-escalation schemeith a loading dose ranging from 100 to 500 mg/m2, fol-

owed by a weekly infusion of 100 to 250 mg/m2 for 7 to 8eeks. Three patients received hyperfractionated RT (76.8y at 1.2 Gy b.i.d.). Adverse reactions included fever,

sthenia, transaminase elevations, nausea, and skin toxici-ies (mostly Grades 1/2). There was one Grade 4 allergiceaction, and no patients developed antibodies against IMC-225. Most acute adverse reactions were those typically

een with RT alone. All patients had an objective response13 complete remissions [CRs] and 2 PRs), and most acutedverse reactions were those typically seen with RT alone.

Most recently, a Phase II study of IMC-C225 in combi-ation with docetaxel in chemotherapy-refractory patientsith advanced NSCLC was reported (47). IMC-C225 was

dministered as 400 mg/m2 i.v. during the first week fol-owed by 250 mg/m2 i.v. weekly. Docetaxel was adminis-

ered at 75 mg/m2 i.v. every 3 weeks. Twenty-five patientsad been enrolled at the time of the report, and 20 patientsere evaluable for response. Preliminary results showed

hat after two cycles of therapy, 4 patients had a PR and 6ad SD. Toxicities included acneiform rash (Grade 2/3) inpatients and febrile neutropenia in 2 patients (Grade 2/3).

OSI-774

OSI-774 is a quinazoline compound that, like ZD1839, issmall-molecule tyrosine kinase inhibitor that exhibits its

ffect at nanomolar concentrations. In preclinical studies,SI-774 was shown to exhibit reversible cell cycle arrest at

1 and apoptosis (48). In vivo, preclinical models demon-trated that OSI-774 administration resulted in a 70% re-uction in EGFR autophosphorylation and marked growthnhibition in human head-and-neck cancer xenografts (HN5nd A431 cells) in nude mice (49). Preclinical studies inung cancer cells in vitro and in vivo have shown enhancedffects of radiation when combined with OSI-774 in humanung cancer cells (H.G. Wu et al., unpublished data). Forxample, when NCI-H460 human lung cancer xenografts inude mice were treated in vivo with 25 mg/kg OSI-774 withr without radiation, a significant delay in tumor growth wasbserved in mice treated with OSI-774/RT (28.8 days)ompared with OSI-774 alone (11.8 days) or RT alone22.2 days). The mechanism of this radiation sensitization ishought to be due to the inhibition of EGFR and Akthosphorylation and downregulation of COX-2 expression.In Phase I studies, OSI-774 was found to be a safe and

ell-tolerated oral drug without severe toxicity (50). Pa-ients with advanced solid malignancies refractory to con-entional therapy were treated in this study. Forty patientsere enrolled, 4 of whom had NSCLC. Diarrhea and skin

ash were the primary toxicities and precluded treatmentith doses greater than 150 mg/day. Most episodes ofiarrhea were mild to moderate (Grades 1/2), but 25%, 67%,nd 86% of patients experienced diarrhea at 100 mg,50 mg, and 200 mg, respectively. Severe diarrhea (Grades/4) was experienced by 2 patients at a dose of 200 mg. Thetudy was amended to treat patients with loperamide, initi-ted at the initial onset of diarrhea. Severe diarrhea was nototed thereafter in patients treated at the 150-mg to 200-mgoses. A cutaneous rash (Grade 1/2), usually involving theace and upper trunk, was experienced by 59% of patients.ased on these results, the recommended dose was set at50 mg/day. Among patients with advanced, platinum-re-ractory NSCLC, 14.3% had an objective response, and8.6% had SD (50).Three Phase II trials (studies 248-1007, 248-101, and

48-1003) with OSI-774 have been conducted in patientsith advanced refractory malignancies, including squamous

ell carcinoma of the head and neck, ovarian carcinoma, andSCLC (51–53). Patients in each of these studies received50 mg/day of OSI-774. Available preliminary data basedn investigator assessments from all three Phase II trialsemonstrate objective response rates of 9% to 15%.

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tudy 248-1007 enrolled 56 patients (all evaluable) withrogressive, recurrent NSCLC previously treated with alatinum-based chemotherapy regimen at five centers (53).ll enrolled patients had measurable tumors that expressedGFR by IHC analysis. Eight patients (14.3%) achieved a

esponse (1 CR amd 7 PRs, 6 confirmed at Week 12 andeyond); 16 patients (28.6%) had SD lasting �12 weeks,nd 28 patients (57.1%) had documented progression ofheir underlying malignancy. A relationship between re-ponse and the degree of EGFR overexpression has not beenstablished. However, it is important to note that IHC levelsf EGFR may not be truly representative of the functionalityf EGFR in the tumor specimen, for several reasons. TheGFR activity may be increased or decreased dispropor-

ionately to IHC levels as a result of mutations, cross talksith heterologous receptors, or increased ligands. Further-ore, it is important to note that this study had a small

ample size, which precludes a definitive conclusion in thisegard. Toxicities included rash (80%) and diarrhea. Rashas mild in 46%, moderate in 29%, and severe in 4%. Mild

Grade 1/2) diarrhea developed in 40 patients, and moderateGrade 3) diarrhea occurred in 3% of patients. The studyrug was not discontinued for OSI-774–related adversevents in any of these patients, and only a single patientequired transient dose reductions because of skin toxicity.

ONGOING/PROPOSED CLINICAL TRIALSINVOLVING RADIATION THERAPY AND EGFR

INHIBITORS IN NSCLC

Phase III trial of cisplatin/etoposide/RT withonsolidation docetaxel followed by maintenance therapyith ZD1839 or placebo in patients with inoperable

ocally advanced Stage III NSCLC (Southwest Oncologyroup [SWOG]-0023)SWOG-0023 is a Phase III, multi-institutional, random-

zed double-blind study designed to assess whether mainte-ance therapy with ZD1839 compared with placebo afternduction cisplatin/etoposide/RT plus consolidation do-etaxel improves overall survival and progression-free sur-ival in patients with unresectable Stage III NSCLC. Otherbjectives are to determine the toxicity profile of long-term

Fig 1. Schema for SWOG-0023, a randomized Ph

dministration of ZD1839 and to obtain samples for correl-tive studies. The target sample size for this study is a totalf 840 patients to be accrued within 3.5 years. The studyas activated in mid 2001, and patient accrual is ongoing.iopsy samples (tissue) and serum will be obtained toerform molecular correlation studies. Serum will be takenefore treatment and 4 months afterward.The clinical protocol for this study is depicted in Fig. 1.

atients receive induction therapy with cisplatin (50 mg/m2).v. on Days 1, 8, 29, and 36 and etoposide (50 mg/m2) i.v.n Days 1 through 5 and 29 through 33. Within 24 h oftarting chemotherapy, patients receive RT 5 days per weekor a total of 33 days. Within 1 to 8 weeks after completion ofhemoradiotherapy, patients with SD or responding diseaseeceive consolidation therapy with docetaxel (75 mg/m2).v. on Day 1 with continued treatment every 21 days for

cycles. Within 1 to 4 weeks after completion of consoli-ation therapy, patients with stable or responding diseasere randomized to one of two treatment arms for mainte-ance therapy.

rm I: Patients receive oral ZD1839 (250 mg) daily for amaximum of 5 years in the absence of disease progres-sion or unacceptable toxicity.

rm II: Patients receive placebo as in Arm I.

The chemotherapy regimen is derived from the results ofWOG-9504, which incorporated consolidation docetaxel

nto combined-modality therapy of Stage III NSCLC. Theesults were highly encouraging with a response rate of 63%52/83 patients), 1-year survival of 78%, and 2-year survivalf 50% (54). The toxicity profile of this therapy comparesavorably with that of other chemoradiotherapy regimensontaining new agents.

ancer and Leukemia Group B (CALGB) 30106: ZD1839NSC #715055) with induction paclitaxel and carboplatinollowed by either radiation or concurrent radiation witheekly paclitaxel and carboplatin Stage III NSCLC, ahase II studyCALGB 30106 is a Phase II, nonrandomized, multi-

nstitutional study designed to determine the tolerability ofD1839 when given concomitantly with RT alone or with

I trial in unresectable IIIA/IIIB NSCLC patients.
ase II

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hemotherapy (paclitaxel and carboplatin) and RT afternduction treatment with paclitaxel, carboplatin, andD1839. The secondary objectives are to determine theverall response rate, failure-free survival, and survivalfter treatment with the regimens outlined above. The tar-eted population is patients with inoperable Stage IIISCLC who have either poor performance status (PS)

stratum 1), or good PS (stratum 2), as outlined in Fig. 2.he target sample size for this protocol is a total of 18 to44 patients (9 to 72 per stratum), and accrual is planned for3 months. The trial has opened recently and is accruingell.Patients will be subdivided based on their risk criteria.

atients with PS of 2 or with PS of 0/1 with weight loss5% over 3 months before initiating therapy will be placed

nto stratum 1 (poor risk). An initial cohort of up to 9atients will be treated in this stratum, and if treatment isolerable, accrual will continue up to a total of 72 patients.he treatment protocol in stratum 1 is as follows: In cyclesand 2, patients will be treated with induction chemother-

py (paclitaxel i.v. 200 mg/m2 every 21 days and carbopla-in i.v. area under the concentration/time curve [AUC] � 6very 21 days) plus ZD1389 (250 mg/day orally). In cyclesto 9, patients will be treated with RT (2 Gy/day � 33

ractions � 66 Gy) plus ZD1839 (250 mg/day orally).inally, in cycles 10�, patients will be treated with ZD1839250 mg/day orally) starting 2 weeks after RT is completedn Week 15 and continuing until disease progression. If aatient is experiencing � Grade 3 toxicity 2 weeks after RTs complete, ZD1839 will be delayed until toxicity is

Grade 2.Stratum 2 is geared toward patients with better perfor-ance status (PS � 0/1 without weight loss �5% over the

revious 3 months). An initial cohort of up to 9 patients wille treated on stratum 2 with the same induction regimen asn stratum 1. The schema for stratum 2 differs at cycles 3

Fig 2. Schema for CALGB 30106: A Phase

hrough 9, which consist of concomitant chemotherapy plusT plus ZD1839 (Fig. 2). During this phase, the RT andD1389 regimen will be identical to stratum 1. However,hemotherapy will include paclitaxel at 50 mg/m2 i.v.very week for 7 weeks, with carboplatin AUC � 2 i.v.very week for 7 weeks. The final cycles are identical totratum 1.

This protocol will evaluate the molecular correlation be-ween response to treatment with ZD1839 (as previouslyefined) and expression of EGFR and cyclooxygenase-2arkers. EGFR will be assayed by IHC analysis.

Phase I/II study of preoperative ZD1839 inombination with chemoradiation therapy in patients withtage IIIA NSCLCThis is a Phase I/II, multi-institutional, open-label, non-

andomized trial designed to study the safety and tolerabil-ty (in particular the treatment-related mortality, esophagi-is, and pneumonitis) of preoperative ZD1839 inombination with chemoradiation therapy in patients withtage IIIA NSCLC. Other objectives are to determine the

mpact of concurrent preoperative ZD1839 with cisplatin/toposide and RT on the rates of operability and resectabil-ty, to evaluate the radiographic and pathologic responseate of preoperative ZD1839 with cisplatin/etoposide andT, and to perform molecular correlation studies as listedelow. The target sample size for this study is 26 patients,nd the protocol opened in 2003 with plans for completionf accrual still ongoing.The study design is as follows (Fig. 3). Patients with

tage IIIA NSCLC will be treated with a single daily dosef 250-mg ZD1839 while receiving cisplatin/etoposidedoses to be determined) and thoracic RT. ZD1839 must betopped at least 7 days before surgery. Cisplatin will beelivered on Days 1, 8, 29, and 36, and etoposide will beelivered on Days 1 through 5, and Days 29 through 33

l in unresectable Stage IIIA/IIIB NSCLC.

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reoperatively. Radiation therapy will be delivered at.8 Gy per fraction for 25 fractions over 5 weeks (totalquals 45 Gy). Surgery will be performed 3 to 4 weeks afterompletion of RT and will be followed by a 3-week restefore reinitiation of therapy. ZD1839 will be resumed at50 mg/day beginning 3 weeks after surgery and continuingntil progressive disease.This study is a Phase I/II trial. The Phase I portion will

nroll up to 6 patients to evaluate the safety of ZD1839dded to this chemoradiation regimen. These 6 patients wille followed for a minimum of 90 days after the start of RT.ssuming there are no unexpected toxicities, there will be

n interim safety assessment after the sixth patient has beenvaluated 90 or more days after the initiation of chemora-iation therapy. If unexpected toxicities are observed, thenterim safety evaluation will take place earlier. If none ofhese 6 patients experience a treatment-related death, thetudy may proceed to Phase II and enroll up to another 20atients for a total of 26 patients.The protein expression of EGFR will be measured in

umors, and an analysis for molecular correlation with out-ome will be performed. Correlation will also be madeetween pathologic tumor response and changes in tumor

Fig 3. Schema for Phase I/II study of preoperative ZD183Stage III NSCLC.

ig 4. Schema of a Phase I/II study of ZD1839 in combination withxternal beam radiation therapy (XRT) and chemotherapy in un-reated patients with locally advanced nonmetastatic NSCLC.

� paclitaxel; C � carboplatin.

xpression levels of EGFR, activated/phosphorylatedGFR, activation of downstream pathways by using anti-odies specific for phosphorylated extracellular-regulatedinases and phosphorylated protein kinase B/Akt, as well asumor cell proliferation and tumor cell apoptosis.

Phase I/II biological, pharmacodynamic, and responsetudy of ZD1839 in combination with external beamadiation (XRT) and chemotherapy in untreated patientsith locally advanced, nonmetastatic NSCLCThis is a Phase I/II, nonrandomized study designed to

stablish the safety profile of daily oral ZD1839 given withoncurrent XRT and chemotherapy in previously untreatedatients with locally advanced, nonmetastatic NSCLC.ther objectives are to determine the response rates, re-

apse-free survival rates, overall survival rates, and molec-lar correlates. The participating institutions will be theniversity of Colorado Heath Science Center (Denver, CO)

nd Memorial Sloan-Kettering Cancer Center (New York,Y). The overall projected accrual for this study is approx-

mately 3 to 6 patients per dose level, for a total of 15 to 18atients over approximately 12 months. The projected com-letion date for the study is on-going.In the initial Phase I study, ZD1839 will be given once

aily, continuously, in escalating doses (doses not yet se-ected) in combination with daily conformal XRT. Once theaximum tolerated dose is determined, an expanded Phase

I cohort study will be performed with ZD1839, XRT, andhemotherapy using weekly carboplatin (AUC � 6) andaclitaxel (200 mg/m2) for patients with locally advanced,onmetastatic EGFR-positive NSCLC (Fig. 4). ZD1839ill be maintained daily for 2 years or until disease pro-ression.Molecular correlations will be determined. Using high-

ressure liquid chromatography or liquid chromatographyandem mass spectrometry methods, plasma concentrationsf ZD1839 will be determined throughout the course ofadiation/chemotherapy treatments such that they corre-pond to the time points of biological studies. The plasma

mbination with chemoradiation therapy in patients with
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oncentrations obtained will then be analyzed withiological data (from skin and tumor biopsies) to determinehether there are significant relationships between dose,lasma concentration, and biological effect. Tumor and skiniopsies will also be taken at baseline and repeated viaesection or core biopsies if feasible 4 to 6 weeks afterompletion of treatment. Because skin contains epidermalrowth factor receptors and is a target tissue for toxicity, itill serve as an internal control. The tumor and serial skiniopsies will be used to determine tissue expression ofGFR and phosphorylated EGFR by IHC analysis, andi-67 level will be assessed for quantitation of cellularroliferation.

Phase II study of IMC-C225 in combination withhemoradiation therapy in patients with Stage IIIA/BSCLC: CA225010This is a Phase II, open-label, multicenter, nonrandom-

zed study designed to evaluate the safety and toxicity of theombined-modality regimen with IMC-C225 for patientsith Stage IIIA/B NSCLC (Fig. 5). Other objectives are toetermine the survival rate of the combined regimen inomparison to established regimens and to determine theotential correlation of EGFR expression with survival rate.he study plans for accrual of a minimum of 70 patients,nd the trial has not yet been opened for enrollment.

In this study protocol, patients will initially receive IMC-225 400 mg/m2 i.v. on Day 1. Beginning Day 8, IMC-225 250 mg/m2 plus paclitaxel 45 mg/m2 and carboplatinUC � 2 weekly for 7 weeks during concurrent RT

Fig 5. Schema of a Phase II study of IMC-C225 inNSCLC.

63.0 Gy in 34 daily fractions over 7 weeks) will be deliv-red. Concurrent IMC-C225 plus chemotherapy/RT will beollowed by 3 weeks of single-agent IMC-C225 at50 mg/m2/week. Patients then receive two cycles of pac-itaxel 200 mg/m2 and carboplatin AUC � 6 every 3 weeks,lus IMC-C225 250 mg/m2/week for 6 weeks. Availableumor tissue samples will be sent for IHC testing for EGFRxpression; however, if tumor tissue is unavailable, this willot serve as a criterion for exclusion. This study is designedlso to correlate EGFR expression with response and sur-ival.

CONCLUSIONS

Molecular targeting of EGFR in the clinical setting is anrea of active investigation. ZD1839, OSI-774, and IMC-225 are currently the most clinically developed com-ounds. Preclinical and early clinical studies support a needor further investigation into combination therapy ofD1839 with chemotherapy/RT in a variety of solid tumors,

ncluding NSCLC. Several proposed or currently ongoingtudies in NSCLC have been designed to determine patientolerability and responsiveness to treatment with EGFRnhibitors in combination with RT and/or chemotherapy.ach of these studies will determine the molecular correla-

ion of EGFR and other relevant biologic molecules toesponse to therapy. These and other forthcoming studiesill hopefully further elucidate the role of EGFR in the

herapy of patients with advanced NSCLC.

ination with chemoradiation therapy in Stage IIIA/B

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