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Gefitinib: Phase II and III Results in Advanced Non–Small CellLung Cancer

Karen Kelly and Steven Averbuch

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everal novel biologic agents have been designed topecifically inhibit different aspects of tumor growthnd progression. The epidermal growth factor recep-or has a pivotal role in tumor biology and thus is anmportant anticancer target. Gefitinib is an orally ac-ive epidermal growth factor receptor tyrosine kinasenhibitor that blocks signal-transduction pathways im-licated in the proliferation and survival of cancer cells.linically meaningful antitumor activity, symptom re-

ief, and a good tolerability profile have been shown inhase II trials of gefitinib monotherapy in patients withecurrent non–small cell lung cancer. Clinical trials arengoing to investigate further applications of this novelgent for the treatment of non–small cell lung cancer.emin Oncol 31 (suppl 1):93-99. © 2004 Elsevier Inc. Allights reserved.

N RECENT years, significant advances havebeen made in our understanding of the molec-

lar mechanisms that underlie malignant transfor-ation of cells and tumor progression. This re-

earch has led to the design of biologic anticancergents that aim to selectively target the intracel-ular or extracellular components involved. Manytandard anticancer treatments, such as platinum-ased chemotherapy and radiotherapy, have con-iderable toxicity and limited efficacy; thus, novelargeted agents aim to provide therapies that areetter tolerated, more effective, and allow for aong-term maintenance approach.

Growth factor signaling pathways have been aain focus of research because of their fundamen-

al role in regulating cell proliferation and differ-ntiation. One important target is the epidermalrowth factor receptor (EGFR), a member of aamily of cell membrane receptors with intrinsicyrosine kinase activity. When specific ligandsind to the extracellular portion of the EGFR, theeceptor dimerizes, leading to activation of its cy-oplasmic tyrosine kinase domain and subsequentascades of downstream signaling events.

The EGFR is an attractive anticancer targethat has been implicated in the pathogenesis ofeveral human tumors, including non–small cellung cancer (NSCLC).1,2 It mediates cell signalingssociated with several aspects of tumor develop-ent, such as increased cell proliferation, in-

reased angiogenesis (the formation of new blood

essels from existing vasculature), and reduced

eminars in Oncology, Vol 31, No 1, Suppl 1 (February), 2004: pp 93-99

poptosis. Several biologic agents have been ration-lly designed to block the function of this receptor,ith the aim of inhibiting cell proliferation and

umor progression.3 Cetuximab and ABX-EGF areonoclonal antibodies targeted against the extra-

ellular ligand-binding domain to obstruct theinding of ligands to the receptor. The small-olecule EGFR tyrosine kinase inhibitors gefitinib

nd erlotinib bind directly to the tyrosine kinaseomain of the receptor to inhibit its activity andrevent signal transduction (Fig 1).4 A number oflternative approaches have also been investi-ated, such as immunotoxin conjugates and bispe-ific antibodies.5 As their name suggests, bispecificntibodies have two different antigen-binding re-ions: one specific for the EGFR and the otherngineered to bind to an immunological effectorell. Thus, upon binding to the EGFR, these mol-cules simultaneously enhance host cytotoxic ef-ector mechanisms. Immunotoxin conjugates con-ist of a potent cellular toxin attached to an anti-GFR antibody. The complex binds the EGFR,ecomes internalized, and the toxin inhibits pro-ein synthesis, resulting in cell death. Of all theselasses of EGFR-targeted compounds, the mostdvanced in development are the monoclonal an-ibodies and the EGFR tyrosine kinase inhibi-ors.3,6 To illustrate the potential therapeutic ap-lications of targeting the EGFR, this review willocus on gefitinib as a representative example of anGFR inhibitor.

PRECLINICAL AND PHASE I DATA

Gefitinib is a novel, orally active, synthetic anili-oquinazoline inhibitor of the EGFR tyrosine kinase

From the University of Colorado Cancer Center, Denver, CO;nd AstraZeneca Pharmaceuticals LP, Wilmington, DE.

Dr Kelly has received research grant support and honoraria fromstraZeneca Pharmaceuticals, LP. Dr Averbuch is an employee ofstraZeneca Pharmaceuticals, LP.Address reprint requests to Karen Kelly, MD, University of

olorado Cancer Center, 4200 E 9th Ave, Box B171, Denver,O 80262.© 2004 Elsevier Inc. All rights reserved.0093-7754/04/3101-0112$30.00/0

doi:10.1053/j.seminoncol.2003.12.020

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94 KELLY AND AVERBUCH

50% inhibitory concentration, 0.033 �mol/L).7n preclinical studies, gefitinib has shown antitu-or activity in a variety of tumor types, including

ung, ovarian, and breast tumors.8 The observedffects of gefitinib treatment on tumor cells areide ranging, with dose-dependent growth inhibi-

ion, reduced cell proliferation, cell cycle arrest,educed angiogenesis, and increased apoptosis.he combination of gefitinib with a variety ofytotoxic drugs produced enhanced growth inhi-ition in human cancer cell lines and xenograftodels.8,9 Gefitinib has also shown synergistic ef-

ects when combined with radiation in preclinicalodels.10,11

Four large, multicenter phase I dose-escalationrials evaluated the tolerability, pharmacokinetics,nd activity of gefitinib monotherapy at doses upo 1,000 mg/day.12-15 A total of 252 patients withrange of malignancies were recruited, including

00 patients with NSCLC. Gefitinib was generallyell tolerated in all four trials, with dose-limitingiarrhea observed at 700 to 1,000 mg/day. Theost common adverse events were mild (grade 1/2)

kin rash and acne, diarrhea, nausea, vomiting,nd asthenia. There was evidence for gefitinib

ntitumor activity across the range of dose levels E

ested. Of note, 10 patients with NSCLC showedpartial response and several patients also exper-

enced disease stabilization. Pharmacodynamicnd pharmacokinetic data showed that biologi-ally relevant levels of gefitinib were achieved atoses of 150 mg/day and above. The data fromhese trials provided the basis for dose selection of50 mg/day and 500 mg/day gefitinib for subse-uent trials; 250 mg/day is higher than the lowestose level at which objective tumor response waseen, and 500 mg/day was the highest dose toler-ted by most patients when taken chronically.

CLINICAL BENEFITS OF MONOTHERAPY

The encouraging results from these phase I stud-es provided a rationale for further clinical devel-pment of gefitinib in NSCLC. Two large-scale,ulticenter double-blind, parallel-group phase II

tudies were undertaken: IDEAL (Iressa Dosevaluation in Advanced Lung cancer) 1 and 2.16,17

hese trials evaluated the efficacy and tolerabilityf gefitinib as a single agent in patients with lo-ally advanced or metastatic NSCLC who hadreviously received platinum-based chemotherapy.

Fig 1. Mechanism of action ofthe EGFR tyrosine kinase inhibi-tor gefitinib. (Reprinted with per-mission.4)

ach trial included approximately 200 patients

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GEFITINIB: PHASE II AND III RESULTS IN NSCLC 95

andomized to receive 250 mg/day or 500 mg/dayf gefitinib (Fig 2).18

In IDEAL-1 (the global trial), patients had pre-iously received one or two chemotherapy regi-ens, at least one of which contained a platinum

gent. Patients were not required to be symptom-tic for NSCLC at trial entry, but 140 patients hadisease-related symptoms and were thereforevaluable for symptom improvement. The patientsnrolled in IDEAL-2 (the United States trial) hadpoorer prognosis; they had previously received

wo or more chemotherapy regimens that includedlatinum and docetaxel, given either concurrentlyr separately, and they had to be symptomatic forSCLC at trial entry. In both trials, data for

he efficacy endpoints were comparable betweenhe 250-mg/day and 500-mg/day groups, but the50-mg/day dose was better tolerated. Thus,50-mg/day gefitinib is the recommended dose forhe treatment of NSCLC patients who have previ-usly received platinum-based chemotherapy andnly data relating to this dose will be discussed fur-her in this article. A summary of the main efficacynd tolerability data from these trials is shown inable 1.Clinically significant antitumor activity was

een with 250-mg/day gefitinib in both trials. Ob-ective tumor response rates in IDEAL-1 andDEAL-2 were 18.4% and 11.8%, respectively,ith responses observed irrespective of the numberf prior regimens received. Disease control ratespartial response plus stable disease) were 54.4%nd 42.2% in IDEAL-1 and -2, respectively. Me-ian progression-free and overall survivals were,espectively, 2.7 months and 7.6 months in

Fig 2. IDEAL-1 and -2 trial de-ign to investigate gefitinib asonotherapy in patients with

retreated NSCLC. (Reprintedith permission from The Oncol-gist. Available at www.heOncologist.com.18)

DEAL-1 and 1.9 months and 6.5 months in

DEAL-2. In both trials, significant improvementsn disease-related symptoms and quality of lifeere reported. These endpoints were evaluatedsing the Functional Assessment of Cancer Ther-py-Lung (FACT-L) questionnaire.19 The com-lete survey, which assesses quality of life, and theACT-L Lung Cancer Subscale, which analyzesmprovements in disease-related symptoms, haveeen independently validated and clinically mean-ngful responses prospectively defined.20 The max-mum, or most asymptomatic, scores attainable are8 for the Lung Cancer Subscale and 136 forACT-L, with improvements defined as increasesf �2 points for the Lung Cancer Subscale and �6oints for FACT-L (to be sustained for at leastweeks in both cases). Symptom improvement

as observed in 40.3% of evaluable patients in

Table 1. Summary of Main IDEAL-1 and -2 Efficacyand Tolerability Results (250 mg/day)

IDEAL-1 IDEAL-2

Objective tumor response rate 18.4% 11.8%Disease control rate* 54.4% 42.2%Median progression-free survival (mos) 2.7 1.9Median overall survival (mos) 7.6 6.5Symptom improvement rate 40.3% 43.1%Quality-of-life improvement rate 23.9% 34.3%Drug-related grade 3/4 adverse events 8.7% 6.9%Drug-related withdrawals 1.9% 1.0%

*Partial response plus stable disease.Abbreviation: IDEAL, Iressa Dose Evaluation in Advanced

Lung Cancer trial.

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DEAL-1 and in 43.1% of patients in IDEAL-2.mprovements in overall quality of life were alsoeported by 23.9% and 34.3% of patients inDEAL-1 and -2, respectively. Importantly, evenatients with stable disease had significant im-rovements in symptoms and quality of life.In accordance with the phase I tolerability re-

ults, the main adverse events with 250-mg/dayefitinib were diarrhea, mild skin rash, pruritus,nd dry skin. These were generally mild in severitygrade 1/2) and noncumulative with chronic treat-ent. Treatment with gefitinib was not typically

ssociated with characteristic chemotherapy-elated adverse events such as neuropathy, neutro-enia, or other hematological toxicities. There waslow incidence of drug-related grade 3/4 adverse

vents with 250-mg/day gefitinib, occurring innly 8.7% and 6.9% of patients in IDEAL-1 and -2,espectively. Withdrawal because of drug-relateddverse events was 1.9% and 1.0% for patientseceiving 250-mg/day gefitinib in IDEAL-1 and -2,espectively.

The evidence of clinically significant antitumorctivity and symptomatic improvement coupledith a favorable tolerability profile provide strong

upport for the use of gefitinib as monotherapy forhe treatment of patients with advanced NSCLC.

FURTHER POTENTIAL THERAPEUTICAPPLICATIONS

ombination With Standard Chemotherapy

The combination of gefitinib with conventionalytotoxic agents and radiotherapy has been showno potentiate antitumor activity in human lungancer xenografts.9,10 Two phase I trials investi-ated gefitinib (250 mg/day and 500 mg/day) inombination with gemcitabine and cisplatin21 andith paclitaxel and carboplatin.22 Objective anti-

umor responses were observed and the combina-ions were well tolerated, with no evidence oflinically significant pharmacokinetic interac-ions. Therefore, it was appropriate to investigatehe effect of gefitinib in combination with stan-ard platinum-based doublet chemotherapy regi-ens in the first-line setting in two large phase III

rials. Gefitinib was evaluated in combinationith gemcitabine and cisplatin in INTACT 1

Iressa NSCLC Trial Assessing Combinationreatment) 123 and in combination with pacli-

24

axel and carboplatin in INTACT 2. Both trials a

ere randomized, double-blind placebo-controlledtudies that each recruited approximately 1,000atients to one of three arms: gefitinib 250 mg/day,efitinib 500 mg/day, or placebo in combinationith six cycles of chemotherapy, followed by ge-tinib or placebo alone. No added benefit wasbserved with gefitinib treatment for any of therial endpoints of overall survival, 1-year survival,r time to progression.23,24 However, there was noorsening of chemotherapy-associated toxicitiesnd the observed side effects of skin rash, acne,nd diarrhea were as predicted from the IDEALrials. These data confirm the good safety profile ofefitinib in a placebo-controlled setting. At thisime, the reason for these disappointing results isnknown. However, it is interesting that no tripletombination chemotherapy regimen has proved toe superior to a platinum-based doublet. Thus, oneypothesis to consider is that maximal antitumorffect is achieved on the susceptible tumor popu-ation by the doublet chemotherapy and that ge-tinib is redundant in this setting. This raises theuestion as to whether or not gefitinib could re-lace one of the components of the doublet che-otherapy regimen for an improved therapeutic

ndex. Gefitinib may also have potential whenombined with other agents in the first-line settingor advanced NSCLC.

aintenance Therapy For Unresectable Stage IIIon–Small Cell Lung Cancer

The development of novel targeted agents hased to renewed interest in using long-term main-enance treatment to provide disease stabilizationollowing chemotherapy and/or radiotherapy.

hile biologic agents are specifically designed tottack different aspects of tumor growth and pro-ression, combinations of these agents, given ei-her concurrently or sequentially, may prevent dis-ase recurrence. The favorable tolerability profilef gefitinib together with its oral availability sug-ests that gefitinib has potential for use as long-erm maintenance therapy.

A phase III trial (Southwest Oncology Group0023) to investigate the activity of gefitinib in aaintenance approach is currently recruiting pa-

ients. This trial has been designed to incorporatehe treatment strategies of definitive chemoradio-herapy and consolidation chemotherapy withaintenance therapy for patients with unresect-

ble stage III NSCLC (Fig 3). Patients receive

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GEFITINIB: PHASE II AND III RESULTS IN NSCLC 97

isplatin and etoposide every 21 days for two cy-les with radiotherapy for 6.5 weeks. Approxi-ately 4 to 8 weeks after the completion of che-otherapy/radiotherapy, patients with stable or

esponding disease receive consolidation chemo-herapy with docetaxel every 21 days for threeycles. Nonprogressive patients then receive main-enance therapy with either gefitinib (250 mg/day)r daily placebo. Both treatment arms will con-inue for a maximum of 5 years unless patientsxperience disease progression or unacceptableoxicity. The primary objective of this trial is toetermine whether gefitinib improves overall androgression-free survival. The trial requires 840atients to enroll, with 80% of patients projectedo receive maintenance therapy.

Cancer and Leukemia Group B has launched ahase II trial investigating gefitinib throughout allhases of treatment for patients with inoperabletage III NSCLC. Patients initially receive neoad-uvant paclitaxel, carboplatin, and gefitinib forwo cycles followed by definitive treatment withaclitaxel, carboplatin, gefitinib, and radiationpoor-risk patients receive only gefitinib and radi-tion). Nonprogressing patients then receive ge-tinib until disease progression or intolerable tox-city. Study endpoints are to determine theesponse rate, progression-free survival, and over-ll survival in patients treated with these regimens.

A similar trial is being pursued by investigatorst the University of Colorado Cancer CenterDenver, CO). In this phase I/II trial, stage IIIatients with inoperable disease will receiveeekly paclitaxel and carboplatin plus gefitinib

Fig 3. Trial design of gefitinib as maintenance therapy foetaxel.

aily with escalating doses of three-dimensional a

onformal radiotherapy starting at 63 Gy. All pa-ients subsequently receive two cycles of paclitaxelnd carboplatin, and then maintenance gefitinibor 2 years. Once the maximum tolerated dose isstablished, a phase II study will be conducted.

djuvant Therapy to Enhance Survival inesectable Lung Cancer

Many patients with resectable NSCLC experi-nce recurrence after surgery, contributing to anverall 5-year survival of 38% to 67% in thisopulation.25 As this is likely to be because ofndetectable micrometastases, the use of systemicherapy following surgical resection could provideignificant clinical benefit. Standard chemother-py and radiotherapy have been investigated inhe adjuvant setting with mixed results and a lackf consensus conclusion.26 As a result, the currenttandard treatment following resection is observa-ion.

To improve prognosis in this population, ahase III trial to investigate the activity of ge-tinib as an adjuvant therapeutic is currently en-olling patients. This large, multinational andulticenter trial aims to recruit 1,160 patientsith completely resected primary stage IB, II, or

IIA NSCLC. These patients will be randomizedo receive either gefitinib (250 mg/day) or placeboor up to 2 years in the absence of disease progres-ion or unacceptable toxicity. The objective of thisrial is to investigate whether gefitinib improvesurvival when administered as an adjuvant ther-

treatment with cisplatin, etoposide, radiotherapy, and do-

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CONCLUSION

Novel biologic agents that specifically inhibitumorigenic processes have the potential to pro-ide therapeutic benefit for NSCLC. The EGFR-yrosine kinase inhibitor gefitinib has shown sig-ificant antitumor activity and improvement inisease-related symptoms when used as mono-herapy in pretreated patients with advancedSCLC. The disappointing results of INTACT-1

nd -2, however, showed that gefitinib should note used in combination with platinum-based che-otherapy doublets in the first-line setting forSCLC. Further applications, such as the use of

efitinib in a maintenance approach following pri-ary treatment for locally advanced disease or in

djuvant therapy to improve survival rates for pa-ients following surgical resection, are being ex-lored. The impressive antitumor activity in andvanced and refractory NSCLC patient popula-ion and the favorable tolerability profile of ge-tinib offer promise for the development of thisgent in long-term treatment strategies forSCLC. The results from ongoing clinical trials

esigned to investigate these potential applica-ions are awaited with interest.

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GEFITINIB: PHASE II AND III RESULTS IN NSCLC 99

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